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The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\nThis framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.\n\n## Introduction\n\nPopulation aging has become the central demographic and economic challenge of high-income health systems, and the question of whether we can extend the period of life spent in good health — healthspan — rather than simply the period of life itself has reshaped the research agenda in geriatrics, cardiology, and nephrology. The question of whether a single protein could meaningfully modify that trajectory has drawn sustained attention to klotho, the longevity-associated protein first described in the context of an accelerated-aging phenotype and since implicated in renal, skeletal, cardiovascular, and cognitive aging. The urgency has grown because, despite decades of work on disease-specific interventions, the gap between lifespan and healthspan continues to widen, and the question of whether anti-aging biology can be translated into therapy has therefore become a question the field is now asking, not dismissing. Recent reviews of klotho biology and clinical correlates have appeared in overlapping but fragmented literatures spanning nephrology, endocrinology, neurology, and exercise physiology, and the question of how these signals reconcile is the one this synthesis addresses.\n\nThe geroscience hypothesis holds that targeting the biology of aging itself, rather than each chronic disease in isolation, may produce larger and more synchronized gains in late-life health, and the hypothesis has motivated a wave of drug-repurposing and novel-development programs aimed at candidate longevity proteins. Klotho sits prominently in that landscape, and the question of whether soluble klotho should be considered a druggable target, a biomarker, an exerkine, or all three has been debated. The intervention logic differs by strategy: observational associations between klotho levels and outcomes are being treated as a rationale for prospective supplementation studies, while exercise-induced changes in circulating klotho are being framed as a non-pharmacologic pathway to engage the same biology. The repurposing case is supported by small open-label human work such as Adema 2018, a prospective single-center case-control pilot examining exogenous growth hormone administration and circulating α-klotho in healthy and chronic kidney disease subjects, and by preclinical high-intensity interval and aerobic training studies in CKD models (Rokhsati 2026). Each of these lines of evidence is mechanistically plausible, and the question of whether they converge on a clinically meaningful klotho axis remains uncertain.\n\nKlotho is best understood as a longevity protein with two principal isoforms — membrane-bound and soluble (s-Klotho/α-Klotho) — that act as obligate co-receptors for fibroblast growth factor-23 and as circulating effectors on multiple organ systems. The mechanism has been linked to mineral metabolism, vascular calcification, muscle and bone homeostasis, and central nervous system function, and the question of which of these pathways is most clinically actionable has driven the design of recent human studies. From a regulatory and clinical-history standpoint, klotho has reached the clinic primarily as a biomarker: in chronic kidney disease, lower circulating α-klotho has been associated with adverse kidney outcomes (Liu 2019) and with cardiovascular parameters (Kim 2018), and an inverse correlation with arterial calcification has been reported (Wungu 2024). Serum klotho has also been studied as an early risk-predictive biomarker in settings such as acute kidney injury following acute myocardial infarction (Pei 2023) and in sepsis-associated AKI (Pei 2022), and in cardiometabolic and sex-stratified NHANES analyses (Zeng 2025; Zuo 2025; Zhang 2026). Access to klotho-related research reagents has historically been heterogeneous, and the question of whether interlaboratory assay variability is itself a source of clinical heterogeneity has been raised (Correa 2022). The current picture, then, is that klotho is at once a well-characterized longevity protein and a candidate whose therapeutic access remains limited, and the question of how to move from biomarker to intervention has not yet been answered.\n\nAdditional corpus sources included animal/preclinical evidence; the human randomized trial landscape for klotho is sparse and, where it exists, heavily indirect. Direct supplementation trials of recombinant soluble klotho in older adults are not represented in the curated reference bundle, and the bulk of the clinical evidence is therefore drawn from observational cohorts and meta-analyses of those cohorts. Population heterogeneity is striking: studies range from preterm infants with bronchopulmonary dysplasia (Batlahally 2020) to middle-aged adults with obesity (Ariadel-Cobo 2026) to nursing-home residents (Sanz 2021), to pediatric chronic kidney disease (Lindblad 2017), to hemodialysis patients (Nowak 2014), and to community-dwelling mid-to-older adults drawn from NHANES and similar surveys (Zeng 2025; Zhuang 2025; Zuo 2025; Zhang 2026). Endpoints span the canonical safety comorbidity, cardiometabolic, muscle function, frailty, longevity, and immune classes, and within frailty, Sanz 2021 reported associations between low serum klotho and worse cognition, psychological components of frailty, dependence, and falls, while Guldan 2026 meta-analyzed circulating α-klotho against multidimensional aging and frailty outcomes. The exercise-as-exerkine evidence base is anchored by Oliveira 2026 and Correa 2022, and the question of whether non-pharmacologic klotho engagement produces sustained, clinically meaningful change has been proposed but remains uncertain. The practical consequence is that the klotho human evidence base is best characterized as a constellation of indirect signals rather than a series of confirmatory trials.\n\nSeveral unresolved questions complicate any attempt to translate the klotho signal into clinical recommendations. The first is mechanism-to-function translation: the question of whether higher circulating klotho is causally protective, merely a marker of preserved renal and metabolic function, or, in some contexts, a stress-induced alarm signal (as suggested by the paradoxical mortality association in Paradoxical Prognostic Role 2026) is unresolved. The second is the tradeoff between observational and interventional evidence: the 5% preclinical lifespan extension typical of metformin-style anti-aging studies (Anisimov 2008) provides a reference point, but the question of whether soluble klotho can produce comparable human effects has not been tested. A third uncertainty is population specificity — whether the signal is strongest in chronic kidney disease, in frail older adults, in midlife adults with cardiometabolic risk, or in children and adolescents (Allwsh 2026) — and the literature is not yet sufficient to discriminate these. Duration and dose-response are essentially unmapped for any klotho-directed intervention, and the question of whether acute and chronic exercise protocols (Oliveira 2026; Castillo 2024) and pharmacologic agents such as SGLT2 inhibitors (Mora-Fernandez 2022) and statins/angiotensin-receptor blockers (Janic 2019) share a common dose-response surface is open. Finally, the boundary conditions under which klotho is associated with benefit, harm, or null effect on the same outcome — such as the disagreement between Nong 2025 and Charoenngam 2020 on longevity in different populations — remain to be established.\n\nThe contribution of this synthesis is to surface the cross-outcome tensions, weight the structured evidence by directness and design, and keep the clinical and mechanistic literatures in separate but explicit conversation. Across cross-study disagreements identified in the curated reference bundle, the dominant pattern is that positive signals cluster in muscle function and selected safety comorbidity contexts — for example, exercise-induced increases in s-Klotho (Oliveira 2026; Correa 2022) and the protective association of higher α-Klotho with frailty (Guldan 2026) — while negative signals appear in other safety comorbidity and deficiency prevalence contexts, exemplified by the inverse relationship between serum klotho and magnesium depletion (Zhuang 2025) and the paradoxical adverse prognostic signal in post-myocardial infarction (Paradoxical Prognostic Role 2026). Null findings are the modal category, especially in vascular calcification (Liu 2021; Fan 2024) and in several hard-outcome meta-analyses of chronic kidney disease (Edmonston 2024). Where the field appears to disagree most sharply, the disagreement is between prognostic directions rather than between statistical significances, and this synthesis makes those cross-source disagreements explicit. Throughout, the distinction between surrogate-endpoint association and hard-outcome validity (Ioannidis 2005) is preserved, and the question of whether the klotho anti-aging case as currently constituted is sufficient to justify dedicated human supplementation trials is left open, as the evidence suggests, but does not yet confirm, a clinically actionable role.\n\n## Background\n\nGeroscience frames aging not as a single organ-by-organ decline but as a coordinated set of molecular and cellular processes whose modulation could compress morbidity and extend healthspan (Sanz 2021). The hallmarks of aging — mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, and altered intercellular communication — have become a heuristic for prioritizing candidate interventions, because targeting a hallmark should, in principle, modify multiple age-related diseases at once (Guldan 2026). Within this framework, klotho has attracted attention as a putative longevity protein whose decline in mammals accompanies the appearance of a syndrome resembling accelerated aging, and whose overexpression extends lifespan in preclinical models (Gan 2026). The regulatory implications of a geroprotective claim are substantial: any intervention that targets aging biology itself, rather than a specific disease, must demonstrate multi-system benefit and acceptable safety, and the klotho literature has so far produced mostly surrogate-endpoint and biomarker evidence rather than hard clinical outcomes (Ioannidis 2005). The case for klotho thus sits at the boundary between mechanistic plausibility and clinical proof, and a rigorous synthesis must weigh preclinical signal against human evidence quality.\n\nThe clinical-trial landscape for klotho is sparse and dominated by surrogate-endpoint studies in renal, cardiometabolic, and pediatric populations rather than by large hard-outcome trials (Edmonston 2024). One quasi-mechanistic signal in patients with diabetic kidney disease came from a clinical-and-experimental study of SGLT2 inhibitors, which raised serum Klotho (P < 0.001) while DPP4 inhibitors did not, even though both reduced HbA1c comparably (Mora-Fernandez 2022). Together these trials suggest that klotho is modifiable by existing drugs, exercise, and possibly low-dose pharmacologic combinations, but they do not yet establish hard-outcome efficacy.\n\n### Evidence Context\n\nThe evidence context combines established clinical use, adjacent human\nevidence, animal or cellular mechanisms, and open translational\nquestions. Separating those evidence types prevents later sections from\ncollapsing unlike forms of support into a single verdict. The central\nresearch problem remains whether mechanistic plausibility and\nsource-traced findings converge strongly enough to justify further\nclinical testing while keeping patient-facing claims conservative.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-klotho-v06-DAILY-2026-06-21T18-39-36Z-R2`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-21.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `klotho AND aging AND human`\n- `soluble klotho AND mortality AND cohort`\n- `klotho AND cognition AND older adults`\n- `klotho AND kidney disease AND aging`\n- `klotho protein AND vascular aging`\n\n### Eligibility criteria\n- Sources whose primary content addresses klotho.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 172 records in the receipt-candidate union, 52 were classified as source candidates and 52 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 172 |\n| Classified source candidates | 52 |\n| No extractable claims | 28 |\n| None-only claim binding | 7 |\n| Mixed partial-or-none claim-binding candidates | 35 |\n| Partial-only claim-binding candidates | 18 |\n| Strict high-confidence sources | 32 |\n| Admitted final sources | 52 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nRisk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Key Findings\n\nSingle-source outcome classes (Dosing and Pharmacokinetics, Frailty, Skeletal, Fracture, and Bone) are treated as hypothesis-generating and receive proportional narrative depth rather than standalone evidentiary weight.\n\n## Results\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Safety and Comorbidity | n=15; claims=500 | no extracted directional signal in 5/15 sources | 9 indirect; 1 mechanistic; 5 review | limited corpus depth in this outcome class |\n| Contextual Adjacent Evidence | n=14; claims=637 | no extracted directional signal in 5/14 sources | 9 indirect; 5 review | limited corpus depth in this outcome class |\n| Deficiency Prevalence | n=9; claims=288 | mixed signal in 3/9 sources | 7 indirect; 2 review | limited corpus depth in this outcome class |\n| Longevity | n=4; claims=28 | negative signal in 2/4 sources | 2 indirect; 2 review | limited corpus depth in this outcome class |\n| Muscle Function | n=3; claims=210 | unclear signal in 1/3 sources | 3 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=2; claims=254 | negative signal in 1/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=2; claims=77 | no extracted directional signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=1; claims=22 | positive signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Frailty | n=1; claims=46 | positive signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Skeletal, Fracture, and Bone | n=1; claims=21 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\n### Results Summary\n\n- Safety and Comorbidity: n=15; claims=500; no extracted directional signal in 5/15 sources | directness: 9 indirect; 1 mechanistic; 5 review; main limitation: no direct clinical anchor.\n- Contextual Adjacent Evidence: n=14; claims=637; no extracted directional signal in 5/14 sources | directness: 9 indirect; 5 review; main limitation: no direct clinical anchor.\n- Deficiency Prevalence: n=9; claims=288; mixed signal in 3/9 sources | directness: 7 indirect; 2 review; main limitation: no direct clinical anchor.\n- Longevity: n=4; claims=28; adverse or limiting signal in 2/4 sources | directness: 2 indirect; 2 review; main limitation: no direct clinical anchor.\n- Muscle Function: n=3; claims=210; benefit signal in 1/3 sources | directness: 3 review; main limitation: no direct clinical anchor.\n- Cardiometabolic: n=2; claims=254; mixed signal in 1/2 sources | directness: 1 indirect; 1 review; main limitation: no direct clinical anchor.\n\n### Cardiometabolic Outcomes\n\nThe cardiometabolic evidence base for klotho centers on two complementary study types. Together, these sources provide both a cross-sectional association map and an intervention-based read on whether Klotho can be pharmacologically mobilized in a high-risk cardiometabolic population.\n\nIn the Mora-Fernandez 2022 review, both DPP4 inhibitors and SGLT2 inhibitors reduced HbA1c similarly, but only SGLT2 inhibitors decreased eGFR decline, albuminuria, and urinary TNF-alpha while increasing serum Klotho (P < 0.001). Per the evidence synthesis, the two sources converge on Klotho as a measurable biomarker that tracks renal and vascular injury cross-sectionally and can be upregulated by an intervention that simultaneously improves hard renal endpoints.\n\nMechanistically, the renal and vascular findings align: Klotho is highly expressed in the kidney, and its soluble form is shed into circulation where it interfaces with FGF-23 signaling and phosphate-calcium handling, both directly implicated in vascular calcification. The concordance across an observational cohort and an intervention-based review supports Klotho as both a marker of cardiometabolic-renal injury and a candidate mediator of SGLT2 inhibitor renoprotection.\n\nWithin-corpus tension on this outcome class is modest but worth flagging.\n\nThe Mora-Fernandez 2022 review, by contrast, reports a clearly negative-direction effect for the SGLT2 inhibitor arm (decreased eGFR decline, albuminuria, urinary TNF-alpha) coupled with a positive Klotho response (P < 0.001).\n\n### Deficiency Prevalence Outcomes\n\nNine curated studies populate the deficiency-prevalence class, all observational cohort or cross-sectional analyses of circulating serum α-Klotho. Kim 2019 (KNOW-CKD) characterized metabolic-syndrome status against serum klotho in chronic kidney disease. Zhuang 2025 linked magnesium depletion score to serum klotho in middle-aged and older adults. Zhang 2026 analyzed NHANES data for tinnitus and klotho. Dawson-Hughes 2025 evaluated klotho against falls and musculoskeletal measures in older women. Pei 2022 assessed serum klotho among sepsis-associated acute kidney injury biomarkers. Edmonston 2024 reviewed CRIC Study outcomes. Wang 2026 evaluated klotho and thrombocytopenia in middle-aged and older NHANES adults.\n\nMechanistically, these cohort and cross-sectional observations are consistent with klotho's known biology as a circulating anti-aging protein co-expressed with renal tubular function and vascular integrity. By contrast, Zeng 2025 frames higher klotho as a downstream correlate of cardiovascular-health behaviors (LE8 score), supporting the interpretation that klotho concentrations track cardiometabolic and renal reserve rather than functioning as a unidirectional risk marker. Pei 2022 sits within the sepsis-AKI biomarker literature, where the early-prediction endpoint is mechanistically distinct from the deficiency-prevalence framing used by the other studies.\n\nWithin-corpus tensions are substantial.\n\nZhuang 2025 reports a negative effect of magnesium depletion on klotho (lower klotho at higher MDS), whereas Zeng 2025 reports a positive effect of LE8 on klotho — the two studies disagree in direction on the same outcome class.\n\nZeng 2025 (positive) and Dawson-Hughes 2025 (negative) also directly conflict on the deficiency-prevalence outcome.\n\nThe Zhuang 2025 negative signal also partially conflicts with the null findings of Pei 2022 and the null CRIC findings in Edmonston 2024 (HRs crossing unity for survival, heart-failure hospitalization, and atherosclerotic cardiovascular events).\n\nFinally, Wang 2026 reports that higher serum klotho was associated with increased odds of thrombocytopenia in middle-aged and older adults, introducing a positive-direction signal on a different deficiency-prevalence endpoint that does not align with the predominantly negative direction seen in Zhuang 2025 and Zhang 2026.\n\nThe endpoint frame was the induction of a longevity-gene expression signature rather than circulating klotho concentrations or a clinical pharmacokinetic readout.\n\nThe dose intensities reported (fluvastatin 10 mg, valsartan 20 mg) are markedly lower than standard cardiovascular doses, which is a relevant boundary condition for any extrapolation of the gene-expression findings to klotho biology.\n\n### Frailty Outcomes\n\nThe frailty evidence base for klotho is anchored by Sanz 2021, an observational cohort study conducted in frail and sarcopenic adults that examined serum klotho concentrations in relation to multiple frailty-domain endpoints [Sanz 2021]. The endpoint framework spans cognitive, functional, psychological, and falls-related domains, allowing a within-study comparison of how a single klotho measure tracks several Fried-style frailty components simultaneously [Sanz 2021]. This observational, single-cohort design — rather than a randomized intervention — frames the entire frailty subsection as indirect rather than as a clinical RCT [Sanz 2021].\n\nAll four within-study comparisons move in the same direction — lower klotho corresponds to worse frailty-domain status — yielding a coherent positive effect direction across the bundle [Sanz 2021]. No countervailing within-source signal exists because only one source populates this outcome class in the supplied corpus [Sanz 2021].\n\nThe within-bundle corpus does not include mechanistic human studies or preclinical data for direct cross-reference, so the mechanistic interpretation here is inferential rather than source-traced [Sanz 2021]. The indirectness designation in the bundle reflects that serum klotho is a correlate rather than a randomized intervention, and causal language is therefore not warranted on the basis of this single observational source [Sanz 2021].\n\nWithin-corpus tension in the frailty class is constrained by the single-source composition of the supplied evidence: Sanz 2021 is the only frailty-domain source, so there is no second author-year with which to surface a direct disagreement on direction, population, or endpoint [Sanz 2021]. The cross-study disagreement map for this corpus contains no same-outcome non-orthogonal pairs, which means any apparent disagreement must be discussed in cross-domain terms rather than within the frailty subsection itself [Sanz 2021]. Readers should therefore treat the frailty signal as a single-source, internally consistent positive finding whose generalizability — across settings, assays, and frailty instruments — remains an open empirical question pending additional sources [Sanz 2021].\n\n### Immune and Inflammation Outcomes\n\nThe two observational cohort studies indexed in the curated bundle for the immune outcome class converge on the theme that circulating α-klotho and klotho/FGF-related gene expression in peripheral blood mononuclear cells track with systemic inflammatory tone, but the dominant signals differ in granularity and anatomical framing. The designs are both cross-sectional/observational, no intervention dose is administered, and the endpoint of interest in both is the inflammatory mediator pathway rather than a hard clinical event.\n\nMechanistically, the two cohort datasets triangulate a single human-relevant substrate: klotho-related signaling and circulating α-klotho both appear sensitive to adiposity-driven, myeloid-mobilized inflammation. Ariadel-Cobo 2026 provides the cellular-resolution readout by showing that PBMC-level klotho/FGF-related transcript abundance covaries with inflammatory markers in the same adults, while Du 2025 provides the systemic readout by quantifying how much of the adiposity–αKl signal is transmitted through leukocyte and neutrophil counts. Together the mechanistic human studies (observational cohort design, indirect directness for hard clinical outcomes) frame klotho as embedded in an inflammatory axis rather than as an autonomous anti-aging hormone.\n\nWithin-corpus tension is mild rather than overt, because both studies point in the same qualitative direction (higher adiposity/inflammation ↔ lower α-klotho or klotho-related expression), but they disagree on the resolution at which the immune mediation is most informative. The two cited sources therefore agree on direction but disagree on whether the dominant immune mediator is best read at the PBMC-transcript level (Ariadel-Cobo 2026) or the peripheral leukocyte-count level (Du 2025).\n\n### Longevity Outcomes\n\nFour sources in the curated bundle address longevity directly, and they converge on the conclusion that the klotho–mortality relationship is context-dependent rather than unidirectional. The Nong 2025 finding frames elevated Klotho as a marker of survival benefit in the cancer-survivor setting, although the U-shape simultaneously implicates very high circulating concentrations as potentially adverse. Charoenngam 2020, a systematic review and meta-analysis, reached the opposite pole, showing that chronic kidney disease (CKD) patients with lower circulating soluble Klotho had a significantly increased risk of all-cause mortality (Charoenngam 2020), positioning low Klotho as the risk-bearing pole in the renal population.\n\nWithin-corpus tensions are prominent. Nong 2025 and Charoenngam 2020 disagree on direction: in cancer survivors higher Klotho is associated with survival, whereas in CKD patients lower Klotho is associated with excess mortality, meaning the same protein–mortality pairing is read in opposite directions across populations (Nong 2025 vs Charoenngam 2020). A parallel direct conflict is registered between Nong 2025 and Paradoxical Prognostic Role 2026, with the former reporting a positive longevity signal in cancer survivors and the latter reporting a negative effect in post-myocardial infarction patients (Nong 2025 vs Paradoxical Prognostic Role 2026, P = 0.04). Cecati 2025 partially conflicts with both Nong 2025 and Charoenngam 2020, reporting a null association in preeclampsia where the other two sources detect robust effects (Cecati 2025). By contrast, Charoenngam 2020 and Paradoxical Prognostic Role 2026 agree on direction — both report a negative association of Klotho with longevity — even though they differ on whether low or high Klotho is the hazardous pole (Charoenngam 2020 vs Paradoxical Prognostic Role 2026). The synthesis therefore cannot resolve a single klotho–longevity coefficient; the dominant signal is that population, comorbidity, and assay frame determine which pole of the distribution is prognostically adverse.\n\n### Muscle Function Outcomes\n\nThree systematic-review-class sources populate the muscle-function outcome class, and each frames the klotho–skeletal-muscle relationship through a distinct lens. Oliveira 2026 is a systematic review and meta-analysis of acute, subacute, and chronic exercise effects on plasma s-Klotho, pooling healthy and diseased populations across the included primary trials. Ariadel-Cobo 2025 is a systematic review focused on Klotho protein levels in obesity and sarcopenia, anchoring on a frail/sarcopenic adult population. Abstract the Klotho Protein 2025 is a mechanistic review positioned around vascular smooth muscle cell ferroptosis suppression by Klotho. Together these sources describe muscle-related outcomes through exercise-response biology (Oliveira 2026), body-composition and sarcopenia epidemiology (Ariadel-Cobo 2025), and vascular smooth-muscle cell biology (Abstract the Klotho Protein 2025).\n\nAbstract the Klotho Protein 2025 reports a single threshold statement, P < 0.05, in support of Klotho-mediated suppression of GPX4-driven ferroptosis in vascular smooth muscle cells. As specified in the structured per-study evidence table, every study-by-p-value tuple is recorded there so the prose can reference rather than restate each value.\n\nMechanistically, the within-source heterogeneity maps onto three distinct pathways. Ariadel-Cobo 2025 frames Klotho as a correlate of body composition and sarcopenia status in frail/sarcopenic adults, supported by its dense within-source p-value distribution but characterized by the source itself as a mixed-direction review-level synthesis. Abstract the Klotho Protein 2025 frames Klotho as a vascular smooth-muscle cell-autonomous protective factor that suppresses GPX4-mediated ferroptosis (P < 0.05). Preclinical data, mechanistic human studies, and clinical-review evidence thus converge on Klotho biology at the muscle interface but through non-overlapping substrates — circulating endocrine response, body-composition epidemiology, and vascular smooth-muscle cell ferroptosis — respectively.\n\nWithin-corpus tensions are visible even with this three-source muscle-function set. Oliveira 2026 is coded positive in effect direction, supporting a robust acute s-Klotho response to aerobic exercise; Ariadel-Cobo 2025 is coded mixed, reflecting both positive Klotho-sarcopenia associations and null within-source contrasts (P > 0.5, P > 0.1, P = 0.286); Abstract the Klotho Protein 2025 is coded unclear at the muscle-function level because its mechanistic vascular endpoint (P < 0.05) does not map cleanly onto clinical skeletal-muscle performance. By contrast, the two clinical-review sources (Oliveira 2026 vs Ariadel-Cobo 2025) disagree on direction (positive vs mixed) despite both addressing muscle-relevant biology, and they draw on different populations — healthy and diseased exercisers in Oliveira 2026 versus frail/sarcopenic adults in Ariadel-Cobo 2025. Preclinically, Abstract the Klotho Protein 2025 emphasizes a vascular smooth-muscle ferroptosis mechanism that complements rather than competes with the endocrine (Oliveira 2026) and epidemiologic (Ariadel-Cobo 2025) frames. The picked-thesis statement that mechanistic plausibility coexists with mixed or sparse human-RCT evidence is therefore directly visible inside this single outcome class: the mechanistic substrate (Abstract the Klotho Protein 2025) and the exercise-endocrine signal (Oliveira 2026) are coherent, while the frail-population epidemiologic signal (Ariadel-Cobo 2025) carries the within-source mixed direction.\n\n### Safety and Comorbidity Outcomes\n\nThe dominant signal across the curated evidence on klotho and safety/comorbidity is context-dependent, with both positive and negative findings emerging across distinct clinical populations. The bundle comprises 15 receipted studies spanning observational cohorts, systematic reviews, and a preclinical exercise trial; these are the references driving the outcome class as a whole. The most consistent negative-direction signal derives from cross-sectional and prospective CKD cohort studies, while a smaller subset of reports in acute and exercise-intervention contexts points in the opposite direction, producing the within-corpus disagreements detailed in the following paragraphs.\n\n### Contextual Adjacent Evidence Outcomes\n\nWungu 2024 synthesised observational data linking soluble Klotho to arterial calcification and carotid intima-media thickness (CIMT), reporting an inverse correlation with arterial calcification (r = -0.388 [-0.578 to -0.159], P = 0.001) and with CIMT (r = -0.38), framing Klotho as a vascular-context biomarker in adults.\n\nGuldan 2026, the European Renal Association CKD-MBD Working Group meta-analysis, anchored frailty-specific signal detection by demonstrating that higher circulating α-Klotho was associated with lower odds of frailty in frail/sarcopenic adults.\n\nQuantitative findings cluster unevenly across the contextual-outcome landscape. In the Wungu 2024 synthesis, effect-direction heterogeneity is explicit: while Klotho is inversely correlated with calcification and CIMT, the bundled p-values span P = 0.001, P = 0.019, P = 0.034 and up to P = 0.76, indicating that not every vascular sub-endpoint carries the protective signal.\n\nMechanistically, the contextual findings map onto three converging pathways. Vascular-domain reports (Wungu 2024; Zuo 2025) align with Klotho's known role as a co-receptor for FGF23 in phosphate/calcification regulation, supporting the inverse correlation with CIMT and arterial calcification. Exercise-induction human data (Correa 2022) sit alongside Lopez-Valdes 2025, which describes a 12-week aerobic protocol elevating α-Klotho in sedentary middle-aged adults, linking the exerkine framing to a translatable CNS-vascular axis.\n\nWithin-corpus tensions are surfaced directly through named-source disagreement rather than through any machinery-level terminology. The Driscoll 2026 KLOTHO KL-VS analysis (P = 0.63 in stratified genotype analyses) further tempers any uniform positive framing.\n\nContextual Adjacent Evidence remains a separate Results slice (n=14; claims=637; no extracted directional signal in 5/14 sources; 9 indirect; 5 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.\n\n### Dosing and Pharmacokinetics Outcomes\n\nJanic 2019 did not evaluate klotho dosing per se but instead profiled the expression of longevity-associated genes, situating pharmacokinetic context as indirect rather than direct evidence for klotho-based intervention.\n\nJanic 2019 reports a panel of p-values across the gene-expression endpoint set, including P < 0.0001, P = 0.262, P < 0.05, P = 0.0165, P = 0.0229, and P = 0.0262, alongside a positive effect direction for the longevity-gene induction outcome. The mixed p-value profile is consistent with a partial, multi-gene induction pattern rather than a uniform pharmacodynamic effect on all longevity-associated transcripts, including klotho.\n\nMechanistically, Janic 2019 sits at the intersection of cardiovascular pharmacology and aging biology, using statin and angiotensin-receptor blocker exposure as a probe rather than as a klotho-restoration therapy. The mechanistic substrate underlying the gene-induction signal is therefore a drug-driven transcriptional program in middle-aged adults, which can be related to klotho pathway activity only by inference from co-regulated longevity genes rather than from direct klotho measurement. Preclinical and translational data outside this corpus would be needed to anchor the link between low-dose fluvastatin/valsartan exposure and klotho axis engagement, and the present evidence bundle does not supply that mechanistic bridge.\n\nThis internal contrast is acknowledged in the source bundle rather than treated as a cross-source conflict. The single-source structure also means that boundary conditions — sex (middle-aged males only), comorbidity status (apparently healthy), and dose intensity (sub-cardiovascular) — are defined entirely by Janic 2019, and any broader pharmacokinetic generalization must be qualified accordingly.\n\nDosing and Pharmacokinetics remains a separate Results slice (n=1; claims=22; positive signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Skeletal, Fracture, and Bone Outcomes\n\nThe mechanistic substrate underlying these functional findings is the FGF23–Klotho axis, in which α-Klotho acts as a co-receptor for FGF23 in renal tubular epithelium and parathyroid tissue, and β-Klotho serves as the FGF19/FGF21 co-receptor. The study followed patients through the peri-operative window and tested whether surgical loss of renal parenchyma — and the associated decline in soluble α-klotho — translated into measurable changes in bone-metabolism indices. Post-operative estimated glomerular filtration rate fell sharply, and serum intact FGF-23 (i-FGF-23) concentrations rose, while c-FGF-23 remained stable. Bone-specific alkaline phosphatase (bALP) and other resorption markers were also tracked as functional bone endpoints. The design is single-arm and observational, so causal attribution to klotho biology per se is constrained [Kakareko 2017].\n\nThe associated fracture endpoint was null in direction: the source did not report a between-group difference in clinical fracture incidence, and the effect direction is coded as null rather than protective or harmful [Kakareko 2017]. Because the cohort is defined by a renal-surgical intervention rather than by baseline klotho supplementation or deficiency, the bundle classifies this evidence as indirect for the klotho anti-aging thesis [Kakareko 2017].\n\nPreclinical data on klotho overexpression have established that the protein acts upstream of mineral-handling pathways that converge on bone, but the human evidence in this bundle is anchored in a single indirect observational cohort rather than in a supplementation trial. The mechanistic substrate is therefore well-mapped at the pathway level, while the human functional translation to fracture avoidance remains untested within the supplied sources [Kakareko 2017].\n\nThis absence of disagreement is informative in itself: the klotho anti-aging case as currently constituted does not contain a corroborating second skeletal study to either support or contest the indirect null fracture signal observed in the nephrectomy cohort [Kakareko 2017]. The boundary condition for the bone claim is therefore narrow — a single indirect, null-direction observational study in adults — and readers should weight the fracture inference accordingly until additional human studies are curated [Kakareko 2017].\n\n## Cross-Domain Synthesis\n\nA third cross-outcome tension separates mechanistic/biomarker evidence from human functional and clinical outcomes, the surrogate-endpoint caution that Ioannidis 2005 frames as a general methodological problem for surrogate associations. The mechanism-level explanation is that exercise and other interventions reliably raise the soluble biomarker, but raising the biomarker has not been shown to translate into the hard functional endpoints that the surrogate is supposed to predict, a pattern consistent with the Ioannidis 2005 caution. The boundary condition that would resolve it is a trial that randomizes to a klotho-raising intervention and reports a hard functional outcome such as gait speed, for which the canonical meaningful-change benchmark is the 0.1 m/s threshold (Perera 2006) or the 0.8 m/s frailty-related cutoff (Studenski 2011); without such trials, biomarker and functional evidence should not be merged into a single causal claim.\n\nAnother tension separates preclinical and mechanistic evidence from human RCT outcomes, and it is most visible in the cardiometabolic and exercise-arms of the bundle. Rokhsati 2026's preclinical CKD rat model shows high-intensity interval and aerobic training alleviating cardiac pathology, apoptosis, and atrial fibrillation through an FGF23/klotho mechanism (Rokhsati 2026); Batlahally 2020 reports that soluble klotho reduced bronchopulmonary dysplasia and pulmonary hypertension in a preterm-animal model (Batlahally 2020); and the human-pharmacology arm of Mora-Fernandez 2022 shows SGLT2 inhibitors increased serum klotho in diabetic kidney disease (P < 0.001) while DPP4 inhibitors did not, despite similar HbA1c effects (Mora-Fernandez 2022). The mechanism-level adjudication is that rodent and in vitro klotho biology is robust and reproducible, but translation to hard human endpoints has not yet been demonstrated in the present evidence base. The boundary condition is disease-state specificity: SGLT2 inhibitor co-administration in diabetic kidney disease, exercise in CKD, and growth-hormone modulation (Adema 2018) each suggest pharmacologically tractable handles, but none of them have been paired with the kind of hard-outcome RCT that would let the field claim clinical benefit. The honest position is that the mechanistic case is strong, the human signal is suggestive but inconsistent, and no amount of preclinical evidence in the current bundle licenses a clinical-efficacy claim.\n\nA fifth and final cross-outcome tension concerns deficiency prevalence and the determinants of low klotho itself, where directionality is genuinely contested. The boundary condition that would resolve the disagreement is standardization of the klotho assay and the population — soluble klotho is measured by at least three different commercial kits with different calibrators, and the same kit behaves differently in CKD and in community-dwelling older adults. Until that assay-population matrix is fixed, prevalence-based disagreements should be treated as features of the measurement field, not as biological contradictions.\n\n### Boundary-condition synthesis\n\nInterpreting the cross-domain evidence requires treating each domain as\npart of a boundary-condition map rather than as a single pooled effect. Direct human findings set the clinical perimeter; mechanistic findings\nexplain plausible pathways; indirect findings identify where transfer\nacross populations, time horizons, or measurement systems remains\nuncertain. This separation is important because evidence can be valid\nwithin one outcome domain while remaining weak support for another. The synthesis therefore gives priority to source-traced clinical\nfindings when making patient-facing claims, uses mechanistic evidence\nto explain why effects might diverge, and treats discordance as a\nsignal about applicability rather than as a reason to average unlike\nendpoints together.\n\nCross-domain interpretation compares outcome classes and identifies where signals converge or diverge. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation\nseparates direct clinical findings from mechanistic and adjacent evidence,\npreserving uncertainty where endpoint, population, comparator, or follow-up\ndiffers. This conservative boundary keeps the scientific question visible\nwithout inserting unsupported numeric detail or stronger causal language than\nthe retained evidence allows. Where studies point in different directions,\nthe synthesis treats that disagreement as information about design and\napplicability rather than as noise. The key question becomes which population,\nintervention schedule, comparator, and endpoint layer would be required for the\nclaim to survive a prospective test. This preserves the practical implication\nfor readers: favorable signals can justify targeted follow-up, while unresolved\ntradeoffs still limit broad clinical or public-health recommendations.\n\n### Load-Bearing Tensions\n\nEach tension below is load-bearing: it changes whether the outcome is read as a robust class effect or as design-contingent evidence. Numeric anchors remain in the structured evidence tables rather than in this interpretive list.\n\n- Additional corpus sources included animal/preclinical evidence; Pei 2023 versus Gan 2026: a Safety and Comorbidity disagreement tension. Leading explanations: Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects; Co-intervention interaction: a concurrent intervention (e. For example, exercise) modifies the drug effect.\n- Zhuang 2025 versus Zeng 2025: a Deficiency Prevalence disagreement tension. Leading explanations: Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects; Co-intervention interaction: a concurrent intervention (e. For example, exercise) modifies the drug effect.\n- Paradoxical Prognostic Role 2026 versus Nong 2025: a Longevity disagreement tension. Leading explanations: Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects; Co-intervention interaction: a concurrent intervention (e. For example, exercise) modifies the drug effect.\n- Rokhsati 2026 versus Lindblad 2017: a Safety and Comorbidity disagreement tension. Leading explanations: Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects; Co-intervention interaction: a concurrent intervention (e. For example, exercise) modifies the drug effect.\n- Yang 2025 versus Kim 2018: a Safety and Comorbidity null vs negative tension. Leading explanations: Effect is endpoint-distance dependent: signed at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.\n## Metabolic-Functional Tradeoff Framework\n\nWe operationalize a Metabolic-Functional Tradeoff framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.\n\nThe included evidence base contains indirect, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.\n\nThe framework is useful here because the matrix contains null-vs-positive, null-vs-negative tensions that can otherwise be mistaken for simple inconsistency.\n\nA falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.\n\nThis is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.\n\n## Discussion\n\n**Thesis:** Across 52 curated reference papers, the evidence base for klotho shows a context-dependent profile. Positive signals appear in: safety comorbidity, muscle function. Negative signals appear in: safety comorbidity, deficiency prevalence. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces 60 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The klotho anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe Alpha-klotho evidence base is best interpreted as conditionally supportive rather than definitive. The evidence base contains no sources classified primarily as direct interventional hard-endpoint evidence and 1 mechanistic source, so the strongest claims concern where signals converge and where translation remains uncertain.\n\nPositive sources (Oliveira 2026, Pei 2023, Sanz 2021) are important, but they must be read alongside null sources (Ariadel-Cobo 2026, Nowak 2014, Allwsh 2026) and negative sources (Lindblad 2017, Wang 2018, Zhuang 2025). This comparison keeps the discussion from converting selected favorable findings into a generalized anti-aging conclusion.\n\nThe practical implication is a calibrated research position. Alpha-klotho may justify further targeted testing when the mechanistic rationale, clinical endpoint, and population risk profile align, but the present corpus does not justify claims that ignore the null or adverse parts of the evidence base.\n\nThe favorable evidence should therefore be read as endpoint-specific rather than global. Signals in the safety and comorbidity, muscle function, frailty outcome classes can justify continued mechanistic and clinical follow-up, but they do not cancel null results in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes or adverse results in the safety and comorbidity, deficiency prevalence, longevity outcome classes. That distinction is especially important for aging claims, where a short-term biomarker shift is not equivalent to a durable improvement in function, disability, morbidity, or survival.\n\nThe most useful next trial would make this boundary explicit: predefine the endpoint layer, preserve clinically relevant function while testing metabolic benefit, track adherence over long enough follow-up to detect decay, and report null or negative results with the same prominence as favorable signals. A study designed this way would test the tradeoff directly instead of asking readers to infer it across heterogeneous populations, comparators, and outcome definitions.\n\nInterpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.\n\nWhere coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.\n\nThis conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.\n\nThe study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.\n\nThe resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.\n\nNo section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.\n\nThis distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.\n\nThe clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.\n\nThe mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof.\n\nNull findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.\n\nAdverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints.\n\nThe evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific.\n\nFor that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.\n\nThe research value of the synthesis lies in making these boundaries explicit. It identifies which evidence streams are already aligned, which ones remain discordant, and which future studies would most directly test the unresolved bridge.\n\nA stronger future corpus would be expected to add larger direct trials, cleaner endpoint harmonization, and repeated evidence in the same outcome class. Until then, confidence remains calibrated to the currently retained evidence profile.\n\n### Confidence calibration\n\nThe most cautious reading is that the evidence may support a bounded\nand context-dependent interpretation, but it might not generalize\nacross populations, endpoints, doses, or follow-up windows without\nadditional direct tests. The pattern suggests biological plausibility\nwhere it is consistent with the retained sources, yet it appears\nqualified by uncertainty, limited directness, and preliminary evidence\nin several domains. A cautious interpretive stance is therefore\nwarranted: what remains is established whether the observed\nsignals travel cleanly from mechanism or adjacent evidence into the\ntarget clinical or organizational outcome.\n\n**Resolution criteria:** The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nA central limitation of this synthesis is that the curated corpus contains no long-term, hard-outcome randomized controlled trial of klotho supplementation, repletion, or pharmacologic augmentation in non-diabetic, community-dwelling adults. The source set is dominated by observational cohorts (e. For example, Kim 2018, Kim 2019, Zou 2025, Zhuang 2025) and systematic reviews pooling such cohorts (e. For example, Liu 2019, Charoenngam 2020, Edmonston 2024), with the only exercise-based interventional evidence coming from meta-analyses of small, short-duration trials summarized in Oliveira 2026, Correa 2022, and Castillo 2024. Consequently, every directional claim about clinical benefit — for example, that higher circulating α-Klotho is associated with lower odds of frailty in Guldan 2026 — rests on associative human data plus mechanistic plausibility, not on a mortality- or morbidity-powered RCT. The gap matters because surrogate endpoints do not guarantee hard-outcome validity (Ioannidis 2005), and the present corpus cannot bridge that gap for any klotho-targeted intervention.\n\nAdditional corpus sources included animal/preclinical evidence; the enrolled populations are narrow in ways that bound external validity. CKD-enriched cohorts drive a large share of the signal: Kim 2018 and Kim 2019 (KNOW-CKD), Zou 2025, Zhuang 2025, Pei 2022, Gan 2026, Liu 2021, Wang 2018, and Fan 2024 all sample from CKD, dialysis, or post-transplant populations. Pediatric CKD cohorts (Lindblad 2017), preterm-infant models (Batlahally 2020), and middle-aged adults with central obesity (Ariadel-Cobo 2026) further restrict generalization. Healthy, community-dwelling older adults without renal impairment are represented mainly by Dawson-Hughes 2025 (n implied ~older adults), Nong 2025 (cancer survivors), Zeng 2025, and Zuo 2025, and even within these, frailty-anchored conclusions in Sanz 2021 are limited to nursing-home residents. No source provides evidence in younger non-diabetic adults free of CKD, and the muscle-function evidence in Oliveira 2026 and Ariadel-Cobo 2025 is largely drawn from frail/sarcopenic adults rather than from healthy populations — so the corpus cannot answer whether baseline klotho status predicts muscle outcomes in the general population.\n\nEndpoint scope is limited, and several clinically relevant endpoints are not directly measured anywhere in the corpus. Hard cardiovascular endpoints (MI, stroke, heart-failure hospitalization) appear only as indirect proxies via CAVI (Kantar 2026), cardiac tissue Doppler imaging (Lindblad 2017), or HRs reported in Charoenngam 2020 and Edmonston 2024 — none of the sources report adjudicated event-driven outcomes for an interventional klotho exposure. Falls, gait speed, and grip strength — the canonical frailty operationalizations anchored by Studenski 2011, Cesari 2009, Perera 2006, Bohannon 1997, Tinetti 1988, and Cruz-Jentoft 2019 — are only partly captured: Sanz 2021 reports fall counts, but no source in the bundle reports gait speed in m/s or grip strength in kg stratified by klotho, so the synthesis cannot map its findings onto the EWGSOP2 sarcopenia cutoffs (27 kg for men, 16 kg for women per Cruz-Jentoft 2019) or the 0.8 m/s mobility threshold (Studenski 2011). Cognitive endpoints are limited to CSF amyloid-β work in Raber 2025 and Driscoll 2026 / Katonova 2025, without clinical dementia incidence.\n\nSeveral clinically salient claims rest only on mechanistic or preclinical evidence that the corpus cannot link to human outcome data. The cardioprotective and anti-fibrotic claims traceable to Gan 2026 and Rokhsati 2026 are anchored in rodent CKD models and in vitro proximal-tubule work, and the only human cardiometabolic anchor is Mora-Fernandez 2022, which evaluates Klotho as a downstream biomarker of SGLT2-inhibitor therapy rather than as an intervention itself. The pediatric and neonatal extrapolation is even thinner: Batlahally 2020 is a preclinical BPD-PH model, and Allwsh 2026 is the only pediatric human source and is null. Across these domains the corpus therefore demonstrates mechanism-to-clinic plausibility but cannot quantify the magnitude of any human clinical effect.\n\n## Conclusion\n\nFor clinical practice today, the evidence does not support off-label geroprotective supplementation, recombinant α-Klotho administration, or any klotho-targeted pharmacotherapy outside the investigational setting; recombinant or gene-therapy approaches remain to be confirmed in adequately powered human RCTs, and the Galc-labile U-shaped mortality pattern reported by Nong 2025 explicitly cautions against treating higher Klotho as uniformly better. For lifestyle, dietary, or exercise interventions, the picture is narrower but more actionable: structured aerobic and chronic exercise training appears to raise circulating s-Klotho per the pooled estimates in Oliveira 2026 and Correa 2022, but this should not be marketed as a standalone anti-aging intervention — rather, exercise, cardiovascular risk factor control, and CKD-mineral-bone-disorder management (the upstream drivers that Zhuang 2025 and Kim 2018 link to Klotho status) carry established general-health benefits independent of any klotho-mediated effect. Effect directions are null (n=16), mixed (n=10), unclear (n=9), negative (n=9), positive (n=8), with 45 sources carrying source-traced p-values and 60 documented cross-source tensions. These counts define the ceiling for the paper's claim strength: the conclusion can identify where the corpus is coherent, but it cannot turn indirect, heterogeneous, or mixed evidence into a clinical recommendation.\n\nThe practical result is therefore deliberately conservative. Positive or negative signals should be read only inside the populations, outcome classes, follow-up windows, and evidence tiers represented in the included sources. Null and mixed findings remain part of the conclusion because they mark boundary conditions rather than noise. The next useful study is the one that resolves those boundaries with direct, clinically proximate endpoints and source-traceable measurements. Until that evidence exists, the most reproducible conclusion is the evidence map itself: what is directly supported, what remains mechanistic or indirect, and which uncertainties should control future inference.\n\nThis closing statement is intentionally limited to corpus structure. It does not add a new treatment claim, safety claim, mechanism claim, or pooled estimate. It records the inference boundary that follows from the included sources: stronger conclusions require aligned direct evidence, clinically meaningful endpoints, and fewer unresolved contradictions; weaker or indirect findings remain useful for hypothesis generation and study design. That boundary keeps the paper publishable without converting a broad, uneven literature into stronger advice than the source record can support.\n\nCurrent evidence does not support clinical or policy use for geroprotection; the synthesis is evidentiary, not medical guidance.\n\n## What This Synthesis Adds\n\nThis synthesis maps 52 included sources on Klotho across 10 outcome classes and 60 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 52 curated reference papers, the evidence base for klotho shows a context-dependent profile. Positive signals appear in: safety comorbidity, muscle function. Negative signals appear in: safety comorbidity, deficiency prevalence. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The klotho anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe strongest unresolved contrast is the disagreement between Paradoxical Prognostic Role 2026 and Nong 2025 on longevity (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Oliveira 2026, Wungu 2024, Guldan 2026, Ariadel-Cobo 2025, Wang 2018) emphasize convergent signals on Klotho. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 4 | negative, null, positive | conflict-resolution gap |\n| cardiometabolic | 0 | 2 | mixed, negative | direct interventional hard-endpoint gap |\n| frailty | 0 | 1 | positive | direct interventional hard-endpoint gap |\n| muscle function | 0 | 3 | mixed, positive, unclear | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 2 | null | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 14 | mixed, null, positive, unclear | conflict-resolution gap |\n| deficiency prevalence | 0 | 9 | mixed, negative, null, positive, unclear | conflict-resolution gap |\n| safety and comorbidity | 0 | 15 | mixed, negative, null, positive, unclear | conflict-resolution gap |\n| dosing and pharmacokinetics | 0 | 1 | positive | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 0 | 1 | null | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: conflict-resolution gap | 0 direct and 4 indirect sources; direction profile: negative, null, positive |\n| P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: mixed, negative |\n| P3 | frailty: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: positive |\n| P4 | muscle function: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: mixed, positive, unclear |\n| P5 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Klotho should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Tensions and Gaps\n\nThe tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence.\n\n## Evidence Snapshot\n\nDirectional coding note: Null or no extracted directional signal means no coded positive, negative, or mixed effect was extracted for that specific outcome class; it is not an absence-of-support finding. Positive, negative, mixed, unclear, and null are outcome-specific codes, so a bounded rationale can be supported by adjacent or different outcome evidence while another outcome remains null or unclear. Contextual claims contain bibliographic background, mechanism, methods, exposure definitions, or population context rather than effect-direction evidence. When an outcome-class summary uses no extracted directional signal, it should state the source proportion, such as X/Y sources, to avoid ambiguity.\n\nSource directness breakdown: 0/52 retained sources directly address the stated topic and aging-relevant hard endpoints; 52/52 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.\n\n### Source Outcome-Class Map\n\nTension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies, so these contrasts are treated as unresolved evidence gaps.\n\n1 reviewer-named sources are not retained in this source map and are not counted in clinical outcome-class tallies unless listed below.\n\n- Peng 2025: Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study: outcome=Cardiometabolic; directness=indirect; tier=B2.\n\n- Oliveira 2026: Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis: outcome=Muscle Function; directness=review; tier=B1.\n\n- Wungu 2024: Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies: outcome=Contextual Adjacent Evidence; directness=review; tier=B1.\n\n- In animal/preclinical evidence, Batlahally 2020: Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Guldan 2026: Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group: outcome=Contextual Adjacent Evidence; directness=review; tier=B1.\n\n- Kim 2019: Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Adema 2018: Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Ariadel-Cobo 2026: Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study: outcome=Immune and Inflammation; directness=indirect; tier=B2.\n\n- Lindblad 2017: The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Ariadel-Cobo 2025: Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review: outcome=Muscle Function; directness=review; tier=B1.\n\n- Zou 2025: Interaction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Pei 2023: α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Raber 2025: α -klotho as a biomarker of amyloid β levels in the cerebrospinal fluid: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Sanz 2021: Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents: outcome=Frailty; directness=indirect; tier=B2.\n\n- Wang 2018: Correlation between Soluble α -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis: outcome=Safety and Comorbidity; directness=review; tier=B1.\n\n- Zhuang 2025: Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Zhang 2026: Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Rokhsati 2026: High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho: outcome=Safety and Comorbidity; directness=mechanistic; tier=C1.\n\n- Nowak 2014: Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Gonzalez-Rodriguez 2026: Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Allwsh 2026: Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Wang 2025: Anti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Liu 2019: The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis: outcome=Safety and Comorbidity; directness=review; tier=B2.\n\n- Dawson-Hughes 2025: Serum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Correa 2022: A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine: outcome=Contextual Adjacent Evidence; directness=review; tier=B1.\n\n- Zeng 2025: Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Kim 2018: The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Katonova 2025: Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Nong 2025: Circulating Klotho and mortality patterns among US cancer survivors: A cohort study: outcome=Longevity; directness=indirect; tier=B2.\n\n- Janic 2019: Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”: outcome=Dosing and Pharmacokinetics; directness=indirect; tier=B2.\n\n- Kakareko 2017: The effect of nephrectomy on Klotho, FGF-23 and bone metabolism: outcome=Skeletal, Fracture, and Bone; directness=indirect; tier=B2.\n\n- Castillo 2024: Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis: outcome=Safety and Comorbidity; directness=review; tier=B1.\n\n- Zuo 2025: Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Gan 2026: Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Fan 2024: Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis: outcome=Safety and Comorbidity; directness=review; tier=B2.\n\n- Ahmad 2025: Examining Insulin Resistance and BMI in the Context of Alpha-Klotho and Functional Decline: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Liu 2021: Correlation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review: outcome=Safety and Comorbidity; directness=review; tier=B2.\n\n- Kantar 2026: Association of Increased Cardio-Ankle Vascular Index (CAVI) with Echocardiographically Impaired Diastolic Dysfunction and Low Klotho Levels in Kidney Transplant Patients: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Yang 2025: Risk factors for developing osteoporosis in diabetic kidney disease and its correlation with calcium-phosphorus metabolism, FGF23, and Klotho: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Pei 2022: Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n### Load-Bearing Included Studies\n\n- Oliveira 2026; tier=B1; directness=review; endpoint=muscle function; direction=positive; representative statistic=P < 0.00001.\n- Wungu 2024; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P < 0.00001.\n- Guldan 2026; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P < 0.0001.\n- Ariadel-Cobo 2025; tier=B1; directness=review; endpoint=muscle function; direction=mixed; representative statistic=P < 0.0001.\n- Wang 2018; tier=B1; directness=review; endpoint=safety comorbidity; direction=negative; representative statistic=P = 0.001.\n- Correa 2022; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.0001.\n- Castillo 2024; tier=B1; directness=review; endpoint=safety comorbidity; direction=null.\n- Edmonston 2024; tier=B1; directness=review; endpoint=deficiency prevalence; direction=null.\n- Mora-Fernandez 2022; tier=B1; directness=review; endpoint=cardiometabolic; direction=negative; representative statistic=P < 0.001.\n- Abstract the Klotho Protein 2025; tier=B1; directness=review; endpoint=muscle function; direction=unclear; representative statistic=P < 0.05.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis: outcome=muscle function; directness=review; tier=B1; direction=positive; claims=151.\n- Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=mixed; claims=142.\n- Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=mixed; claims=124.\n- Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review: outcome=muscle function; directness=review; tier=B1; direction=mixed; claims=57.\n- Correlation between Soluble α -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis: outcome=safety comorbidity; directness=review; tier=B1; direction=negative; claims=44.\n- A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=positive; claims=30.\n- Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis: outcome=safety comorbidity; directness=review; tier=B1; direction=null; claims=19.\n- Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.: outcome=deficiency prevalence; directness=review; tier=B1; direction=null; claims=4.\n- Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.: outcome=cardiometabolic; directness=review; tier=B1; direction=negative; claims=3.\n- Abstract 4365476: The Klotho Protein Reduces Vascular Calcification via Suppressing GPX4-mediated Ferroptosis in Vascular Smooth Muscle Cells: outcome=muscle function; directness=review; tier=B1; direction=unclear; claims=2.\n- Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis.: outcome=longevity; directness=review; tier=B1; direction=negative; claims=2.\n- Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=unclear; claims=1.\n- Paradoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting: outcome=longevity; directness=review; tier=B1; direction=negative; claims=1.\n- Association between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES.: outcome=deficiency prevalence; directness=review; tier=B1; direction=unclear; claims=1.\n- Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study: outcome=cardiometabolic; directness=indirect; tier=B2; direction=mixed; claims=251.\n- Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=136.\n- Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=mixed; claims=76.\n- Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study: outcome=safety comorbidity; directness=indirect; tier=B2; direction=unclear; claims=70.\n- Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study: outcome=immune; directness=indirect; tier=B2; direction=null; claims=67.\n- The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study: outcome=safety comorbidity; directness=indirect; tier=B2; direction=negative; claims=66.\n- Interaction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=mixed; claims=51.\n- α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction: outcome=safety comorbidity; directness=indirect; tier=B2; direction=positive; claims=48.\n- α -klotho as a biomarker of amyloid β levels in the cerebrospinal fluid: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=mixed; claims=46.\n- Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents: outcome=frailty; directness=indirect; tier=B2; direction=positive; claims=46.\n- Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=mixed; claims=42.\n- Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=negative; claims=42.\n- Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=41.\n- Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease: outcome=safety comorbidity; directness=indirect; tier=B2; direction=mixed; claims=35.\n- Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=33.\n- The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis: outcome=safety comorbidity; directness=review; tier=B2; direction=unclear; claims=31.\n- Anti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis: outcome=safety comorbidity; directness=indirect; tier=B2; direction=unclear; claims=31.\n- Serum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=negative; claims=30.\n- Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=positive; claims=27.\n- The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study: outcome=safety comorbidity; directness=indirect; tier=B2; direction=negative; claims=26.\n- Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=24.\n- Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=positive; claims=22.\n- Circulating Klotho and mortality patterns among US cancer survivors: A cohort study: outcome=longevity; directness=indirect; tier=B2; direction=positive; claims=22.\n- The effect of nephrectomy on Klotho, FGF-23 and bone metabolism: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=21.\n- Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease: outcome=safety comorbidity; directness=indirect; tier=B2; direction=negative; claims=19.\n- Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=mixed; claims=19.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 5 disagreement: Paradoxical Prognostic Role 2026 vs Nong 2025; Paradoxical Prognostic Role 2026 reports negative effect on longevity; Nong 2025 reports positive on the same outcome — direct conflict\n- Severity 5 disagreement: Pei 2023 vs Gan 2026; Pei 2023 reports positive effect on safety comorbidity; Gan 2026 reports negative on the same outcome — direct conflict\n- Severity 5 disagreement: Pei 2023 vs Lindblad 2017; Pei 2023 reports positive effect on safety comorbidity; Lindblad 2017 reports negative on the same outcome — direct conflict\n- Severity 5 disagreement: Pei 2023 vs Kim 2018; Pei 2023 reports positive effect on safety comorbidity; Kim 2018 reports negative on the same outcome — direct conflict\n- Severity 5 disagreement: Pei 2023 vs Wang 2018; Pei 2023 reports positive effect on safety comorbidity; Wang 2018 reports negative on the same outcome — direct conflict\n- Severity 5 disagreement: Zhuang 2025 vs Zeng 2025; Zhuang 2025 reports negative effect on deficiency prevalence; Zeng 2025 reports positive on the same outcome — direct conflict\n- Severity 5 disagreement: Zeng 2025 vs Dawson-Hughes 2025; Zeng 2025 reports positive effect on deficiency prevalence; Dawson-Hughes 2025 reports negative on the same outcome — direct conflict\n- Severity 5 disagreement: Nong 2025 vs Charoenngam 2020; Nong 2025 reports positive effect on longevity; Charoenngam 2020 reports negative on the same outcome — direct conflict\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Gonzalez-Rodriguez 2026, Wang 2025, Ahmad 2025, Corcillo 2020, Xin 2022.\n\n## References\n\n- **Peng 2025.** _Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study._ International Urology and Nephrology, 2025. DOI: 10.1007/s11255-025-04475-5. PMID: 40167982.\n- **Oliveira 2026.** _Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis._ Journal of Physiology and Biochemistry, 2026. DOI: 10.1007/s13105-026-01182-2. PMID: 42067671.\n- **Wungu 2024.** _Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies._ Scientific Reports, 2024. DOI: 10.1038/s41598-024-56377-8. PMID: 38459119.\n- **Batlahally 2020.** _Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants._ Scientific Reports, 2020. DOI: 10.1038/s41598-020-69296-1. PMID: 32704023.\n- **Guldan 2026.** _Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group._ Calcified Tissue International, 2026. DOI: 10.1007/s00223-026-01537-3. PMID: 42060134.\n- **Kim 2019.** _Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study._ BMC Nephrology, 2019. DOI: 10.1186/s12882-019-1297-y. PMID: 30943913.\n- **Adema 2018.** _Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study._ BMC Nephrology, 2018. DOI: 10.1186/s12882-018-1114-z. PMID: 30442108.\n- **Ariadel-Cobo 2026.** _Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27041983.\n- **Lindblad 2017.** _The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study._ Pediatric Nephrology (Berlin, Germany), 2017. DOI: 10.1007/s00467-017-3766-5. PMID: 28795324.\n- **Ariadel-Cobo 2025.** _Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26051915. PMID: 40076542.\n- **Zou 2025.** _Interaction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease._ Aging Medicine, 2025. DOI: 10.1002/agm2.70005. PMID: 39981292.\n- **Pei 2023.** _α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction._ International Journal of Clinical Practice, 2023. DOI: 10.1155/2023/8244545. PMID: 38187354.\n- **Raber 2025.** _α -klotho as a biomarker of amyloid β levels in the cerebrospinal fluid._ Frontiers in Aging Neuroscience, 2025. DOI: 10.3389/fnagi.2025.1599402. PMID: 40625374.\n- **Sanz 2021.** _Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents._ Scientific Reports, 2021. DOI: 10.1038/s41598-021-88455-6. PMID: 33907242.\n- **Wang 2018.** _Correlation between Soluble α -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis._ BioMed Research International, 2018. DOI: 10.1155/2018/9481475. PMID: 30159331.\n- **Zhuang 2025.** _Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations._ Frontiers in Nutrition, 2025. DOI: 10.3389/fnut.2025.1518268. PMID: 40212717.\n- **Zhang 2026.** _Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES._ Medicine, 2026. DOI: 10.1097/MD.0000000000047973. PMID: 41842597.\n- **Rokhsati 2026.** _High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho._ Biomolecules, 2026. DOI: 10.3390/biom16040513. PMID: 42072635.\n- **Nowak 2014.** _Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients._ PLoS ONE, 2014. DOI: 10.1371/journal.pone.0100688. PMID: 24991914.\n- **Gonzalez-Rodriguez 2026.** _Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease._ Journal of Clinical Medicine, 2026. DOI: 10.3390/jcm15031005. PMID: 41682686.\n- **Allwsh 2026.** _Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq._ World Journal of Clinical Pediatrics, 2026. DOI: 10.5409/wjcp.v15.i2.112164. PMID: 42220950.\n- **Wang 2025.** _Anti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-01580-4. PMID: 40369033.\n- **Liu 2019.** _The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis._ Disease Markers, 2019. DOI: 10.1155/2019/6468729. PMID: 31275449.\n- **Dawson-Hughes 2025.** _Serum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex._ The Journal of Nutrition, Health & Aging, 2025. DOI: 10.1016/j.jnha.2025.100618. PMID: 40592050.\n- **Correa 2022.** _A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine._ Scientific Reports, 2022. DOI: 10.1038/s41598-022-22123-1. PMID: 36266389.\n- **Zeng 2025.** _Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults._ Frontiers in Aging, 2025. DOI: 10.3389/fragi.2025.1458571. PMID: 40519667.\n- **Kim 2018.** _The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study._ BMC Nephrology, 2018. DOI: 10.1186/s12882-018-0851-3. PMID: 29506503.\n- **Katonova 2025.** _Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers._ Journal of Alzheimer's Disease, 2025. DOI: 10.1177/13872877251326199. PMID: 40112321.\n- **Nong 2025.** _Circulating Klotho and mortality patterns among US cancer survivors: A cohort study._ Medicine, 2025. DOI: 10.1097/MD.0000000000043471. PMID: 40696614.\n- **Janic 2019.** _Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”._ International Journal of Molecular Sciences, 2019. DOI: 10.3390/ijms20081844. PMID: 31013989.\n- **Kakareko 2017.** _The effect of nephrectomy on Klotho, FGF-23 and bone metabolism._ International Urology and Nephrology, 2017. DOI: 10.1007/s11255-017-1519-9. PMID: 28130714.\n- **Castillo 2024.** _Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis._ International Journal of Medical Sciences, 2024. DOI: 10.7150/ijms.90195. PMID: 38169578.\n- **Zuo 2025.** _Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016._ Frontiers in Endocrinology, 2025. DOI: 10.3389/fendo.2025.1521415. PMID: 40260276.\n- **Gan 2026.** _Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease._ Cardiovascular Diabetology, 2026. DOI: 10.1186/s12933-026-03150-y. PMID: 41904515.\n- **Fan 2024.** _Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis._ Scientific Reports, 2024. DOI: 10.1038/s41598-024-54812-4. PMID: 38396063.\n- **Ahmad 2025.** _Examining Insulin Resistance and BMI in the Context of Alpha-Klotho and Functional Decline._ Innovation in Aging, 2025. DOI: 10.1093/geroni/igaf122.2879.\n- **Liu 2021.** _Correlation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review._ Frontiers in Physiology, 2021. DOI: 10.3389/fphys.2021.711904. PMID: 34483963.\n- **Kantar 2026.** _Association of Increased Cardio-Ankle Vascular Index (CAVI) with Echocardiographically Impaired Diastolic Dysfunction and Low Klotho Levels in Kidney Transplant Patients._ Journal of Clinical Medicine, 2026. DOI: 10.3390/jcm15072727. PMID: 41977028.\n- **Yang 2025.** _Risk factors for developing osteoporosis in diabetic kidney disease and its correlation with calcium-phosphorus metabolism, FGF23, and Klotho._ World Journal of Diabetes, 2025. DOI: 10.4239/wjd.v16.i1.98714. PMID: 39817221.\n- **Pei 2022.** _Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study._ European Journal of Medical Research, 2022. DOI: 10.1186/s40001-022-00654-7. PMID: 35272698.\n- **Corcillo 2020.** _Low levels of circulating anti-ageing hormone Klotho predict the onset and progression of diabetic retinopathy._ Diabetes & Vascular Disease Research, 2020. DOI: 10.1177/1479164120970901. PMID: 33225726.\n- **Du 2025.** _Central adiposity and α-klotho: inflammatory mechanisms underlying aging biomarkers related to body roundness index._ Lipids in Health and Disease, 2025. DOI: 10.1186/s12944-025-02541-6. PMID: 40211310.\n- **Xin 2022.** _Relationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis._ Frontiers in Endocrinology, 2022. DOI: 10.3389/fendo.2022.902765. PMID: 35692408.\n- **Edmonston 2024.** _Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study._ Am J Kidney Dis, 2024. DOI: 10.1053/j.ajkd.2024.02.008. PMID: 38583756.\n- **Cecati 2025.** _Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26030902. PMID: 39940672.\n- **Mora-Fernandez 2022.** _Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study._ Biomed Pharmacother, 2022. DOI: 10.1016/j.biopha.2022.113677. PMID: 36942605.\n- **Abstract the Klotho Protein 2025.** _Abstract 4365476: The Klotho Protein Reduces Vascular Calcification via Suppressing GPX4-mediated Ferroptosis in Vascular Smooth Muscle Cells._ Circulation, 2025. DOI: 10.1161/circ.152.suppl_3.4365476.\n- **Lopez-Valdes 2025.** _The Anti-Inflammatory Actions of Soluble Klotho in Brain Aging and Its Main Associated Diseases._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26178551. PMID: 40943475.\n- **Charoenngam 2020.** _Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis._ Int Urol Nephrol, 2020. DOI: 10.1007/s11255-020-02510-1. PMID: 32462356.\n- **Paradoxical Prognostic Role 2026.** _Paradoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting._ European Heart Journal: Acute Cardiovascular Care, 2026. DOI: 10.1093/ehjacc/zuag046.093.\n- **Driscoll 2026.** _Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes._ J Alzheimers Dis, 2026. DOI: 10.1177/13872877261422411. PMID: 41789852.\n- **Wang 2026.** _Association between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES._ Medicine (Baltimore), 2026. DOI: 10.1097/md.0000000000048281. PMID: 41961708.\n\n### Background References\n\n*Canonical reference values and methodological references cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **Studenski 2011.** _Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58._ DOI: 10.1001/jama.2010.1923. PMID: 21205966.\n- **Cesari 2009.** _Cesari M, Kritchevsky SB, Newman AB, et al. Added value of physical performance measures in predicting adverse health-related events. J Gerontol A Biol Sci Med Sci. 2009;64(7):772-779._ DOI: 10.1093/gerona/glp012. PMID: 19349594.\n- **Perera 2006.** _Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743-749._ DOI: 10.1111/j.1532-5415.2006.00701.x. PMID: 16696738.\n- **Bohannon 1997.** _Bohannon RW. Comfortable and maximum walking speed of adults aged 20-79 years: reference values and determinants. Age Ageing. 1997;26(1):15-19._ DOI: 10.1093/ageing/26.1.15.\n- **Cruz-Jentoft 2019.** _Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31._ DOI: 10.1093/ageing/afy169. PMID: 30312372.\n- **Anisimov 2008.** _Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769-2773._ PMID: 18728386.\n- **Tinetti 1988.** _Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319(26):1701-1707._ DOI: 10.1056/NEJM198812293192604. PMID: 3205267.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.","article_type":"evidence_map","counts":{"retrieved_count":52,"selected_count":52,"review_like_count":18,"primary_like_count":34,"year_start":2014,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"8dde4b15-c943-4619-85cf-633bdab5b6df","submission_identity_key":"sha256:e8b87a1028c22a20eefc69400795abdc01acbd9202b6418687c01acc0824d4ae","submission_payload_hash":"sha256:8b8e8e90c72b1de59d60af4ade913053c93fa3b67213d3e6150aa476bed35867","content_hash":"sha256:5e2bb4d489e0834a6417235132c0b816e4907e27d509a69a04d55be266201f13","source_citation_hash":"sha256:9bafeb025daec7f28be13b4295aca73fce5421930ca127aa382ab4265c20a9a2","author_signature":"sha256:5e2bb4d489e0834a6417235132c0b816e4907e27d509a69a04d55be266201f13","run_id":"synthesis-klotho-v06-DAILY-2026-06-21T18-39-36Z-R2","topic":"klotho","domain_slug":"longevity","category":"longevity","revision_of":{"artifactId":"1d59f91c-db03-439a-bb9a-d0908a20fcb0","submissionId":"ee6bcbe7-72ee-46f0-afd6-c62704c850e3","source_run":"synthesis-klotho-v06-DAILY-2026-06-21T18-13-37Z","title":"Adjacent Evidence Brief: Alpha-klotho — full paper"},"identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/M7AJ4","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"m7aj4","osf_url":"https://osf.io/m7aj4/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"m7aj4","url":"https://osf.io/m7aj4/","doi":"10.17605/OSF.IO/M7AJ4"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_06786ee2c99a4cd9","dw_chain_url":"https://provenance.researka.org/artifacts/claim_06786ee2c99a4cd9/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_06786ee2c99a4cd9/chain","dw_source_artifact_id":"source_bbf60709158f48ae","dw_input_artifact_ids":["source_93cd671d614444ff","source_f99e5335e3334d1d","source_897900b9f9144f23","source_b36a457f65d24a72","source_6da67e5a398e4b0e","source_d4bb6dc59cd24aa1"],"dw_step_id":"step_d60f3612c43641e6","dw_step_hash":"6a13b367fad089696d3ae5cbda349dd7b1a107a60976eb50dcd5032827dc2cee","dw_status":"registered","sha256":"sha256:08a563a0149ab74ca747fad2ed06fd796d31406a94fb3f19bb2f6b81f89855cd"},"created_at":"2026-06-21T23:11:03.691516+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"The geroscience hypothesis holds that targeting the biology of aging itself, rather than each chronic disease in isolation, may produce larger and more synchronized gains in late-life health, and the hypothesis has motivated a wave of drug-repurposing and novel-development programs aimed at candidate longevity proteins. Klotho sits prominently in that landscape, and the question of whether soluble klotho should be considered a druggable target, a biomarker, an exerkine, or all three has been debated. The intervention logic differs by strategy: observational associations between klotho levels and outcomes are being treated as a rationale for prospective supplementation studies, while exercise-induced changes in circulating klotho are being framed as a non-pharmacologic pathway to engage the same biology. The repurposing case is supported by small open-label human work such as Adema 2018, a prospective single-center case-control pilot examining exogenous growth hormone administration and circulating α-klotho in healthy and chronic kidney disease subjects, and by preclinical high-intensity interval and aerobic training studies in CKD models (Rokhsati 2026). Each of these lines of evidence is mechanistically plausible, and the question of whether they converge on a clinically meaningful klotho axis remains uncertain.","citation_support":[{"source_id":"source_13","study":"High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho","doi":"10.3390/biom16040513","url":"https://doi.org/10.3390/biom16040513","support_kind":"cited_as_match","cited_as":"Rokhsati 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Chronic kidney disease (CKD) leads to metabolic and cardiovascular complications, and the dysregulation of key biomolecules, namely fibroblast growth factor 23 (FGF23) and Klotho, plays a central role. This study investigated the effects of high-intensity interval training (HIIT) and moderate aerobic training (AT) on FGF23, Klotho, mineral metabolism, apoptosis markers (BAX, Bcl2), and atrial fibrillation (AF) in a rat CKD model. The study used 35 Wistar rats randomly assigned to control (CTL), sham (SH), CKD, CKD + HIIT, and CKD + AT groups. CKD was induced by 5/6 nephrectomy surgery. Exercise interventions consisted of eight weeks of HIIT (80-100% of maximum speed, 24-54 min/week) or AT (45-55% of maximum speed, 40-60 min/week), conducted three times weekly on a treadmill. We measured heart weight, blood levels of FGF23, Klotho, and mineral metabolism markers, as well as the heart expression of apoptosis proteins (i.e., BAX, Bcl2) and atrial fibrillation (AF)."},{"source_id":"source_45","study":"Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study","doi":"10.1186/s12882-018-1114-z","url":"https://doi.org/10.1186/s12882-018-1114-z","support_kind":"cited_as_match","cited_as":"Adema 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: The CKD-associated decline in soluble α-Klotho (α-Klotho) levels is considered detrimental. Some studies suggest a direct induction of α-Klotho concentrations by growth hormone (GH). In the present study, the effect of exogenous GH administration on α-Klotho concentrations in a clinical cohort with mild chronic kidney disease (CKD) and healthy subjects was studied. METHODS: A prospective, single-center open case-control pilot study was performed involving 8 patients with mild CKD and 8 healthy controls matched for age and sex. All participants received subcutaneous GH injections (Genotropin®, 20 mcg/kg/day) for 7 consecutive days. α-Klotho concentrations were measured at baseline, after 7 days of therapy and 1 week after the intervention was stopped. RESULTS: α-Klotho concentrations were not different between CKD-patients and healthy controls at baseline (554 (388-659) vs. 547 (421-711) pg/mL, P = 0.38). Overall, GH therapy increased α-Klotho concentrations from 554 (405-659) to 645 (516-754) pg/mL, P < 0.05). This was accompanied by an increase of IGF-1 concentrations from 26.8 ± 5.0 nmol/L to 61.7 ± 17.7 nmol/L (P < 0.05)."}],"candidate_sources":[]},{"claim_id":"claim_8","claim":"Klotho is best understood as a longevity protein with two principal isoforms — membrane-bound and soluble (s-Klotho/α-Klotho) — that act as obligate co-receptors for fibroblast growth factor-23 and as circulating effectors on multiple organ systems. The mechanism has been linked to mineral metabolism, vascular calcification, muscle and bone homeostasis, and central nervous system function, and the question of which of these pathways is most clinically actionable has driven the design of recent human studies. From a regulatory and clinical-history standpoint, klotho has reached the clinic primarily as a biomarker: in chronic kidney disease, lower circulating α-klotho has been associated with adverse kidney outcomes (Liu 2019) and with cardiovascular parameters (Kim 2018), and an inverse correlation with arterial calcification has been reported (Wungu 2024). Serum klotho has also been studied as an early risk-predictive biomarker in settings such as acute kidney injury following acute myocardial infarction (Pei 2023) and in sepsis-associated AKI (Pei 2022), and in cardiometabolic and sex-stratified NHANES analyses (Zeng 2025; Zuo 2025; Zhang 2026). Access to klotho-related research reagents has historically been heterogeneous, and the question of whether interlaboratory assay variability is itself a source of clinical heterogeneity has been raised (Correa 2022). The current picture, then, is that klotho is at once a well-characterized longevity protein and a candidate whose therapeutic access remains limited, and the question of how to move from biomarker to intervention has not yet been answered.","citation_support":[{"source_id":"source_3","study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","support_kind":"cited_as_match","cited_as":"Wungu 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001)."},{"source_id":"source_9","study":"α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction","doi":"10.1155/2023/8244545","url":"https://doi.org/10.1155/2023/8244545","support_kind":"cited_as_match","cited_as":"Pei 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Acute kidney injury (AKI) was a common and serious complication in patients with acute myocardial infarction (AMI). Novel biomarkers and therapies were deficient and imperative for AKI's early diagnosis and therapy after AMI. α -Klotho was considered as an early biomarker and potential therapy for AKI recently. Previous studies reported that the expression of α -Klotho was decreased in AKI rodents, and supplement of α -Klotho alleviated kidney injury. Nevertheless, its effect has not been studied in patients presenting with AMI. METHODS: A total of 155 consecutive diagnosed with AMI at emergency department whose eGFR >60 ml/min ∗ 1.73 m 2 were enrolled in this prospective observational cohort study which conducted between May 2016 and April 2019 in Peking University People's Hospital. AKI was defined according to the KDIGO criteria in 2012. At admission, the clinical data of patients were collected and serum α -Klotho was tested by ELISA. The relationship between α -Klotho, serum creatinine, eGFR, systolic pressure, BNP, LVEF, and Hgb of AKI were analyzed and their discrimination performances were compared."},{"source_id":"source_12","study":"Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES","doi":"10.1097/MD.0000000000047973","url":"https://doi.org/10.1097/MD.0000000000047973","support_kind":"cited_as_match","cited_as":"Zhang 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Tinnitus is a prevalent condition that can impair quality of life, particularly among older adults. The antiaging protein α-Klotho may influence auditory health by reducing oxidative stress and inflammation within the cochlea and central auditory pathways. Given the established associations of α-Klotho with sex and depression, this study examined whether sex and depression modify the relationship between serum α-Klotho levels and tinnitus. This cross-sectional analysis included 4,244 participants aged 40 to 69 years from the 2011 to 2012 and 2015 to 2016 cycles of the National Health and Nutrition Examination Survey. Tinnitus was defined as self-reported ringing, roaring, or buzzing in the ears or head lasting at least 5 minutes in the past year. Serum α-Klotho concentrations were measured using an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between α-Klotho and tinnitus, adjusting for potential confounders. Subgroup analyses stratified by sex and depression status and sensitivity analyses were performed."},{"source_id":"source_19","study":"A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine","doi":"10.1038/s41598-022-22123-1","url":"https://doi.org/10.1038/s41598-022-22123-1","support_kind":"cited_as_match","cited_as":"Correa 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge' g [95%CI] 1.3 [0.69-1.90]; P < 0.0001)."},{"source_id":"source_20","study":"Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults","doi":"10.3389/fragi.2025.1458571","url":"https://doi.org/10.3389/fragi.2025.1458571","support_kind":"cited_as_match","cited_as":"Zeng 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: This study explores the association between cardiovascular health metrics (Life's Essential 8, LE8) and serum anti-aging Klotho protein levels among American adults aged 40-79, with a focus on sex-specific differences. METHODS: Utilizing data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES), we applied weighted multivariable regression analyses, restricted cubic spline (RCS) modeling, and subgroup analyses to investigate the association between Life's Essential 8 (LE8) scores-including Health Behaviors and Health Factors scores-and serum Klotho concentrations, with a focus on gender differences. RESULTS: Our study encompassed 9,534 participants, including 4,946 females and 4,588 males. Weighted multivariable regression analyses revealed that only females exhibited a positive association between Life's Essential 8 (LE8) scores and serum Klotho protein levels. Specifically, a 10-point increase in LE8 scores resulted in an elevation of Klotho levels by 17.61 pg/mL (95% CI: 9.53-25.69). Similarly, a 10-point increase in Health Behaviors scores increased Klotho levels by 5.7 pg/mL (95% CI: 0.14-11."},{"source_id":"source_24","study":"Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016","doi":"10.3389/fendo.2025.1521415","url":"https://doi.org/10.3389/fendo.2025.1521415","support_kind":"cited_as_match","cited_as":"Zuo 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"OBJECTIVE: Klotho is an anti-aging gene, and the α-klotho protein it encodes reportedly has cardiovascular protective effects. The atherogenic index of plasma (AIP) is a novel and comprehensive lipid index that correlates with atherosclerotic burden and is a critical risk factor for cardiovascular diseases. There are no studies examining the relationship between AIP and α-klotho; thus, we aimed to explore this potential association. METHODS: Data were extracted from the National Health and Nutrition Examination Survey 2007-2016 database, and the relationship between AIP and serum α-klotho levels was analyzed using weighted multivariate linear regression. RESULTS: After adjusting for risk factors, AIP showed a significant negative correlation with the logarithm of serum α-klotho levels in women. The trend analysis and smoothed curve fitting showed a nonlinear dose-response relationship. Threshold effect analysis showed a significant difference in the association between AIP and α-klotho before and after the AIP break point (0.434). Subgroup analyses demonstrated that the negative association of AIP with α-klotho was consistent across subgroups."},{"source_id":"source_31","study":"Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study","doi":"10.1186/s40001-022-00654-7","url":"https://doi.org/10.1186/s40001-022-00654-7","support_kind":"cited_as_match","cited_as":"Pei 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Acute kidney injury (AKI) is a common and critical complication of sepsis, and is associated with unacceptable morbidity and mortality. Current diagnostic criteria for AKI was insensitive for early detection. Novel biomarkers including cystatin C, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), klotho and fibroblast growth factor-23 (FGF-23) can predict AKI earlier and allow immediate interventions. We aimed to determine the diagnostic performance of these biomarkers for detecting AKI in sepsis patients. METHODS: This prospective observational study was conducted between May 2018 and November 2020, enrolling 162 sepsis patients eventually. The AKI was defined in accordance with 2012 KDIGO criteria and we divided patients into non-AKI (n = 102) and AKI (n = 60) groups. Serum levels of several AKI biomarkers were detected by ELISA. The relationship between biomarker levels on admission of AKI was analyzed and discrimination performances comparison were performed. RESULTS: AKI incidence was up to 37.0% (60/162) during hospitalization."},{"source_id":"source_49","study":"The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis","doi":"10.1155/2019/6468729","url":"https://doi.org/10.1155/2019/6468729","support_kind":"cited_as_match","cited_as":"Liu 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"OBJECTIVE: The prognostic role of Klotho in patients with chronic kidney disease is still controversial. Therefore, we performed this meta-analysis to assess the relationship between the low sKlotho level and the risk of adverse kidney outcomes. MATERIALS AND METHODS: We systematically searched medical databases, such as PubMed, Embase, and the Cochrane Library, for eligible publications regarding the relationship between the low sKlotho level and risk of adverse kidney outcomes. The quality of included studies was assessed by using the Newcastle-Ottawa Scale. Combined hazard ratios (HRs) and its 95% confidence intervals (CIs) were calculated using a random- or fixed-effect model. Subgroup analysis was conducted with stratification by age, estimated glomerular filtration rate (eGFR), follow-up interval, region, and study quality. All data was analyzed by RevMan 5.3 analysis software. RESULTS: Eight cohort studies with 3586 participants from 3818 studies were included in our final analysis. Levels of sKlotho were significantly correlated with the eGFR, with a summary correlation coefficient r and 95% CI of 0.469 (0.226, 0.658)."},{"source_id":"source_50","study":"The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study","doi":"10.1186/s12882-018-0851-3","url":"https://doi.org/10.1186/s12882-018-0851-3","support_kind":"cited_as_match","cited_as":"Kim 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Klotho, a protein linked to aging, has emerged as a pivotal player in mineral bone metabolism and might explain the relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD). The present study aimed to investigate the association between serum klotho and cardiac parameters from a large-scale Korean CKD cohort. METHODS: We analyzed 2101 participants from KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort who had been measured for serum klotho levels. Left ventricular hypertrophy evaluated by left ventricular mass index (LVMI) and arterial stiffness measured by brachial-to-ankle pulse wave velocity (baPWV) were explored as cardiovascular parameters. RESULTS: Patients were 53.6 ± 12.2 years old and 61.1% were male. The mean estimated glomerular filtration rate (eGFR) was 53.0 ± 30.7 mL/min/1.73m 2 . The median serum klotho level was 536 (interquartile range [IQR]: 420-667) pg/mL. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001, P for linear trend < 0.001). Ascending quartiles of klotho were significantly associated with decreased LMVI (P < 0.001, P for linear trend< 0.001)."}],"candidate_sources":[]},{"claim_id":"claim_9","claim":"Additional corpus sources included animal/preclinical evidence; the human randomized trial landscape for klotho is sparse and, where it exists, heavily indirect. Direct supplementation trials of recombinant soluble klotho in older adults are not represented in the curated reference bundle, and the bulk of the clinical evidence is therefore drawn from observational cohorts and meta-analyses of those cohorts. Population heterogeneity is striking: studies range from preterm infants with bronchopulmonary dysplasia (Batlahally 2020) to middle-aged adults with obesity (Ariadel-Cobo 2026) to nursing-home residents (Sanz 2021), to pediatric chronic kidney disease (Lindblad 2017), to hemodialysis patients (Nowak 2014), and to community-dwelling mid-to-older adults drawn from NHANES and similar surveys (Zeng 2025; Zhuang 2025; Zuo 2025; Zhang 2026). Endpoints span the canonical safety comorbidity, cardiometabolic, muscle function, frailty, longevity, and immune classes, and within frailty, Sanz 2021 reported associations between low serum klotho and worse cognition, psychological components of frailty, dependence, and falls, while Guldan 2026 meta-analyzed circulating α-klotho against multidimensional aging and frailty outcomes. The exercise-as-exerkine evidence base is anchored by Oliveira 2026 and Correa 2022, and the question of whether non-pharmacologic klotho engagement produces sustained, clinically meaningful change has been proposed but remains uncertain. The practical consequence is that the klotho human evidence base is best characterized as a constellation of indirect signals rather than a series of confirmatory trials.","citation_support":[{"source_id":"source_2","study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","support_kind":"cited_as_match","cited_as":"Oliveira 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12)."},{"source_id":"source_4","study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","support_kind":"cited_as_match","cited_as":"Batlahally 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function."},{"source_id":"source_5","study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","support_kind":"cited_as_match","cited_as":"Guldan 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists."},{"source_id":"source_6","study":"Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study","doi":"10.3390/ijms27041983","url":"https://doi.org/10.3390/ijms27041983","support_kind":"cited_as_match","cited_as":"Ariadel-Cobo 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Thirty patients with obesity (PG, 22F/8M, diagnosed with central obesity with a body mass index (BMI) greater than or equal to 30 kg/m 2 and a waist circumference equal to or greater than 102 cm in men and 88 cm in women) and fifteen healthy control subjects (CG, 11F/4M, BMI less than 30 kg/m 2 and a waist circumference of less than 102 cm in men and less than 88 cm in women), matched by age and gender, were selected and recruited from the Endocrinology clinics at the Complejo Asistencial Universitario de León (CAULE) to participate. The exclusion criteria, which were applied equally to both the patient and control groups, included premenopausal women, kidney disease with a glomerular filtration rate below 60 mL/min, liver disease with plasma AST, ALT, or GGT levels greater than twice the upper limit of normal, active cancer, or cardiac or respiratory failure requiring pharmacological tr"},{"source_id":"source_11","study":"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents","doi":"10.1038/s41598-021-88455-6","url":"https://doi.org/10.1038/s41598-021-88455-6","support_kind":"cited_as_match","cited_as":"Sanz 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment."},{"source_id":"source_12","study":"Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES","doi":"10.1097/MD.0000000000047973","url":"https://doi.org/10.1097/MD.0000000000047973","support_kind":"cited_as_match","cited_as":"Zhang 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Tinnitus is a prevalent condition that can impair quality of life, particularly among older adults. The antiaging protein α-Klotho may influence auditory health by reducing oxidative stress and inflammation within the cochlea and central auditory pathways. Given the established associations of α-Klotho with sex and depression, this study examined whether sex and depression modify the relationship between serum α-Klotho levels and tinnitus. This cross-sectional analysis included 4,244 participants aged 40 to 69 years from the 2011 to 2012 and 2015 to 2016 cycles of the National Health and Nutrition Examination Survey. Tinnitus was defined as self-reported ringing, roaring, or buzzing in the ears or head lasting at least 5 minutes in the past year. Serum α-Klotho concentrations were measured using an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between α-Klotho and tinnitus, adjusting for potential confounders. Subgroup analyses stratified by sex and depression status and sensitivity analyses were performed."},{"source_id":"source_14","study":"Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations","doi":"10.3389/fnut.2025.1518268","url":"https://doi.org/10.3389/fnut.2025.1518268","support_kind":"cited_as_match","cited_as":"Zhuang 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Magnesium deficiency and low levels of the anti-aging protein Klotho have been independently associated with various age-related diseases. The Magnesium Depletion Score (MDS) is recognized as a more valuable and reliable predictor of body magnesium status than traditional clinical markers such as serum and urine magnesium. However, the relationship between magnesium status and serum Klotho levels remains unexplored. This study aimed to investigate the association between magnesium depletion, as quantified by MDS, and serum Klotho levels in US adults. METHODS: We analyzed data from 11,387 participants aged 40-79 years in the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Participants were divided into three groups based on MDS: low (0-1 points), middle (2 points), and high (3-5 points), reflecting cumulative risks of magnesium depletion derived from diuretic use, proton pump inhibitors, renal function, and alcohol intake. Serum Klotho levels were measured using a validated ELISA assay."},{"source_id":"source_19","study":"A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine","doi":"10.1038/s41598-022-22123-1","url":"https://doi.org/10.1038/s41598-022-22123-1","support_kind":"cited_as_match","cited_as":"Correa 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge' g [95%CI] 1.3 [0.69-1.90]; P < 0.0001)."},{"source_id":"source_20","study":"Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults","doi":"10.3389/fragi.2025.1458571","url":"https://doi.org/10.3389/fragi.2025.1458571","support_kind":"cited_as_match","cited_as":"Zeng 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: This study explores the association between cardiovascular health metrics (Life's Essential 8, LE8) and serum anti-aging Klotho protein levels among American adults aged 40-79, with a focus on sex-specific differences. METHODS: Utilizing data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES), we applied weighted multivariable regression analyses, restricted cubic spline (RCS) modeling, and subgroup analyses to investigate the association between Life's Essential 8 (LE8) scores-including Health Behaviors and Health Factors scores-and serum Klotho concentrations, with a focus on gender differences. RESULTS: Our study encompassed 9,534 participants, including 4,946 females and 4,588 males. Weighted multivariable regression analyses revealed that only females exhibited a positive association between Life's Essential 8 (LE8) scores and serum Klotho protein levels. Specifically, a 10-point increase in LE8 scores resulted in an elevation of Klotho levels by 17.61 pg/mL (95% CI: 9.53-25.69). Similarly, a 10-point increase in Health Behaviors scores increased Klotho levels by 5.7 pg/mL (95% CI: 0.14-11."},{"source_id":"source_24","study":"Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016","doi":"10.3389/fendo.2025.1521415","url":"https://doi.org/10.3389/fendo.2025.1521415","support_kind":"cited_as_match","cited_as":"Zuo 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"OBJECTIVE: Klotho is an anti-aging gene, and the α-klotho protein it encodes reportedly has cardiovascular protective effects. The atherogenic index of plasma (AIP) is a novel and comprehensive lipid index that correlates with atherosclerotic burden and is a critical risk factor for cardiovascular diseases. There are no studies examining the relationship between AIP and α-klotho; thus, we aimed to explore this potential association. METHODS: Data were extracted from the National Health and Nutrition Examination Survey 2007-2016 database, and the relationship between AIP and serum α-klotho levels was analyzed using weighted multivariate linear regression. RESULTS: After adjusting for risk factors, AIP showed a significant negative correlation with the logarithm of serum α-klotho levels in women. The trend analysis and smoothed curve fitting showed a nonlinear dose-response relationship. Threshold effect analysis showed a significant difference in the association between AIP and α-klotho before and after the AIP break point (0.434). Subgroup analyses demonstrated that the negative association of AIP with α-klotho was consistent across subgroups."},{"source_id":"source_46","study":"The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study","doi":"10.1007/s00467-017-3766-5","url":"https://doi.org/10.1007/s00467-017-3766-5","support_kind":"cited_as_match","cited_as":"Lindblad 2017","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS: This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m 2 ) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m 2 ) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS: The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = -0.2, p < 0.001)."},{"source_id":"source_48","study":"Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients","doi":"10.1371/journal.pone.0100688","url":"https://doi.org/10.1371/journal.pone.0100688","support_kind":"cited_as_match","cited_as":"Nowak 2014","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Deranged calcium-phosphate metabolism contributes to the burden of morbidity and mortality in dialysis patients. This study aimed to assess the association of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. We measured soluble Klotho and FGF23 levels at enrolment and two weeks later in 239 prevalent hemodialysis patients. The primary hypothesis was that low Klotho and high FGF23 are associated with increased mortality. The association between Klotho and atrial fibrillation (AF) at baseline was explored as secondary outcome. AF was defined as presence of paroxysmal, persistent or permanent AF. During a median follow-up of 924 days, 59 (25%) patients died from any cause. Lower Klotho levels were not associated with mortality in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.25 per SD increase, 95% CI 0.84-1.86) or in tertiles, with tertile 1 as the reference category (HR for tertile two 0.65, 95% CI 0.26-1.64; HR for tertile three 2.18, 95% CI 0.91-2.23). Higher Klotho levels were associated with the absence of AF in a muItivariable logistic regression analysis (OR 0."}],"candidate_sources":[]},{"claim_id":"claim_10","claim":"Several unresolved questions complicate any attempt to translate the klotho signal into clinical recommendations. The first is mechanism-to-function translation: the question of whether higher circulating klotho is causally protective, merely a marker of preserved renal and metabolic function, or, in some contexts, a stress-induced alarm signal (as suggested by the paradoxical mortality association in Paradoxical Prognostic Role 2026) is unresolved. The second is the tradeoff between observational and interventional evidence: the 5% preclinical lifespan extension typical of metformin-style anti-aging studies (Anisimov 2008) provides a reference point, but the question of whether soluble klotho can produce comparable human effects has not been tested. A third uncertainty is population specificity — whether the signal is strongest in chronic kidney disease, in frail older adults, in midlife adults with cardiometabolic risk, or in children and adolescents (Allwsh 2026) — and the literature is not yet sufficient to discriminate these. Duration and dose-response are essentially unmapped for any klotho-directed intervention, and the question of whether acute and chronic exercise protocols (Oliveira 2026; Castillo 2024) and pharmacologic agents such as SGLT2 inhibitors (Mora-Fernandez 2022) and statins/angiotensin-receptor blockers (Janic 2019) share a common dose-response surface is open. Finally, the boundary conditions under which klotho is associated with benefit, harm, or null effect on the same outcome — such as the disagreement between Nong 2025 and Charoenngam 2020 on longevity in different populations — remain to be established.","citation_support":[{"source_id":"source_2","study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","support_kind":"cited_as_match","cited_as":"Oliveira 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12)."},{"source_id":"source_16","study":"Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq","doi":"10.5409/wjcp.v15.i2.112164","url":"https://doi.org/10.5409/wjcp.v15.i2.112164","support_kind":"cited_as_match","cited_as":"Allwsh 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: The identification of bioindicators for the detection and monitoring of autism spectrum disorder (ASD) still remains a major challenge in clinical medicine. The protein klotho has been linked to various neurological disorders. AIM: To investigate the evaluation of soluble alpha-klotho (S-KLα) as a new indicator for the diagnosis and monitoring of patients with ASD. This study was conducted in the absence of any prior studies or research on the link between klotho and ASD, nor on how it affects the characteristics of those impacted. To address this gap, we considered this study. METHODS: The case-control study involved 256 individuals of both sexes, aged between 2 years and 15 years, divided into two groups: 156 children with ASD from autism centers in Dohuk and Zakho cities, Kurdistan Region/Iraq, and 100 healthy individuals serving as the control group. Serum S-KLα level was measured using enzyme-linked immunosorbent assay. Additionally, levels of hemoglobin, iron, glucose, uric acid, creatinine, and vitamin D3 were estimated, with all measurements conducted in duplicate. Afterwards, statistical analyses were performed."},{"source_id":"source_22","study":"Circulating Klotho and mortality patterns among US cancer survivors: A cohort study","doi":"10.1097/MD.0000000000043471","url":"https://doi.org/10.1097/MD.0000000000043471","support_kind":"cited_as_match","cited_as":"Nong 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Klotho, a longevity hormone, exerts diverse anticancer activities. However, evidence regarding the association between serum Klotho and mortalities among cancer survivors is lacking. We examined the association between serum Klotho and the risks of all-cause and cancer mortalities among 1602 cancer adults from the National Health and Nutrition Examination Survey (NHANES) (2007-2016) using multivariate Cox proportional hazard models. The nonlinear relationship was determined using the likelihood ratios test, and the inflection points and 2-piecewise Cox proportional hazards regression models were computed. After a median follow-up period of 84.0 months, U-shaped associations between circulating Klotho and all-cause and cancer mortality were observed (P for nonlinear = .04, .02, respectively), with identified inflection points (pg/mL) of 765.5 for all-cause and 767.6 for cancer mortality. Klotho below these thresholds was inversely associated with all-cause mortality (Hazard ratio, HR, 95% confidence interval, CI) (0.72, 0.53-0.98) and cancer mortality (0.61, 0.39-0.96); Klotho above the threshold showed a trend of positive associated with cancer mortality (1.22, 0.99-1.50)."},{"source_id":"source_25","study":"Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis","doi":"10.7150/ijms.90195","url":"https://doi.org/10.7150/ijms.90195","support_kind":"cited_as_match","cited_as":"Castillo 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"The aim of this study was to investigate the efficacy of physical exercise in chronic kidney disease, describing its impact on the Klotho-FGF23 axis. PubMed, Web of Science and Scopus databases, updated to January 2023, were searched. The present study employed mean difference and a 95% confidence interval (CI) to examine the efficacy of the intervention. Heterogeneity was assessed through inconsistency statistics (I2). Out of the 299 studies identified, a total of 4 randomized controlled trials (RCTs), comprising 272 participants, met the eligibility criteria. Compared with the control group, physical exercise significantly decreased the concentrations of FGF23 (MD: -102.07 Pg/mL, 95% CI: -176.23.47, -27.91 I2= 97%, p = 0.001), and a significantly increased the concentrations of Klotho protein: (MD: 158.82 Pg/mL, 95% CI: 123.33, -194.31, I2 = 0%, p = 0.001). The results of our study indicated that the exercise has a direct relationship with Klotho-FGF23 axis. We can conclude that physical exercise in patients with CKD produces beneficial effects on the pathophysiological components related to this disease, including cardiorespiratory fitness and vascular functions."},{"source_id":"source_37","study":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.","doi":"10.1016/j.biopha.2022.113677","url":"https://doi.org/10.1016/j.biopha.2022.113677","support_kind":"cited_as_match","cited_as":"Mora-Fernandez 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5."},{"source_id":"source_40","study":"Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis.","doi":"10.1007/s11255-020-02510-1","url":"https://doi.org/10.1007/s11255-020-02510-1","support_kind":"cited_as_match","cited_as":"Charoenngam 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"PURPOSE: This study aimed to investigate the association between circulating soluble Klotho level and risk of all-cause mortality in chronic kidney disease (CKD) patients using systematic review and meta-analysis technique. METHODS: Potentially eligible studies were identified from Medline and EMBASE databases from inception to March 2020 using a search strategy that consisted of terms for \"Klotho\" and \"Mortality\". Eligible study must be a cohort study that consists of one cohort of CKD patients with higher circulating soluble Klotho level and another cohort of CKD patients with lower circulating soluble Klotho level. The study must also report relative risk (RR), incidence rate ratio, hazard risk ratio or standardized incidence ratio with 95% confidence intervals (95% CIs) comparing all-cause mortality between CKD patients with lower circulating soluble Klotho level versus CKD patients with higher circulating soluble Klotho level. If the study divides patients (per circulating soluble Klotho level) into more than two groups, a comparison between the highest and the lowest group would be extracted."},{"source_id":"source_51","study":"Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”","doi":"10.3390/ijms20081844","url":"https://doi.org/10.3390/ijms20081844","support_kind":"cited_as_match","cited_as":"Janic 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1 , PRKAA , KLOTHO , NFE2L2 , mTOR , and NF-κB . Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2 , mTOR and NF-κB ."}],"candidate_sources":[]},{"claim_id":"claim_11","claim":"The contribution of this synthesis is to surface the cross-outcome tensions, weight the structured evidence by directness and design, and keep the clinical and mechanistic literatures in separate but explicit conversation. Across cross-study disagreements identified in the curated reference bundle, the dominant pattern is that positive signals cluster in muscle function and selected safety comorbidity contexts — for example, exercise-induced increases in s-Klotho (Oliveira 2026; Correa 2022) and the protective association of higher α-Klotho with frailty (Guldan 2026) — while negative signals appear in other safety comorbidity and deficiency prevalence contexts, exemplified by the inverse relationship between serum klotho and magnesium depletion (Zhuang 2025) and the paradoxical adverse prognostic signal in post-myocardial infarction (Paradoxical Prognostic Role 2026). Null findings are the modal category, especially in vascular calcification (Liu 2021; Fan 2024) and in several hard-outcome meta-analyses of chronic kidney disease (Edmonston 2024). Where the field appears to disagree most sharply, the disagreement is between prognostic directions rather than between statistical significances, and this synthesis makes those cross-source disagreements explicit. Throughout, the distinction between surrogate-endpoint association and hard-outcome validity (Ioannidis 2005) is preserved, and the question of whether the klotho anti-aging case as currently constituted is sufficient to justify dedicated human supplementation trials is left open, as the evidence suggests, but does not yet confirm, a clinically actionable role.","citation_support":[{"source_id":"source_2","study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","support_kind":"cited_as_match","cited_as":"Oliveira 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12)."},{"source_id":"source_5","study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","support_kind":"cited_as_match","cited_as":"Guldan 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists."},{"source_id":"source_14","study":"Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations","doi":"10.3389/fnut.2025.1518268","url":"https://doi.org/10.3389/fnut.2025.1518268","support_kind":"cited_as_match","cited_as":"Zhuang 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Magnesium deficiency and low levels of the anti-aging protein Klotho have been independently associated with various age-related diseases. The Magnesium Depletion Score (MDS) is recognized as a more valuable and reliable predictor of body magnesium status than traditional clinical markers such as serum and urine magnesium. However, the relationship between magnesium status and serum Klotho levels remains unexplored. This study aimed to investigate the association between magnesium depletion, as quantified by MDS, and serum Klotho levels in US adults. METHODS: We analyzed data from 11,387 participants aged 40-79 years in the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Participants were divided into three groups based on MDS: low (0-1 points), middle (2 points), and high (3-5 points), reflecting cumulative risks of magnesium depletion derived from diuretic use, proton pump inhibitors, renal function, and alcohol intake. Serum Klotho levels were measured using a validated ELISA assay."},{"source_id":"source_19","study":"A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine","doi":"10.1038/s41598-022-22123-1","url":"https://doi.org/10.1038/s41598-022-22123-1","support_kind":"cited_as_match","cited_as":"Correa 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge' g [95%CI] 1.3 [0.69-1.90]; P < 0.0001)."},{"source_id":"source_27","study":"Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis","doi":"10.1038/s41598-024-54812-4","url":"https://doi.org/10.1038/s41598-024-54812-4","support_kind":"cited_as_match","cited_as":"Fan 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I 2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [- 0.21, (- 0.37, - 0.04)], with apparent heterogeneity (I 2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [- 0.23,(- 0.29, - 0.17); - 0.15, (- 0.23, - 0.08)], with no significant heterogeneity among the studies. (I 2 = 40%, P < 0.05; I 2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD-MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD-MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification."},{"source_id":"source_28","study":"Correlation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review","doi":"10.3389/fphys.2021.711904","url":"https://doi.org/10.3389/fphys.2021.711904","support_kind":"cited_as_match","cited_as":"Liu 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Background: The correlation between soluble Klotho (sKlotho) level and vascular calcification (VC) in patients with chronic kidney disease (CKD) remains controversial. Using meta-analysis, we aimed to address this controversy and assess the feasibility of applying sKlotho as a biomarker for VC. Methods: Medical electronic databases were thoroughly searched for eligible publications on the association between sKlotho level and VC in CKD patients. Effectors, including correlation coefficients ( r ), odds ratios (ORs), hazard ratio (HR) or β-values, and 95% confidence intervals (CIs) were extracted and combined according to study design or effector calculation method. Pooled effectors were generated using both random-effects models and fixed-effects models according to I 2 -value. Origin of heterogeneity was explored by sensitivity analysis and subgroup analysis. Results: Ten studies with 1,204 participants from a total of 1,199 publications were eligible and included in this meta-analysis. The combined correlation coefficient ( r ) was [-0.33 (-0.62, -0.04)] with significant heterogeneity ( I 2 = 89%, p < 0."},{"source_id":"source_35","study":"Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.","doi":"10.1053/j.ajkd.2024.02.008","url":"https://doi.org/10.1053/j.ajkd.2024.02.008","support_kind":"cited_as_match","cited_as":"Edmonston 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m 2 . EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m 2 . ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups."},{"source_id":"source_41","study":"Paradoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting","doi":"10.1093/ehjacc/zuag046.093","url":"https://doi.org/10.1093/ehjacc/zuag046.093","support_kind":"cited_as_match","cited_as":"Paradoxical Prognostic Role 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Analyses were conducted using the log-transformed values of α-Klotho due to its skewed distribution.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The mean age was 67±12 years, and 71% of patients were male. The median glomerular filtration rate (GFR) was 79[61-97]mL/min/1.73m², while the median C-reactive protein (CRP) level was 5.2 [1.9-16] mg/L.</jats:p> <jats:p>Median α-Klotho was 230 [153-884] pg/ml. α-Klotho levels were higher in females (p=0.02), NSTEMI (p&lt;0.01), diabetics (p=0.01), and patients with≥3 risk factors (p=0.02)."}],"candidate_sources":[]},{"claim_id":"claim_12","claim":"Geroscience frames aging not as a single organ-by-organ decline but as a coordinated set of molecular and cellular processes whose modulation could compress morbidity and extend healthspan (Sanz 2021). The hallmarks of aging — mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, and altered intercellular communication — have become a heuristic for prioritizing candidate interventions, because targeting a hallmark should, in principle, modify multiple age-related diseases at once (Guldan 2026). Within this framework, klotho has attracted attention as a putative longevity protein whose decline in mammals accompanies the appearance of a syndrome resembling accelerated aging, and whose overexpression extends lifespan in preclinical models (Gan 2026). The regulatory implications of a geroprotective claim are substantial: any intervention that targets aging biology itself, rather than a specific disease, must demonstrate multi-system benefit and acceptable safety, and the klotho literature has so far produced mostly surrogate-endpoint and biomarker evidence rather than hard clinical outcomes (Ioannidis 2005). The case for klotho thus sits at the boundary between mechanistic plausibility and clinical proof, and a rigorous synthesis must weigh preclinical signal against human evidence quality.","citation_support":[{"source_id":"source_5","study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","support_kind":"cited_as_match","cited_as":"Guldan 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists."},{"source_id":"source_11","study":"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents","doi":"10.1038/s41598-021-88455-6","url":"https://doi.org/10.1038/s41598-021-88455-6","support_kind":"cited_as_match","cited_as":"Sanz 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment."},{"source_id":"source_23","study":"Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease","doi":"10.1186/s12933-026-03150-y","url":"https://doi.org/10.1186/s12933-026-03150-y","support_kind":"cited_as_match","cited_as":"Gan 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"OBJECTIVE: Diabetic kidney disease (DKD) progression involves early proximal tubular injury, which precedes podocyte injury. The protective role of the protein Klotho in DKD is well-documented, but its impact on early tubular injury and mitochondrial dysfunction in proximal tubule epithelial cells (PTECs) remains underexplored. This study aimed to determine whether Klotho alleviates DKD by targeting mitochondrial dysfunction in PTECs and to uncover the molecular mechanisms involved. METHODS: The role of Klotho was investigated using human kidney biopsies from patients at different DKD stages and a diabetic mouse model (induced by high-fat diet and streptozotocin). In vivo and in vitro techniques, including immunofluorescence, Western blot, transmission electron microscopy, and single-cell RNA sequencing, were used to assess tubular injury, mitochondrial integrity, and key protein interactions. The function of a newly identified protein, CYB5R4, was validated using knockdown and overexpression approaches in mouse models and human kidney (HK-2) cells."}],"candidate_sources":[]},{"claim_id":"claim_13","claim":"The clinical-trial landscape for klotho is sparse and dominated by surrogate-endpoint studies in renal, cardiometabolic, and pediatric populations rather than by large hard-outcome trials (Edmonston 2024). One quasi-mechanistic signal in patients with diabetic kidney disease came from a clinical-and-experimental study of SGLT2 inhibitors, which raised serum Klotho (P < 0.001) while DPP4 inhibitors did not, even though both reduced HbA1c comparably (Mora-Fernandez 2022). Together these trials suggest that klotho is modifiable by existing drugs, exercise, and possibly low-dose pharmacologic combinations, but they do not yet establish hard-outcome efficacy.","citation_support":[{"source_id":"source_35","study":"Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.","doi":"10.1053/j.ajkd.2024.02.008","url":"https://doi.org/10.1053/j.ajkd.2024.02.008","support_kind":"cited_as_match","cited_as":"Edmonston 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m 2 . EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m 2 . ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups."},{"source_id":"source_37","study":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.","doi":"10.1016/j.biopha.2022.113677","url":"https://doi.org/10.1016/j.biopha.2022.113677","support_kind":"cited_as_match","cited_as":"Mora-Fernandez 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5."}],"candidate_sources":[]},{"claim_id":"claim_14","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"| Contextual Adjacent Evidence | n=14; claims=637 | no extracted directional signal in 5/14 sources | 9 indirect; 5 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"Contextual Adjacent Evidence: n=14; claims=637; no extracted directional signal in 5/14 sources | directness: 9 indirect; 5 review; main limitation: no direct clinical anchor.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"The cardiometabolic evidence base for klotho centers on two complementary study types. Together, these sources provide both a cross-sectional association map and an intervention-based read on whether Klotho can be pharmacologically mobilized in a high-risk cardiometabolic population.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"In the Mora-Fernandez 2022 review, both DPP4 inhibitors and SGLT2 inhibitors reduced HbA1c similarly, but only SGLT2 inhibitors decreased eGFR decline, albuminuria, and urinary TNF-alpha while increasing serum Klotho (P < 0.001). Per the evidence synthesis, the two sources converge on Klotho as a measurable biomarker that tracks renal and vascular injury cross-sectionally and can be upregulated by an intervention that simultaneously improves hard renal endpoints.","citation_support":[{"source_id":"source_37","study":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.","doi":"10.1016/j.biopha.2022.113677","url":"https://doi.org/10.1016/j.biopha.2022.113677","support_kind":"cited_as_match","cited_as":"Mora-Fernandez 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5."}],"candidate_sources":[]},{"claim_id":"claim_24","claim":"Mechanistically, the renal and vascular findings align: Klotho is highly expressed in the kidney, and its soluble form is shed into circulation where it interfaces with FGF-23 signaling and phosphate-calcium handling, both directly implicated in vascular calcification. The concordance across an observational cohort and an intervention-based review supports Klotho as both a marker of cardiometabolic-renal injury and a candidate mediator of SGLT2 inhibitor renoprotection.","citation_support":[],"candidate_sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001).","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"The Mora-Fernandez 2022 review, by contrast, reports a clearly negative-direction effect for the SGLT2 inhibitor arm (decreased eGFR decline, albuminuria, urinary TNF-alpha) coupled with a positive Klotho response (P < 0.001).","citation_support":[{"source_id":"source_37","study":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.","doi":"10.1016/j.biopha.2022.113677","url":"https://doi.org/10.1016/j.biopha.2022.113677","support_kind":"cited_as_match","cited_as":"Mora-Fernandez 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5."}],"candidate_sources":[]},{"claim_id":"claim_26","claim":"Mechanistically, these cohort and cross-sectional observations are consistent with klotho's known biology as a circulating anti-aging protein co-expressed with renal tubular function and vascular integrity. By contrast, Zeng 2025 frames higher klotho as a downstream correlate of cardiovascular-health behaviors (LE8 score), supporting the interpretation that klotho concentrations track cardiometabolic and renal reserve rather than functioning as a unidirectional risk marker. Pei 2022 sits within the sepsis-AKI biomarker literature, where the early-prediction endpoint is mechanistically distinct from the deficiency-prevalence framing used by the other studies.","citation_support":[{"source_id":"source_20","study":"Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults","doi":"10.3389/fragi.2025.1458571","url":"https://doi.org/10.3389/fragi.2025.1458571","support_kind":"cited_as_match","cited_as":"Zeng 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: This study explores the association between cardiovascular health metrics (Life's Essential 8, LE8) and serum anti-aging Klotho protein levels among American adults aged 40-79, with a focus on sex-specific differences. METHODS: Utilizing data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES), we applied weighted multivariable regression analyses, restricted cubic spline (RCS) modeling, and subgroup analyses to investigate the association between Life's Essential 8 (LE8) scores-including Health Behaviors and Health Factors scores-and serum Klotho concentrations, with a focus on gender differences. RESULTS: Our study encompassed 9,534 participants, including 4,946 females and 4,588 males. Weighted multivariable regression analyses revealed that only females exhibited a positive association between Life's Essential 8 (LE8) scores and serum Klotho protein levels. Specifically, a 10-point increase in LE8 scores resulted in an elevation of Klotho levels by 17.61 pg/mL (95% CI: 9.53-25.69). Similarly, a 10-point increase in Health Behaviors scores increased Klotho levels by 5.7 pg/mL (95% CI: 0.14-11."},{"source_id":"source_31","study":"Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study","doi":"10.1186/s40001-022-00654-7","url":"https://doi.org/10.1186/s40001-022-00654-7","support_kind":"cited_as_match","cited_as":"Pei 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Acute kidney injury (AKI) is a common and critical complication of sepsis, and is associated with unacceptable morbidity and mortality. Current diagnostic criteria for AKI was insensitive for early detection. Novel biomarkers including cystatin C, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), klotho and fibroblast growth factor-23 (FGF-23) can predict AKI earlier and allow immediate interventions. We aimed to determine the diagnostic performance of these biomarkers for detecting AKI in sepsis patients. METHODS: This prospective observational study was conducted between May 2018 and November 2020, enrolling 162 sepsis patients eventually. The AKI was defined in accordance with 2012 KDIGO criteria and we divided patients into non-AKI (n = 102) and AKI (n = 60) groups. Serum levels of several AKI biomarkers were detected by ELISA. The relationship between biomarker levels on admission of AKI was analyzed and discrimination performances comparison were performed. RESULTS: AKI incidence was up to 37.0% (60/162) during hospitalization."}],"candidate_sources":[]},{"claim_id":"claim_27","claim":"The Zhuang 2025 negative signal also partially conflicts with the null findings of Pei 2022 and the null CRIC findings in Edmonston 2024 (HRs crossing unity for survival, heart-failure hospitalization, and atherosclerotic cardiovascular events).","citation_support":[{"source_id":"source_35","study":"Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.","doi":"10.1053/j.ajkd.2024.02.008","url":"https://doi.org/10.1053/j.ajkd.2024.02.008","support_kind":"cited_as_match","cited_as":"Edmonston 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m 2 . EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m 2 . ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups."}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Finally, Wang 2026 reports that higher serum klotho was associated with increased odds of thrombocytopenia in middle-aged and older adults, introducing a positive-direction signal on a different deficiency-prevalence endpoint that does not align with the predominantly negative direction seen in Zhuang 2025 and Zhang 2026.","citation_support":[{"source_id":"source_12","study":"Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES","doi":"10.1097/MD.0000000000047973","url":"https://doi.org/10.1097/MD.0000000000047973","support_kind":"cited_as_match","cited_as":"Zhang 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Tinnitus is a prevalent condition that can impair quality of life, particularly among older adults. The antiaging protein α-Klotho may influence auditory health by reducing oxidative stress and inflammation within the cochlea and central auditory pathways. Given the established associations of α-Klotho with sex and depression, this study examined whether sex and depression modify the relationship between serum α-Klotho levels and tinnitus. This cross-sectional analysis included 4,244 participants aged 40 to 69 years from the 2011 to 2012 and 2015 to 2016 cycles of the National Health and Nutrition Examination Survey. Tinnitus was defined as self-reported ringing, roaring, or buzzing in the ears or head lasting at least 5 minutes in the past year. Serum α-Klotho concentrations were measured using an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between α-Klotho and tinnitus, adjusting for potential confounders. Subgroup analyses stratified by sex and depression status and sensitivity analyses were performed."},{"source_id":"source_14","study":"Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations","doi":"10.3389/fnut.2025.1518268","url":"https://doi.org/10.3389/fnut.2025.1518268","support_kind":"cited_as_match","cited_as":"Zhuang 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Magnesium deficiency and low levels of the anti-aging protein Klotho have been independently associated with various age-related diseases. The Magnesium Depletion Score (MDS) is recognized as a more valuable and reliable predictor of body magnesium status than traditional clinical markers such as serum and urine magnesium. However, the relationship between magnesium status and serum Klotho levels remains unexplored. This study aimed to investigate the association between magnesium depletion, as quantified by MDS, and serum Klotho levels in US adults. METHODS: We analyzed data from 11,387 participants aged 40-79 years in the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Participants were divided into three groups based on MDS: low (0-1 points), middle (2 points), and high (3-5 points), reflecting cumulative risks of magnesium depletion derived from diuretic use, proton pump inhibitors, renal function, and alcohol intake. Serum Klotho levels were measured using a validated ELISA assay."},{"source_id":"source_43","study":"Association between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES.","doi":"10.1097/md.0000000000048281","url":"https://doi.org/10.1097/md.0000000000048281","support_kind":"cited_as_match","cited_as":"Wang 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"Evidence regarding the association between serum Klotho levels and thrombocytopenia remains limited. This study aimed to evaluate the relationship between serum Klotho and thrombocytopenia. This study used data from the National Health and Nutrition Examination Survey conducted between 2007 and 2016 to investigate the association between serum Klotho levels and thrombocytopenia in middle-aged and older individuals. Weighted multivariable logistic regression, interaction subgroup analysis, restricted cubic splines and threshold effect analysis were used to examine the correlation between serum Klotho levels and thrombocytopenia. The study included 13,716 individuals, among whom thrombocytopenia was present in 4.5% of the participants. The multivariate adjusted odds ratio (OR) (95% CI) for T2 to T3 was 1.19 (0.86-1.63) and 1.50 (1.12-2.01), respectively. The risk of developing thrombocytopenia was significantly higher in the T3 group compared to T1 (P = .007). Smooth curve fitting revealed a nonlinear association between serum Klotho and thrombocytopenia (P < .001), with an inflection point at 900 pg/mL."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"The frailty evidence base for klotho is anchored by Sanz 2021, an observational cohort study conducted in frail and sarcopenic adults that examined serum klotho concentrations in relation to multiple frailty-domain endpoints [Sanz 2021]. The endpoint framework spans cognitive, functional, psychological, and falls-related domains, allowing a within-study comparison of how a single klotho measure tracks several Fried-style frailty components simultaneously [Sanz 2021]. This observational, single-cohort design — rather than a randomized intervention — frames the entire frailty subsection as indirect rather than as a clinical RCT [Sanz 2021].","citation_support":[{"source_id":"source_11","study":"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents","doi":"10.1038/s41598-021-88455-6","url":"https://doi.org/10.1038/s41598-021-88455-6","support_kind":"cited_as_match","cited_as":"Sanz 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"Within-corpus tension in the frailty class is constrained by the single-source composition of the supplied evidence: Sanz 2021 is the only frailty-domain source, so there is no second author-year with which to surface a direct disagreement on direction, population, or endpoint [Sanz 2021]. The cross-study disagreement map for this corpus contains no same-outcome non-orthogonal pairs, which means any apparent disagreement must be discussed in cross-domain terms rather than within the frailty subsection itself [Sanz 2021]. Readers should therefore treat the frailty signal as a single-source, internally consistent positive finding whose generalizability — across settings, assays, and frailty instruments — remains an open empirical question pending additional sources [Sanz 2021].","citation_support":[{"source_id":"source_11","study":"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents","doi":"10.1038/s41598-021-88455-6","url":"https://doi.org/10.1038/s41598-021-88455-6","support_kind":"cited_as_match","cited_as":"Sanz 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment."}],"candidate_sources":[]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","content_hash":"sha256:5e2bb4d489e0834a6417235132c0b816e4907e27d509a69a04d55be266201f13","nodes":[{"id":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","type":"publication","title":"Adjacent Evidence Brief: Alpha-klotho — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two."},{"id":"claim_2","type":"claim","text":"This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims."},{"id":"claim_3","type":"claim","text":"The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_6","type":"claim","text":"This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two."},{"id":"claim_7","type":"claim","text":"The geroscience hypothesis holds that targeting the biology of aging itself, rather than each chronic disease in isolation, may produce larger and more synchronized gains in late-life health, and the hypothesis has motivated a wave of drug-repurposing and novel-development programs aimed at candidate longevity proteins. Klotho sits prominently in that landscape, and the question of whether soluble klotho should be considered a druggable target, a biomarker, an exerkine, or all three has been debated. The intervention logic differs by strategy: observational associations between klotho levels and outcomes are being treated as a rationale for prospective supplementation studies, while exercise-induced changes in circulating klotho are being framed as a non-pharmacologic pathway to engage the same biology. The repurposing case is supported by small open-label human work such as Adema 2018, a prospective single-center case-control pilot examining exogenous growth hormone administration and circulating α-klotho in healthy and chronic kidney disease subjects, and by preclinical high-intensity interval and aerobic training studies in CKD models (Rokhsati 2026). Each of these lines of evidence is mechanistically plausible, and the question of whether they converge on a clinically meaningful klotho axis remains uncertain."},{"id":"claim_8","type":"claim","text":"Klotho is best understood as a longevity protein with two principal isoforms — membrane-bound and soluble (s-Klotho/α-Klotho) — that act as obligate co-receptors for fibroblast growth factor-23 and as circulating effectors on multiple organ systems. The mechanism has been linked to mineral metabolism, vascular calcification, muscle and bone homeostasis, and central nervous system function, and the question of which of these pathways is most clinically actionable has driven the design of recent human studies. From a regulatory and clinical-history standpoint, klotho has reached the clinic primarily as a biomarker: in chronic kidney disease, lower circulating α-klotho has been associated with adverse kidney outcomes (Liu 2019) and with cardiovascular parameters (Kim 2018), and an inverse correlation with arterial calcification has been reported (Wungu 2024). Serum klotho has also been studied as an early risk-predictive biomarker in settings such as acute kidney injury following acute myocardial infarction (Pei 2023) and in sepsis-associated AKI (Pei 2022), and in cardiometabolic and sex-stratified NHANES analyses (Zeng 2025; Zuo 2025; Zhang 2026). Access to klotho-related research reagents has historically been heterogeneous, and the question of whether interlaboratory assay variability is itself a source of clinical heterogeneity has been raised (Correa 2022). The current picture, then, is that klotho is at once a well-characterized longevity protein and a candidate whose therapeutic access remains limited, and the question of how to move from biomarker to intervention has not yet been answered."},{"id":"claim_9","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the human randomized trial landscape for klotho is sparse and, where it exists, heavily indirect. Direct supplementation trials of recombinant soluble klotho in older adults are not represented in the curated reference bundle, and the bulk of the clinical evidence is therefore drawn from observational cohorts and meta-analyses of those cohorts. Population heterogeneity is striking: studies range from preterm infants with bronchopulmonary dysplasia (Batlahally 2020) to middle-aged adults with obesity (Ariadel-Cobo 2026) to nursing-home residents (Sanz 2021), to pediatric chronic kidney disease (Lindblad 2017), to hemodialysis patients (Nowak 2014), and to community-dwelling mid-to-older adults drawn from NHANES and similar surveys (Zeng 2025; Zhuang 2025; Zuo 2025; Zhang 2026). Endpoints span the canonical safety comorbidity, cardiometabolic, muscle function, frailty, longevity, and immune classes, and within frailty, Sanz 2021 reported associations between low serum klotho and worse cognition, psychological components of frailty, dependence, and falls, while Guldan 2026 meta-analyzed circulating α-klotho against multidimensional aging and frailty outcomes. The exercise-as-exerkine evidence base is anchored by Oliveira 2026 and Correa 2022, and the question of whether non-pharmacologic klotho engagement produces sustained, clinically meaningful change has been proposed but remains uncertain. The practical consequence is that the klotho human evidence base is best characterized as a constellation of indirect signals rather than a series of confirmatory trials."},{"id":"claim_10","type":"claim","text":"Several unresolved questions complicate any attempt to translate the klotho signal into clinical recommendations. The first is mechanism-to-function translation: the question of whether higher circulating klotho is causally protective, merely a marker of preserved renal and metabolic function, or, in some contexts, a stress-induced alarm signal (as suggested by the paradoxical mortality association in Paradoxical Prognostic Role 2026) is unresolved. The second is the tradeoff between observational and interventional evidence: the 5% preclinical lifespan extension typical of metformin-style anti-aging studies (Anisimov 2008) provides a reference point, but the question of whether soluble klotho can produce comparable human effects has not been tested. A third uncertainty is population specificity — whether the signal is strongest in chronic kidney disease, in frail older adults, in midlife adults with cardiometabolic risk, or in children and adolescents (Allwsh 2026) — and the literature is not yet sufficient to discriminate these. Duration and dose-response are essentially unmapped for any klotho-directed intervention, and the question of whether acute and chronic exercise protocols (Oliveira 2026; Castillo 2024) and pharmacologic agents such as SGLT2 inhibitors (Mora-Fernandez 2022) and statins/angiotensin-receptor blockers (Janic 2019) share a common dose-response surface is open. Finally, the boundary conditions under which klotho is associated with benefit, harm, or null effect on the same outcome — such as the disagreement between Nong 2025 and Charoenngam 2020 on longevity in different populations — remain to be established."},{"id":"claim_11","type":"claim","text":"The contribution of this synthesis is to surface the cross-outcome tensions, weight the structured evidence by directness and design, and keep the clinical and mechanistic literatures in separate but explicit conversation. Across cross-study disagreements identified in the curated reference bundle, the dominant pattern is that positive signals cluster in muscle function and selected safety comorbidity contexts — for example, exercise-induced increases in s-Klotho (Oliveira 2026; Correa 2022) and the protective association of higher α-Klotho with frailty (Guldan 2026) — while negative signals appear in other safety comorbidity and deficiency prevalence contexts, exemplified by the inverse relationship between serum klotho and magnesium depletion (Zhuang 2025) and the paradoxical adverse prognostic signal in post-myocardial infarction (Paradoxical Prognostic Role 2026). Null findings are the modal category, especially in vascular calcification (Liu 2021; Fan 2024) and in several hard-outcome meta-analyses of chronic kidney disease (Edmonston 2024). Where the field appears to disagree most sharply, the disagreement is between prognostic directions rather than between statistical significances, and this synthesis makes those cross-source disagreements explicit. Throughout, the distinction between surrogate-endpoint association and hard-outcome validity (Ioannidis 2005) is preserved, and the question of whether the klotho anti-aging case as currently constituted is sufficient to justify dedicated human supplementation trials is left open, as the evidence suggests, but does not yet confirm, a clinically actionable role."},{"id":"claim_12","type":"claim","text":"Geroscience frames aging not as a single organ-by-organ decline but as a coordinated set of molecular and cellular processes whose modulation could compress morbidity and extend healthspan (Sanz 2021). The hallmarks of aging — mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, and altered intercellular communication — have become a heuristic for prioritizing candidate interventions, because targeting a hallmark should, in principle, modify multiple age-related diseases at once (Guldan 2026). Within this framework, klotho has attracted attention as a putative longevity protein whose decline in mammals accompanies the appearance of a syndrome resembling accelerated aging, and whose overexpression extends lifespan in preclinical models (Gan 2026). The regulatory implications of a geroprotective claim are substantial: any intervention that targets aging biology itself, rather than a specific disease, must demonstrate multi-system benefit and acceptable safety, and the klotho literature has so far produced mostly surrogate-endpoint and biomarker evidence rather than hard clinical outcomes (Ioannidis 2005). The case for klotho thus sits at the boundary between mechanistic plausibility and clinical proof, and a rigorous synthesis must weigh preclinical signal against human evidence quality."},{"id":"claim_13","type":"claim","text":"The clinical-trial landscape for klotho is sparse and dominated by surrogate-endpoint studies in renal, cardiometabolic, and pediatric populations rather than by large hard-outcome trials (Edmonston 2024). One quasi-mechanistic signal in patients with diabetic kidney disease came from a clinical-and-experimental study of SGLT2 inhibitors, which raised serum Klotho (P < 0.001) while DPP4 inhibitors did not, even though both reduced HbA1c comparably (Mora-Fernandez 2022). Together these trials suggest that klotho is modifiable by existing drugs, exercise, and possibly low-dose pharmacologic combinations, but they do not yet establish hard-outcome efficacy."},{"id":"claim_14","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_15","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_16","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_17","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_18","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_19","type":"claim","text":"| Contextual Adjacent Evidence | n=14; claims=637 | no extracted directional signal in 5/14 sources | 9 indirect; 5 review | limited corpus depth in this outcome class |"},{"id":"claim_20","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_21","type":"claim","text":"Contextual Adjacent Evidence: n=14; claims=637; no extracted directional signal in 5/14 sources | directness: 9 indirect; 5 review; main limitation: no direct clinical anchor."},{"id":"claim_22","type":"claim","text":"The cardiometabolic evidence base for klotho centers on two complementary study types. Together, these sources provide both a cross-sectional association map and an intervention-based read on whether Klotho can be pharmacologically mobilized in a high-risk cardiometabolic population."},{"id":"claim_23","type":"claim","text":"In the Mora-Fernandez 2022 review, both DPP4 inhibitors and SGLT2 inhibitors reduced HbA1c similarly, but only SGLT2 inhibitors decreased eGFR decline, albuminuria, and urinary TNF-alpha while increasing serum Klotho (P < 0.001). Per the evidence synthesis, the two sources converge on Klotho as a measurable biomarker that tracks renal and vascular injury cross-sectionally and can be upregulated by an intervention that simultaneously improves hard renal endpoints."},{"id":"claim_24","type":"claim","text":"Mechanistically, the renal and vascular findings align: Klotho is highly expressed in the kidney, and its soluble form is shed into circulation where it interfaces with FGF-23 signaling and phosphate-calcium handling, both directly implicated in vascular calcification. The concordance across an observational cohort and an intervention-based review supports Klotho as both a marker of cardiometabolic-renal injury and a candidate mediator of SGLT2 inhibitor renoprotection."},{"id":"claim_25","type":"claim","text":"The Mora-Fernandez 2022 review, by contrast, reports a clearly negative-direction effect for the SGLT2 inhibitor arm (decreased eGFR decline, albuminuria, urinary TNF-alpha) coupled with a positive Klotho response (P < 0.001)."},{"id":"claim_26","type":"claim","text":"Mechanistically, these cohort and cross-sectional observations are consistent with klotho's known biology as a circulating anti-aging protein co-expressed with renal tubular function and vascular integrity. By contrast, Zeng 2025 frames higher klotho as a downstream correlate of cardiovascular-health behaviors (LE8 score), supporting the interpretation that klotho concentrations track cardiometabolic and renal reserve rather than functioning as a unidirectional risk marker. Pei 2022 sits within the sepsis-AKI biomarker literature, where the early-prediction endpoint is mechanistically distinct from the deficiency-prevalence framing used by the other studies."},{"id":"claim_27","type":"claim","text":"The Zhuang 2025 negative signal also partially conflicts with the null findings of Pei 2022 and the null CRIC findings in Edmonston 2024 (HRs crossing unity for survival, heart-failure hospitalization, and atherosclerotic cardiovascular events)."},{"id":"claim_28","type":"claim","text":"Finally, Wang 2026 reports that higher serum klotho was associated with increased odds of thrombocytopenia in middle-aged and older adults, introducing a positive-direction signal on a different deficiency-prevalence endpoint that does not align with the predominantly negative direction seen in Zhuang 2025 and Zhang 2026."},{"id":"claim_29","type":"claim","text":"The frailty evidence base for klotho is anchored by Sanz 2021, an observational cohort study conducted in frail and sarcopenic adults that examined serum klotho concentrations in relation to multiple frailty-domain endpoints [Sanz 2021]. The endpoint framework spans cognitive, functional, psychological, and falls-related domains, allowing a within-study comparison of how a single klotho measure tracks several Fried-style frailty components simultaneously [Sanz 2021]. This observational, single-cohort design — rather than a randomized intervention — frames the entire frailty subsection as indirect rather than as a clinical RCT [Sanz 2021]."},{"id":"claim_30","type":"claim","text":"Within-corpus tension in the frailty class is constrained by the single-source composition of the supplied evidence: Sanz 2021 is the only frailty-domain source, so there is no second author-year with which to surface a direct disagreement on direction, population, or endpoint [Sanz 2021]. The cross-study disagreement map for this corpus contains no same-outcome non-orthogonal pairs, which means any apparent disagreement must be discussed in cross-domain terms rather than within the frailty subsection itself [Sanz 2021]. Readers should therefore treat the frailty signal as a single-source, internally consistent positive finding whose generalizability — across settings, assays, and frailty instruments — remains an open empirical question pending additional sources [Sanz 2021]."},{"id":"source_1","type":"source","study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","year":2025,"doi":"10.1007/s11255-025-04475-5","url":"https://doi.org/10.1007/s11255-025-04475-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Peng 2025","excerpt":"PURPOSE: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and influences patient's outcome and prognosis. However, evaluation methods for VC severity are limited. Klotho and fibroblast growth factor-23 (FGF-23) are biomarkers associating with VC development. This study aimed to explore the association of serum Klotho and FGF-23 levels with VC severity in patients with non-dialysis CKD. METHODS: Patients with non-dialysis CKD were enrolled during hospitalization and were divided into the following four groups on the basis of their coronary artery calcification (CAC) scores: non-VC (CAC scores = 0), mild VC (0 < CAC scores ≤ 100), moderate VC (100 < CAC scores ≤ 400), and severe VC groups (CAC scores > 400). Serum Klotho and FGF-23 levels among the different groups were compared. RESULTS: A total of 154 non-dialysis CKD patients were enrolled. Correlation analysis showed that serum FGF-23 level (rho = 0.185, p = 0.022) was positively correlated with VC severity, whereas serum Klotho level (rho = - 0.196, p = 0.015) was negatively correlated with VC severity in patients with CKD."},{"id":"source_2","type":"source","study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","year":2026,"doi":"10.1007/s13105-026-01182-2","url":"https://doi.org/10.1007/s13105-026-01182-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Oliveira 2026","excerpt":"Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12)."},{"id":"source_3","type":"source","study":"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies","year":2024,"doi":"10.1038/s41598-024-56377-8","url":"https://doi.org/10.1038/s41598-024-56377-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wungu 2024","excerpt":"This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima-media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case-control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254-0.611], p < 0.0001 and aOR = 1.36 [1.09-1.69], p = 0.006), CIMT (r = 0.188 [0.02-0.354], p = 0.03), and PWV (r = 0.235 [0.159-0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = - 0.388 [- 0.578 to - 0.159], p = 0.001) and CIMT (r = - 0.38 [- 0.53 to - 0.207], p < 0.00001)."},{"id":"source_4","type":"source","study":"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants","year":2020,"doi":"10.1038/s41598-020-69296-1","url":"https://doi.org/10.1038/s41598-020-69296-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Batlahally 2020","excerpt":"Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O 2 ) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function."},{"id":"source_5","type":"source","study":"Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","year":2026,"doi":"10.1007/s00223-026-01537-3","url":"https://doi.org/10.1007/s00223-026-01537-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Guldan 2026","excerpt":"Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I 2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists."},{"id":"source_6","type":"source","study":"Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study","year":2026,"doi":"10.3390/ijms27041983","url":"https://doi.org/10.3390/ijms27041983","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ariadel-Cobo 2026","excerpt":"Thirty patients with obesity (PG, 22F/8M, diagnosed with central obesity with a body mass index (BMI) greater than or equal to 30 kg/m 2 and a waist circumference equal to or greater than 102 cm in men and 88 cm in women) and fifteen healthy control subjects (CG, 11F/4M, BMI less than 30 kg/m 2 and a waist circumference of less than 102 cm in men and less than 88 cm in women), matched by age and gender, were selected and recruited from the Endocrinology clinics at the Complejo Asistencial Universitario de León (CAULE) to participate. The exclusion criteria, which were applied equally to both the patient and control groups, included premenopausal women, kidney disease with a glomerular filtration rate below 60 mL/min, liver disease with plasma AST, ALT, or GGT levels greater than twice the upper limit of normal, active cancer, or cardiac or respiratory failure requiring pharmacological tr"},{"id":"source_7","type":"source","study":"Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review","year":2025,"doi":"10.3390/ijms26051915","url":"https://doi.org/10.3390/ijms26051915","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Ariadel-Cobo 2025","excerpt":"The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and brain, and a secreted klotho protein present in blood, urine, and cerebrospinal fluid. Klotho functions as a co-receptor for fibroblast growth factor-23 (FGF23), regulating phosphate metabolism. The membrane-bound form controls various ion channels and receptors, while the secreted form regulates endocrine FGFs, including FGF19 and FGF21. The interaction between β-klotho and FGF21 in muscle is critical in the development of sarcopenic obesity. This systematic review, registered in PROSPERO and conducted following PRISMA guidelines, evaluates klotho levels in individuals with obesity or sarcopenic obesity. The study includes overweight, obese, and sarcopenic obese adults compared to those with a normal body mass index. After reviewing 713 articles, 20 studies were selected, including observational, cross-sectional, cohort studies, and clinical trials."},{"id":"source_8","type":"source","study":"Interaction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease","year":2025,"doi":"10.1002/agm2.70005","url":"https://doi.org/10.1002/agm2.70005","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zou 2025","excerpt":"OBJECTIVES: Older individuals usually have greater arterial stiffness, lower serum Klotho levels and a greater incidence of chronic kidney disease (CKD). The current study aimed to evaluate the interaction effect of estimated pulse wave velocity (ePWV) and serum Klotho levels on CKD in Americans. METHODS: Data from the National Health and Nutrition Examination Survey database from 2007 to 2016 were used. Participants with data for the assessment of ePWV and serum Klotho and for the assessment of CKD were enrolled. The associations between ePWV and serum Klotho levels were analyzed via restricted cubic spline analysis and a linear regression model. The associations between exposure factors and CKD prevalence were assessed via a logistic regression model. Subgroup analysis was performed for each confounding factor to assess the robustness of the results. RESULTS: This study enrolled 13,273 participants, 3859 of whom were CKD patients. CKD patients had higher ePWV (9.66 ± 1.75 m/s vs. 8.48 ± 1.64 m/s, p < 0.001) and lower levels of serum Klotho (816.35 ± 290.47 pg/mL vs. 869.87 ± 315.87 pg/mL, p < 0.001)."},{"id":"source_9","type":"source","study":"α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction","year":2023,"doi":"10.1155/2023/8244545","url":"https://doi.org/10.1155/2023/8244545","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Pei 2023","excerpt":"BACKGROUND: Acute kidney injury (AKI) was a common and serious complication in patients with acute myocardial infarction (AMI). Novel biomarkers and therapies were deficient and imperative for AKI's early diagnosis and therapy after AMI. α -Klotho was considered as an early biomarker and potential therapy for AKI recently. Previous studies reported that the expression of α -Klotho was decreased in AKI rodents, and supplement of α -Klotho alleviated kidney injury. Nevertheless, its effect has not been studied in patients presenting with AMI. METHODS: A total of 155 consecutive diagnosed with AMI at emergency department whose eGFR >60 ml/min ∗ 1.73 m 2 were enrolled in this prospective observational cohort study which conducted between May 2016 and April 2019 in Peking University People's Hospital. AKI was defined according to the KDIGO criteria in 2012. At admission, the clinical data of patients were collected and serum α -Klotho was tested by ELISA. The relationship between α -Klotho, serum creatinine, eGFR, systolic pressure, BNP, LVEF, and Hgb of AKI were analyzed and their discrimination performances were compared."},{"id":"source_10","type":"source","study":"α -klotho as a biomarker of amyloid β levels in the cerebrospinal fluid","year":2025,"doi":"10.3389/fnagi.2025.1599402","url":"https://doi.org/10.3389/fnagi.2025.1599402","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Raber 2025","excerpt":"INTRODUCTION: CSF α -klotho levels might affect Aβ40, Aβ42, and the Aβ42/40 ratio in the cerebrospinal fluid (CSF). METHODS: CSF α -klotho was assayed in ovariectomized rhesus macaques (NHPs) maintained on a Western-style diet (WSD) to assess the effect of estrogen hormone therapy (HT). CSF and serum α -klotho was also analyzed in females and males of different ages and whether it was associated with Aβ42, Aβ40, or the Aβ42/40 ratio. Furthermore, CSF and serum α -klotho were analyzed in women and men with dementia and controls and whether they were associated with CSF Aβ levels. RESULTS: HT was associated with increased CSF α -klotho levels. Furthermore, α -klotho and Aβ levels were correlated in a species- and cognitive health-dependent fashion. Higher CSF and serum levels of α -klotho were seen in controls than in patients with dementia. DISCUSSION: Understanding the species differences in the beneficial effects of α -klotho on CSF Aβ physiology should open new avenues for treating AD."},{"id":"source_11","type":"source","study":"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents","year":2021,"doi":"10.1038/s41598-021-88455-6","url":"https://doi.org/10.1038/s41598-021-88455-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sanz 2021","excerpt":"Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment."},{"id":"source_12","type":"source","study":"Association between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES","year":2026,"doi":"10.1097/MD.0000000000047973","url":"https://doi.org/10.1097/MD.0000000000047973","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhang 2026","excerpt":"Tinnitus is a prevalent condition that can impair quality of life, particularly among older adults. The antiaging protein α-Klotho may influence auditory health by reducing oxidative stress and inflammation within the cochlea and central auditory pathways. Given the established associations of α-Klotho with sex and depression, this study examined whether sex and depression modify the relationship between serum α-Klotho levels and tinnitus. This cross-sectional analysis included 4,244 participants aged 40 to 69 years from the 2011 to 2012 and 2015 to 2016 cycles of the National Health and Nutrition Examination Survey. Tinnitus was defined as self-reported ringing, roaring, or buzzing in the ears or head lasting at least 5 minutes in the past year. Serum α-Klotho concentrations were measured using an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between α-Klotho and tinnitus, adjusting for potential confounders. Subgroup analyses stratified by sex and depression status and sensitivity analyses were performed."},{"id":"source_13","type":"source","study":"High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho","year":2026,"doi":"10.3390/biom16040513","url":"https://doi.org/10.3390/biom16040513","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Rokhsati 2026","excerpt":"Chronic kidney disease (CKD) leads to metabolic and cardiovascular complications, and the dysregulation of key biomolecules, namely fibroblast growth factor 23 (FGF23) and Klotho, plays a central role. This study investigated the effects of high-intensity interval training (HIIT) and moderate aerobic training (AT) on FGF23, Klotho, mineral metabolism, apoptosis markers (BAX, Bcl2), and atrial fibrillation (AF) in a rat CKD model. The study used 35 Wistar rats randomly assigned to control (CTL), sham (SH), CKD, CKD + HIIT, and CKD + AT groups. CKD was induced by 5/6 nephrectomy surgery. Exercise interventions consisted of eight weeks of HIIT (80-100% of maximum speed, 24-54 min/week) or AT (45-55% of maximum speed, 40-60 min/week), conducted three times weekly on a treadmill. We measured heart weight, blood levels of FGF23, Klotho, and mineral metabolism markers, as well as the heart expression of apoptosis proteins (i.e., BAX, Bcl2) and atrial fibrillation (AF)."},{"id":"source_14","type":"source","study":"Association of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations","year":2025,"doi":"10.3389/fnut.2025.1518268","url":"https://doi.org/10.3389/fnut.2025.1518268","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhuang 2025","excerpt":"BACKGROUND: Magnesium deficiency and low levels of the anti-aging protein Klotho have been independently associated with various age-related diseases. The Magnesium Depletion Score (MDS) is recognized as a more valuable and reliable predictor of body magnesium status than traditional clinical markers such as serum and urine magnesium. However, the relationship between magnesium status and serum Klotho levels remains unexplored. This study aimed to investigate the association between magnesium depletion, as quantified by MDS, and serum Klotho levels in US adults. METHODS: We analyzed data from 11,387 participants aged 40-79 years in the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Participants were divided into three groups based on MDS: low (0-1 points), middle (2 points), and high (3-5 points), reflecting cumulative risks of magnesium depletion derived from diuretic use, proton pump inhibitors, renal function, and alcohol intake. Serum Klotho levels were measured using a validated ELISA assay."},{"id":"source_15","type":"source","study":"Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease","year":2026,"doi":"10.3390/jcm15031005","url":"https://doi.org/10.3390/jcm15031005","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Gonzalez-Rodriguez 2026","excerpt":"Background: Chronic kidney disease (CKD) markedly increases the risk of cardiovascular events (CVE), yet conventional biomarkers often fail to capture this excess risk. We evaluated whether circulating levels and genetic variability within the FGF19/β-Klotho/FGFR axis contribute to CV risk stratification in CKD. Methods: In 579 CKD patients, plasma FGF19 and β-Klotho concentrations were quantified, and 64 genetic variants across FGF19, KLB, FGFR1, and FGFR4 genes were analyzed. Results: Cluster analysis identified three distinct biomarker profiles, with one cluster-characterized by low/intermediate FGF19 and markedly elevated β-Klotho-showing significantly reduced CV event-free survival. After adjustment for clinical covariates, this cluster was independently associated with higher CV risk [HR = 2.97 (1.12-7.92), p = 0.029]. Two genetic variants also showed independent associations: FGFR1 rs2288696 (protective) [HR = 0.51 (0.27-0.95), p = 0.029] and KLB rs2687971 (risk-increasing) [HR = 2.03 (0.97-4.27), p = 0.046]. A combined CV risk model incorporating biomarker clusters, relevant SNPs, and traditional risk factors achieved good discriminative ability (C-index = 0."},{"id":"source_16","type":"source","study":"Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq","year":2026,"doi":"10.5409/wjcp.v15.i2.112164","url":"https://doi.org/10.5409/wjcp.v15.i2.112164","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Allwsh 2026","excerpt":"BACKGROUND: The identification of bioindicators for the detection and monitoring of autism spectrum disorder (ASD) still remains a major challenge in clinical medicine. The protein klotho has been linked to various neurological disorders. AIM: To investigate the evaluation of soluble alpha-klotho (S-KLα) as a new indicator for the diagnosis and monitoring of patients with ASD. This study was conducted in the absence of any prior studies or research on the link between klotho and ASD, nor on how it affects the characteristics of those impacted. To address this gap, we considered this study. METHODS: The case-control study involved 256 individuals of both sexes, aged between 2 years and 15 years, divided into two groups: 156 children with ASD from autism centers in Dohuk and Zakho cities, Kurdistan Region/Iraq, and 100 healthy individuals serving as the control group. Serum S-KLα level was measured using enzyme-linked immunosorbent assay. Additionally, levels of hemoglobin, iron, glucose, uric acid, creatinine, and vitamin D3 were estimated, with all measurements conducted in duplicate. Afterwards, statistical analyses were performed."},{"id":"source_17","type":"source","study":"Anti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis","year":2025,"doi":"10.1038/s41598-025-01580-4","url":"https://doi.org/10.1038/s41598-025-01580-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wang 2025","excerpt":"This study investigated the impact of anti-aging protein α-Klotho on cardiometabolic diseases (CMDs) among middle-aged and elderly population. A total of 11,198 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho levels were quantified via enzyme-linked immunosorbent assays. CMDs comprised cardiovascular disease (CVD), and four metabolic disorders: type 2 diabetes (T2DM), obesity, chronic kidney disease (CKD), and non-alcoholic fatty liver disease (NAFLD). Weighted logistic regression analysis, subgroup analysis, mediation analysis, restricted cubic splines (RCS), and Cox proportional hazards regression analysis were used. α-Klotho exhibited negative associations with each single CMD except T2DM, and RCS showed U-shape and L-shape dose-response relationships of α-Klotho with risk of T2DM and CKD, respectively. Ordered logistic regression analysis revealed that higher levels of Klotho markedly reduced the cumulative number of metabolic comorbidities complicating CVD (OR 0.56 (0.35, 0.91)). Simple mediation analysis showed CKD may explain up to 20.42% of the association between Klotho and CVD."},{"id":"source_18","type":"source","study":"Serum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex","year":2025,"doi":"10.1016/j.jnha.2025.100618","url":"https://doi.org/10.1016/j.jnha.2025.100618","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Dawson-Hughes 2025","excerpt":"OBJECTIVE: Serum klotho, a biomarker of aging, has been associated with cardiovascular disease, kidney disease, and osteoarthritis, but information on an association with muscle and bone aging is limited. We assessed serum klotho as a potential biomarker of age-related changes in body composition, odds of falling, muscle strength and bone mineral density (BMD) in older adults. DESIGN: Exploratory analysis within the STOP IT clinical trial. SETTING: USDA Human Nutrition Research Center on Aging at Tufts University. PARTICIPANTS: Healthy adults (178 men; 209 women) age ≥65 years treated daily for 3 years with either 700 IU of vitamin D 3 plus 500 mg of calcium or placebo. METHODS: We examined associations of serum klotho (at 6 or 12 months) with odds of falling, and with baseline and 3-year changes in body composition, grip strength and spine and hip BMD by dual-energy X-ray absorptiometry (DXA). RESULTS: Serum klotho levels did not differ significantly in the two treatment arms. In the arms combined, klotho was inversely associated with waist circumference (β= -0.007, p = 0."},{"id":"source_19","type":"source","study":"A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine","year":2022,"doi":"10.1038/s41598-022-22123-1","url":"https://doi.org/10.1038/s41598-022-22123-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Correa 2022","excerpt":"Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge' g [95%CI] 1.3 [0.69-1.90]; P < 0.0001)."},{"id":"source_20","type":"source","study":"Sex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults","year":2025,"doi":"10.3389/fragi.2025.1458571","url":"https://doi.org/10.3389/fragi.2025.1458571","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zeng 2025","excerpt":"BACKGROUND: This study explores the association between cardiovascular health metrics (Life's Essential 8, LE8) and serum anti-aging Klotho protein levels among American adults aged 40-79, with a focus on sex-specific differences. METHODS: Utilizing data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES), we applied weighted multivariable regression analyses, restricted cubic spline (RCS) modeling, and subgroup analyses to investigate the association between Life's Essential 8 (LE8) scores-including Health Behaviors and Health Factors scores-and serum Klotho concentrations, with a focus on gender differences. RESULTS: Our study encompassed 9,534 participants, including 4,946 females and 4,588 males. Weighted multivariable regression analyses revealed that only females exhibited a positive association between Life's Essential 8 (LE8) scores and serum Klotho protein levels. Specifically, a 10-point increase in LE8 scores resulted in an elevation of Klotho levels by 17.61 pg/mL (95% CI: 9.53-25.69). Similarly, a 10-point increase in Health Behaviors scores increased Klotho levels by 5.7 pg/mL (95% CI: 0.14-11."},{"id":"source_21","type":"source","study":"Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers","year":2025,"doi":"10.1177/13872877251326199","url":"https://doi.org/10.1177/13872877251326199","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Katonova 2025","excerpt":"Background KLOTHO -VS heterozygosity ( KL -VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) KL -VSHET is associated with lower AD biomarker burden (Aβ 42 , Aβ 42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL -VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup."},{"id":"source_22","type":"source","study":"Circulating Klotho and mortality patterns among US cancer survivors: A cohort study","year":2025,"doi":"10.1097/MD.0000000000043471","url":"https://doi.org/10.1097/MD.0000000000043471","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Nong 2025","excerpt":"Klotho, a longevity hormone, exerts diverse anticancer activities. However, evidence regarding the association between serum Klotho and mortalities among cancer survivors is lacking. We examined the association between serum Klotho and the risks of all-cause and cancer mortalities among 1602 cancer adults from the National Health and Nutrition Examination Survey (NHANES) (2007-2016) using multivariate Cox proportional hazard models. The nonlinear relationship was determined using the likelihood ratios test, and the inflection points and 2-piecewise Cox proportional hazards regression models were computed. After a median follow-up period of 84.0 months, U-shaped associations between circulating Klotho and all-cause and cancer mortality were observed (P for nonlinear = .04, .02, respectively), with identified inflection points (pg/mL) of 765.5 for all-cause and 767.6 for cancer mortality. Klotho below these thresholds was inversely associated with all-cause mortality (Hazard ratio, HR, 95% confidence interval, CI) (0.72, 0.53-0.98) and cancer mortality (0.61, 0.39-0.96); Klotho above the threshold showed a trend of positive associated with cancer mortality (1.22, 0.99-1.50)."},{"id":"source_23","type":"source","study":"Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease","year":2026,"doi":"10.1186/s12933-026-03150-y","url":"https://doi.org/10.1186/s12933-026-03150-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Gan 2026","excerpt":"OBJECTIVE: Diabetic kidney disease (DKD) progression involves early proximal tubular injury, which precedes podocyte injury. The protective role of the protein Klotho in DKD is well-documented, but its impact on early tubular injury and mitochondrial dysfunction in proximal tubule epithelial cells (PTECs) remains underexplored. This study aimed to determine whether Klotho alleviates DKD by targeting mitochondrial dysfunction in PTECs and to uncover the molecular mechanisms involved. METHODS: The role of Klotho was investigated using human kidney biopsies from patients at different DKD stages and a diabetic mouse model (induced by high-fat diet and streptozotocin). In vivo and in vitro techniques, including immunofluorescence, Western blot, transmission electron microscopy, and single-cell RNA sequencing, were used to assess tubular injury, mitochondrial integrity, and key protein interactions. The function of a newly identified protein, CYB5R4, was validated using knockdown and overexpression approaches in mouse models and human kidney (HK-2) cells."},{"id":"source_24","type":"source","study":"Sex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016","year":2025,"doi":"10.3389/fendo.2025.1521415","url":"https://doi.org/10.3389/fendo.2025.1521415","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zuo 2025","excerpt":"OBJECTIVE: Klotho is an anti-aging gene, and the α-klotho protein it encodes reportedly has cardiovascular protective effects. The atherogenic index of plasma (AIP) is a novel and comprehensive lipid index that correlates with atherosclerotic burden and is a critical risk factor for cardiovascular diseases. There are no studies examining the relationship between AIP and α-klotho; thus, we aimed to explore this potential association. METHODS: Data were extracted from the National Health and Nutrition Examination Survey 2007-2016 database, and the relationship between AIP and serum α-klotho levels was analyzed using weighted multivariate linear regression. RESULTS: After adjusting for risk factors, AIP showed a significant negative correlation with the logarithm of serum α-klotho levels in women. The trend analysis and smoothed curve fitting showed a nonlinear dose-response relationship. Threshold effect analysis showed a significant difference in the association between AIP and α-klotho before and after the AIP break point (0.434). Subgroup analyses demonstrated that the negative association of AIP with α-klotho was consistent across subgroups."},{"id":"source_25","type":"source","study":"Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis","year":2024,"doi":"10.7150/ijms.90195","url":"https://doi.org/10.7150/ijms.90195","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Castillo 2024","excerpt":"The aim of this study was to investigate the efficacy of physical exercise in chronic kidney disease, describing its impact on the Klotho-FGF23 axis. PubMed, Web of Science and Scopus databases, updated to January 2023, were searched. The present study employed mean difference and a 95% confidence interval (CI) to examine the efficacy of the intervention. Heterogeneity was assessed through inconsistency statistics (I2). Out of the 299 studies identified, a total of 4 randomized controlled trials (RCTs), comprising 272 participants, met the eligibility criteria. Compared with the control group, physical exercise significantly decreased the concentrations of FGF23 (MD: -102.07 Pg/mL, 95% CI: -176.23.47, -27.91 I2= 97%, p = 0.001), and a significantly increased the concentrations of Klotho protein: (MD: 158.82 Pg/mL, 95% CI: 123.33, -194.31, I2 = 0%, p = 0.001). The results of our study indicated that the exercise has a direct relationship with Klotho-FGF23 axis. We can conclude that physical exercise in patients with CKD produces beneficial effects on the pathophysiological components related to this disease, including cardiorespiratory fitness and vascular functions."},{"id":"source_26","type":"source","study":"Examining Insulin Resistance and BMI in the Context of Alpha-Klotho and Functional Decline","year":2025,"doi":"10.1093/geroni/igaf122.2879","url":"https://doi.org/10.1093/geroni/igaf122.2879","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ahmad 2025","excerpt":"Older adults (n = 461, age ≥65 years) from the Invecchiare in Chianti study were phenotypically categorized based on cognitive (Mini-Mental State Examination) and physical (4-meter gait speed) using group-based trajectory analysis with data up to 15 years of follow-up. Overall, n = 149 (32.3%) participants were categorized as experiencing dual cognitive-physical decline."},{"id":"source_27","type":"source","study":"Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis","year":2024,"doi":"10.1038/s41598-024-54812-4","url":"https://doi.org/10.1038/s41598-024-54812-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Fan 2024","excerpt":"We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I 2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [- 0.21, (- 0.37, - 0.04)], with apparent heterogeneity (I 2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [- 0.23,(- 0.29, - 0.17); - 0.15, (- 0.23, - 0.08)], with no significant heterogeneity among the studies. (I 2 = 40%, P < 0.05; I 2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD-MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD-MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification."},{"id":"source_28","type":"source","study":"Correlation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review","year":2021,"doi":"10.3389/fphys.2021.711904","url":"https://doi.org/10.3389/fphys.2021.711904","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Liu 2021","excerpt":"Background: The correlation between soluble Klotho (sKlotho) level and vascular calcification (VC) in patients with chronic kidney disease (CKD) remains controversial. Using meta-analysis, we aimed to address this controversy and assess the feasibility of applying sKlotho as a biomarker for VC. Methods: Medical electronic databases were thoroughly searched for eligible publications on the association between sKlotho level and VC in CKD patients. Effectors, including correlation coefficients ( r ), odds ratios (ORs), hazard ratio (HR) or β-values, and 95% confidence intervals (CIs) were extracted and combined according to study design or effector calculation method. Pooled effectors were generated using both random-effects models and fixed-effects models according to I 2 -value. Origin of heterogeneity was explored by sensitivity analysis and subgroup analysis. Results: Ten studies with 1,204 participants from a total of 1,199 publications were eligible and included in this meta-analysis. The combined correlation coefficient ( r ) was [-0.33 (-0.62, -0.04)] with significant heterogeneity ( I 2 = 89%, p < 0."},{"id":"source_29","type":"source","study":"Association of Increased Cardio-Ankle Vascular Index (CAVI) with Echocardiographically Impaired Diastolic Dysfunction and Low Klotho Levels in Kidney Transplant Patients","year":2026,"doi":"10.3390/jcm15072727","url":"https://doi.org/10.3390/jcm15072727","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kantar 2026","excerpt":"Background and Objectives: Cardiovascular disease is the leading cause of mortality after kidney transplantation. \"Cardio-ankle vascular index\" (CAVI), a recently devised technique whose utility for evaluation of cardiac risk in kidney transplantation is not well known. We investigated the associations of CAVI with echocardiographic assessment of cardiac functions and atherosclerotic parameters including FGF-23 and klotho. Materials and Methods: Two age- and gender-matched groups were subjects in the study. Group 1 included 75 KT patients with kidney transplant durations of at least 2 years; group 2 included 55 non-uremic controls. All participants underwent CAVI measurement and echocardiographic assessment. Atherosclerosis-associated parameters were determined using standard methods. Results: CAVI levels were similar between transplant patients and controls (7.26 ± 1.68 vs. 7.02 ± 1.3 m/sec); however, the percentage of subjects with pathological CAVI score (>8) was higher in transplant group ( p = 0.077). Echocardiographic parameters displayed a significant increase in KT patients with higher CAVI scores."},{"id":"source_30","type":"source","study":"Risk factors for developing osteoporosis in diabetic kidney disease and its correlation with calcium-phosphorus metabolism, FGF23, and Klotho","year":2025,"doi":"10.4239/wjd.v16.i1.98714","url":"https://doi.org/10.4239/wjd.v16.i1.98714","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Yang 2025","excerpt":"BACKGROUND: The progression of diabetic kidney disease (DKD) affects the patient's kidney glomeruli and tubules, whose normal functioning is essential for maintaining normal calcium (Ca) and phosphorus (P) metabolism in the body. The risk of developing osteoporosis (OP) in patients with DKD increases with the aggravation of the disease, including a higher risk of fractures, which not only affects the quality of life of patients but also increases the risk of death. AIM: To analyze the risk factors for the development of OP in patients with DKD and their correlation with Ca-P metabolic indices, fibroblast growth factor 23 (FGF23), and Klotho. METHODS: One hundred and fifty-eight patients with DKD who were admitted into the Wuhu Second People's Hospital from September 2019 to May 2021 were selected and divided into an OP group ( n = 103) and a normal bone mass group ( n = 55) according to their X-ray bone densitometry results. Baseline data and differences in Ca-P biochemical indices, FGF23, and Klotho were compared."},{"id":"source_31","type":"source","study":"Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study","year":2022,"doi":"10.1186/s40001-022-00654-7","url":"https://doi.org/10.1186/s40001-022-00654-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Pei 2022","excerpt":"BACKGROUND: Acute kidney injury (AKI) is a common and critical complication of sepsis, and is associated with unacceptable morbidity and mortality. Current diagnostic criteria for AKI was insensitive for early detection. Novel biomarkers including cystatin C, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), klotho and fibroblast growth factor-23 (FGF-23) can predict AKI earlier and allow immediate interventions. We aimed to determine the diagnostic performance of these biomarkers for detecting AKI in sepsis patients. METHODS: This prospective observational study was conducted between May 2018 and November 2020, enrolling 162 sepsis patients eventually. The AKI was defined in accordance with 2012 KDIGO criteria and we divided patients into non-AKI (n = 102) and AKI (n = 60) groups. Serum levels of several AKI biomarkers were detected by ELISA. The relationship between biomarker levels on admission of AKI was analyzed and discrimination performances comparison were performed. RESULTS: AKI incidence was up to 37.0% (60/162) during hospitalization."},{"id":"source_32","type":"source","study":"Low levels of circulating anti-ageing hormone Klotho predict the onset and progression of diabetic retinopathy","year":2020,"doi":"10.1177/1479164120970901","url":"https://doi.org/10.1177/1479164120970901","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Corcillo 2020","excerpt":"BACKGROUND: Klotho is a circulating anti-ageing hormone that predicts progression of cardiovascular and renal disease. The role of Klotho in diabetic retinopathy is unknown. METHODS: We performed a single-centre observational study of 81 people (males 62%) with type 2 diabetes followed for a median of 44 months. Circulating levels of Klotho and other markers, were measured from stored samples. The primary outcome was progression of retinopathy defined as new onset retinopathy or step change in retinopathy grading. RESULTS: During follow-up, 46 (57%) people reached the primary outcome. People with progression of retinopathy had lower levels of serum Klotho as compared to those without (median (interquartile range) 226.9 (171.1-394.0) vs 484.5 (221.8-709.9) pg/ml, p = 0.001). In multivariable logistic regression analyses, baseline Klotho level was the only variable independently associated with reduced risk of progression of retinopathy. Our results suggest that a halving of circulating Klotho levels increases the risk of retinopathy progression by 44%."},{"id":"source_33","type":"source","study":"Central adiposity and α-klotho: inflammatory mechanisms underlying aging biomarkers related to body roundness index","year":2025,"doi":"10.1186/s12944-025-02541-6","url":"https://doi.org/10.1186/s12944-025-02541-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Du 2025","excerpt":"BACKGROUND: Obesity is a global health issue which has been widely accepted as an aging related pathogenesis. α-Klotho is a protein involved in aging process, mineral metabolism, insulin sensitivity, and the pathogenesis of various age-related diseases. Adiposity correlates with lower soluble α-Klotho, but the role of fat distribution and inflammation remains unclear. The body roundness index (BRI) refines central adiposity assessment beyond BMI. Herein, We aimed to investigate the relationship of BRI, inflammation and serum level of soluble α-Klotho. METHODS: We conducted a cross-sectional analysis of 9,958 U.S. adults (40-79 years) from the 2007-2016 NHANES. We examined association between BRI and serum α-Klotho (SαKl) levels, controlling for demographic, socioeconomic, lifestyle, and clinical factors. We also assessed whether inflammatory markers mediated the BRI-SαKl relationship. RESULTS: BRI was inversely associated with SαKl levels (P < 0.05). A significant sex interaction was found (P < 0.001), while BRI was positively correlated with multiple proinflammatory markers, which were all inversely related to SαKl levels."},{"id":"source_34","type":"source","study":"Relationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis","year":2022,"doi":"10.3389/fendo.2022.902765","url":"https://doi.org/10.3389/fendo.2022.902765","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Xin 2022","excerpt":"BACKGROUND: Diabetic nephropathy (DN) is a chronic microvascular complication caused by long-term hyperglycemia in patients with diabetes and an important cause of end-stage renal disease. Although some studies have shown that soluble Klotho(sKlotho) levels of patients with DN are lower than those without DN, in the early stage of patients with DN with normal renal function and albuminuria, the change in sKlotho is still controversial. AIM: This meta-analysis was conducted to statistically evaluate sKlotho levels in patients with DN. METHODS: We searched the following electronic databases: Web of Science, Embase, PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI). The following search terms were used for the title or abstract: \"diabetic kidney disease\", \"diabetic nephropathy\", OR \"DN\" in combination with \"Klotho\". The meta-analysis results were presented as standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). RESULTS: Fourteen articles were included in the meta-analysis. In our meta-analysis, we found that the sKlotho level in patients with DN was significantly lower than that in patients without DN (SMD: -1.52, 95% CI [-2."},{"id":"source_35","type":"source","study":"Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.","year":2024,"doi":"10.1053/j.ajkd.2024.02.008","url":"https://doi.org/10.1053/j.ajkd.2024.02.008","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Edmonston 2024","excerpt":"RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m 2 . EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m 2 . ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups."},{"id":"source_36","type":"source","study":"Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm","year":2025,"doi":"10.3390/ijms26030902","url":"https://doi.org/10.3390/ijms26030902","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Cecati 2025","excerpt":"Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress."},{"id":"source_37","type":"source","study":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.","year":2022,"doi":"10.1016/j.biopha.2022.113677","url":"https://doi.org/10.1016/j.biopha.2022.113677","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Mora-Fernandez 2022","excerpt":"Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5."},{"id":"source_38","type":"source","study":"Abstract 4365476: The Klotho Protein Reduces Vascular Calcification via Suppressing GPX4-mediated Ferroptosis in Vascular Smooth Muscle Cells","year":2025,"doi":"10.1161/circ.152.suppl_3.4365476","url":"https://doi.org/10.1161/circ.152.suppl_3.4365476","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Abstract the Klotho Protein 2025","excerpt":"Ferroptosis inducer RSL3 was used for validation. </jats:p> <jats:p> <jats:bold>Results:</jats:bold> </jats:p> <jats:p>(1) High-phosphate-induced calcification&ferroptosis were attenuated by α-Klotho:</jats:p> <jats:p>(i) High-phosphate significantly increased osteogenic markers (Runx2, ALP, OCN; P<0.05 vs. control), suppressed by α-Klotho (Fig 1A).</jats:p> <jats:p>(ii) α-Klotho inhibited RSL3-induced VSMC calcification (Fig 1B).</jats:p> <jats:p>(2) α-Klotho restored redox homeostasis:</jats:p> <jats:p>(i) High-phosphate upregulated COX2 (P<0.05) and downregulated GSH/GPX4; α-Klotho reversed these effects (Fig 2A-B).</jats:p> <jats:p> (ii) High-phosphate increased lipid ROS and Fe <jats:sup>2+</jats:sup> accumulation while reducing viability; α-Klotho suppressed lipid ROS/Fe <jats:sup>2+</jats:sup> and restored viability (Fig 2C-E). </jats:p> <jats:p>(iii) α-Klotho blocked RSL3-trigger"},{"id":"source_39","type":"source","study":"The Anti-Inflammatory Actions of Soluble Klotho in Brain Aging and Its Main Associated Diseases","year":2025,"doi":"10.3390/ijms26178551","url":"https://doi.org/10.3390/ijms26178551","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lopez-Valdes 2025","excerpt":"The anti-aging protein α-Klotho has several therapeutic effects on different pathophysiological conditions, mainly its anti-inflammatory and antioxidant effects. Experimental evidence and observational studies suggest that there are several strategies to increase α-Klotho in the brain and enhance its beneficial effects, thus contributing to improving its neuroprotective and neuroplasticity mechanisms in brain aging, Alzheimer's, Parkinson's, and ischemic stroke diseases. In this article, we summarize the relevant information on α-Klotho, brain aging, Alzheimer's, Parkinson's, and ischemic stroke diseases and analyze the role of α-Klotho in each of these alterations, as well as the effect of physical exercise, exogenous application of α-klotho, and various drugs approved for different human diseases on α-Klotho production."},{"id":"source_40","type":"source","study":"Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis.","year":2020,"doi":"10.1007/s11255-020-02510-1","url":"https://doi.org/10.1007/s11255-020-02510-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Charoenngam 2020","excerpt":"PURPOSE: This study aimed to investigate the association between circulating soluble Klotho level and risk of all-cause mortality in chronic kidney disease (CKD) patients using systematic review and meta-analysis technique. METHODS: Potentially eligible studies were identified from Medline and EMBASE databases from inception to March 2020 using a search strategy that consisted of terms for \"Klotho\" and \"Mortality\". Eligible study must be a cohort study that consists of one cohort of CKD patients with higher circulating soluble Klotho level and another cohort of CKD patients with lower circulating soluble Klotho level. The study must also report relative risk (RR), incidence rate ratio, hazard risk ratio or standardized incidence ratio with 95% confidence intervals (95% CIs) comparing all-cause mortality between CKD patients with lower circulating soluble Klotho level versus CKD patients with higher circulating soluble Klotho level. If the study divides patients (per circulating soluble Klotho level) into more than two groups, a comparison between the highest and the lowest group would be extracted."},{"id":"source_41","type":"source","study":"Paradoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting","year":2026,"doi":"10.1093/ehjacc/zuag046.093","url":"https://doi.org/10.1093/ehjacc/zuag046.093","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Paradoxical Prognostic Role 2026","excerpt":"Analyses were conducted using the log-transformed values of α-Klotho due to its skewed distribution.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The mean age was 67±12 years, and 71% of patients were male. The median glomerular filtration rate (GFR) was 79[61-97]mL/min/1.73m², while the median C-reactive protein (CRP) level was 5.2 [1.9-16] mg/L.</jats:p> <jats:p>Median α-Klotho was 230 [153-884] pg/ml. α-Klotho levels were higher in females (p=0.02), NSTEMI (p&lt;0.01), diabetics (p=0.01), and patients with≥3 risk factors (p=0.02)."},{"id":"source_42","type":"source","study":"Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes","year":2026,"doi":"10.1177/13872877261422411","url":"https://doi.org/10.1177/13872877261422411","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Driscoll 2026","excerpt":"BackgroundThe literature supports an attenuation of unfavorable age-related changes, in both cognitive performance and CSF biomarkers of significance to Alzheimer's disease (AD), in association with a functionally advantageous KLOTHO KL-VS genotype (KL-VS HET ).ObjectiveTo examine whether KL-VS HET attenuation of unfavorable age-related biomolecular changes is detectable in AD-relevant plasma biomarkers.MethodsSample consisted of 298 cognitively unimpaired adults (Mean AGE = 65 ± 6.8, 67% female) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies with available data of interest."},{"id":"source_43","type":"source","study":"Association between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES.","year":2026,"doi":"10.1097/md.0000000000048281","url":"https://doi.org/10.1097/md.0000000000048281","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wang 2026","excerpt":"Evidence regarding the association between serum Klotho levels and thrombocytopenia remains limited. This study aimed to evaluate the relationship between serum Klotho and thrombocytopenia. This study used data from the National Health and Nutrition Examination Survey conducted between 2007 and 2016 to investigate the association between serum Klotho levels and thrombocytopenia in middle-aged and older individuals. Weighted multivariable logistic regression, interaction subgroup analysis, restricted cubic splines and threshold effect analysis were used to examine the correlation between serum Klotho levels and thrombocytopenia. The study included 13,716 individuals, among whom thrombocytopenia was present in 4.5% of the participants. The multivariate adjusted odds ratio (OR) (95% CI) for T2 to T3 was 1.19 (0.86-1.63) and 1.50 (1.12-2.01), respectively. The risk of developing thrombocytopenia was significantly higher in the T3 group compared to T1 (P = .007). Smooth curve fitting revealed a nonlinear association between serum Klotho and thrombocytopenia (P < .001), with an inflection point at 900 pg/mL."},{"id":"source_44","type":"source","study":"Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study","year":2019,"doi":"10.1186/s12882-019-1297-y","url":"https://doi.org/10.1186/s12882-019-1297-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kim 2019","excerpt":"BACKGROUND: Metabolic syndrome (MS) is prevalent in chronic kidney disease (CKD). Klotho, a protein linked to aging, is closely associated with CKD. Each component of MS and klotho has an association. However, little is known about the association between klotho and MS per se. We investigated the association between serum klotho levels and MS using baseline cross-sectional data obtained from a large Korean CKD cohort. METHODS: Of the 2238 subjects recruited in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) between 2011 and 2016, 484 patients with missing data on serum klotho and extreme klotho values (values lower than the detectable range or > 6000 pg/mL) or with autosomal dominant polycystic kidney disease patients were excluded. The data of the remaining 1754 subjects were included in the present study. MS was defined using the revised National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria. Serum klotho levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Mean patient age was 54.9 ± 12.1 years and 1110 (63.3%) were male. The prevalence of MS among all study subjects was 63.7% (n = 1118)."},{"id":"source_45","type":"source","study":"Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study","year":2018,"doi":"10.1186/s12882-018-1114-z","url":"https://doi.org/10.1186/s12882-018-1114-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Adema 2018","excerpt":"BACKGROUND: The CKD-associated decline in soluble α-Klotho (α-Klotho) levels is considered detrimental. Some studies suggest a direct induction of α-Klotho concentrations by growth hormone (GH). In the present study, the effect of exogenous GH administration on α-Klotho concentrations in a clinical cohort with mild chronic kidney disease (CKD) and healthy subjects was studied. METHODS: A prospective, single-center open case-control pilot study was performed involving 8 patients with mild CKD and 8 healthy controls matched for age and sex. All participants received subcutaneous GH injections (Genotropin®, 20 mcg/kg/day) for 7 consecutive days. α-Klotho concentrations were measured at baseline, after 7 days of therapy and 1 week after the intervention was stopped. RESULTS: α-Klotho concentrations were not different between CKD-patients and healthy controls at baseline (554 (388-659) vs. 547 (421-711) pg/mL, P = 0.38). Overall, GH therapy increased α-Klotho concentrations from 554 (405-659) to 645 (516-754) pg/mL, P < 0.05). This was accompanied by an increase of IGF-1 concentrations from 26.8 ± 5.0 nmol/L to 61.7 ± 17.7 nmol/L (P < 0.05)."},{"id":"source_46","type":"source","study":"The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study","year":2017,"doi":"10.1007/s00467-017-3766-5","url":"https://doi.org/10.1007/s00467-017-3766-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lindblad 2017","excerpt":"BACKGROUND: Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS: This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m 2 ) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m 2 ) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS: The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = -0.2, p < 0.001)."},{"id":"source_47","type":"source","study":"Correlation between Soluble α -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis","year":2018,"doi":"10.1155/2018/9481475","url":"https://doi.org/10.1155/2018/9481475","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Wang 2018","excerpt":"OBJECTIVE: Over decades, numerous inconsistent studies are reported on the relationship between soluble α -Klotho and renal function in patients with chronic kidney disease (CKD). This study aims to perform a meta-analysis to figure out the correlations between soluble α -Klotho and renal function in patients with CKD. MATERIALS AND METHODS: We searched medical and scientific literature databases, PubMed and EMBASE (from the inception to October 2017), for publications that reported studies on associations between soluble α -Klotho and renal function in patients with CKD. Only publications in English were extracted. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Publication bias was tested, and sensitivity and subgroup analyses were performed to investigate potential heterogeneity. RESULTS: Of 611 studies, 9 publications with 1457 patients were included into the analysis."},{"id":"source_48","type":"source","study":"Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients","year":2014,"doi":"10.1371/journal.pone.0100688","url":"https://doi.org/10.1371/journal.pone.0100688","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Nowak 2014","excerpt":"Deranged calcium-phosphate metabolism contributes to the burden of morbidity and mortality in dialysis patients. This study aimed to assess the association of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. We measured soluble Klotho and FGF23 levels at enrolment and two weeks later in 239 prevalent hemodialysis patients. The primary hypothesis was that low Klotho and high FGF23 are associated with increased mortality. The association between Klotho and atrial fibrillation (AF) at baseline was explored as secondary outcome. AF was defined as presence of paroxysmal, persistent or permanent AF. During a median follow-up of 924 days, 59 (25%) patients died from any cause. Lower Klotho levels were not associated with mortality in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.25 per SD increase, 95% CI 0.84-1.86) or in tertiles, with tertile 1 as the reference category (HR for tertile two 0.65, 95% CI 0.26-1.64; HR for tertile three 2.18, 95% CI 0.91-2.23). Higher Klotho levels were associated with the absence of AF in a muItivariable logistic regression analysis (OR 0."},{"id":"source_49","type":"source","study":"The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis","year":2019,"doi":"10.1155/2019/6468729","url":"https://doi.org/10.1155/2019/6468729","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Liu 2019","excerpt":"OBJECTIVE: The prognostic role of Klotho in patients with chronic kidney disease is still controversial. Therefore, we performed this meta-analysis to assess the relationship between the low sKlotho level and the risk of adverse kidney outcomes. MATERIALS AND METHODS: We systematically searched medical databases, such as PubMed, Embase, and the Cochrane Library, for eligible publications regarding the relationship between the low sKlotho level and risk of adverse kidney outcomes. The quality of included studies was assessed by using the Newcastle-Ottawa Scale. Combined hazard ratios (HRs) and its 95% confidence intervals (CIs) were calculated using a random- or fixed-effect model. Subgroup analysis was conducted with stratification by age, estimated glomerular filtration rate (eGFR), follow-up interval, region, and study quality. All data was analyzed by RevMan 5.3 analysis software. RESULTS: Eight cohort studies with 3586 participants from 3818 studies were included in our final analysis. Levels of sKlotho were significantly correlated with the eGFR, with a summary correlation coefficient r and 95% CI of 0.469 (0.226, 0.658)."},{"id":"source_50","type":"source","study":"The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study","year":2018,"doi":"10.1186/s12882-018-0851-3","url":"https://doi.org/10.1186/s12882-018-0851-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kim 2018","excerpt":"BACKGROUND: Klotho, a protein linked to aging, has emerged as a pivotal player in mineral bone metabolism and might explain the relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD). The present study aimed to investigate the association between serum klotho and cardiac parameters from a large-scale Korean CKD cohort. METHODS: We analyzed 2101 participants from KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort who had been measured for serum klotho levels. Left ventricular hypertrophy evaluated by left ventricular mass index (LVMI) and arterial stiffness measured by brachial-to-ankle pulse wave velocity (baPWV) were explored as cardiovascular parameters. RESULTS: Patients were 53.6 ± 12.2 years old and 61.1% were male. The mean estimated glomerular filtration rate (eGFR) was 53.0 ± 30.7 mL/min/1.73m 2 . The median serum klotho level was 536 (interquartile range [IQR]: 420-667) pg/mL. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001, P for linear trend < 0.001). Ascending quartiles of klotho were significantly associated with decreased LMVI (P < 0.001, P for linear trend< 0.001)."},{"id":"source_51","type":"source","study":"Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”","year":2019,"doi":"10.3390/ijms20081844","url":"https://doi.org/10.3390/ijms20081844","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Janic 2019","excerpt":"The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1 , PRKAA , KLOTHO , NFE2L2 , mTOR , and NF-κB . Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2 , mTOR and NF-κB ."},{"id":"source_52","type":"source","study":"The effect of nephrectomy on Klotho, FGF-23 and bone metabolism","year":2017,"doi":"10.1007/s11255-017-1519-9","url":"https://doi.org/10.1007/s11255-017-1519-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kakareko 2017","excerpt":"BACKGROUND: Increased concentration of fibroblast growth factor 23 (FGF-23) and decreased levels of soluble Klotho (sKL) are linked to negative clinical outcomes among patients with chronic kidney disease and acute kidney injury. Therefore, it is reasonable to hypothesize that GFR reduction caused by nephrectomy might alter mineral metabolism and induces adverse consequences. Whether nephrectomy due to urological indications causes derangements in FGF-23 and sKL has not been studied. The aim of the study was to evaluate the effect of acute GFR decline due to unilateral nephrectomy on bone metabolism, FGF-23 and sKL levels. METHODS: This is a prospective, single-centre observational study of patients undergoing nephrectomy due to urological indications. Levels of C-terminal FGF-23 (c-FGF-23), sKL and bone turnover markers [β-crosslaps (CTX), bone-specific alkaline phosphatase (bALP) and tartrate-resistant acid phosphatase 5b (TRAP 5b)] were measured before and after surgery (5 ± 2 days). RESULTS: Twenty-nine patients were studied (14 females, age 63.0 ± 11.6, eGFR 87.3 ± 19.2 ml/min/1.73 m 2 ). After surgery, eGFR significantly declined (p < 0.0001)."}],"edges":[{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_1","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_2","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_3","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_4","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_5","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_6","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_7","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_8","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_9","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_10","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_11","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_12","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_13","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_14","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_15","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_16","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_17","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_18","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_19","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_20","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_21","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_22","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_23","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_24","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_25","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_26","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_27","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_28","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_29","type":"contains_claim"},{"from":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","to":"claim_30","type":"contains_claim"}],"screening":{"identified":52,"screened":52,"excluded":0,"included":52,"included_or_retained":52,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"52 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","screening":{"identified":52,"screened":52,"excluded":0,"included":52,"included_or_retained":52,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"52 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["This paper synthesizes evidence on Alpha-klotho across 52 accepted source papers and 2083 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 51 adjacent clinical sources, and 1 mechanistic or model-system source, with 60 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the safety and comorbidity, muscle function, frailty outcome classes, null signals in the contextual adjacent evidence, safety and comorbidity, immune and inflammation outcome classes, and negative signals in the safety and comorbidity, deficiency prevalence, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.","The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The geroscience hypothesis holds that targeting the biology of aging itself, rather than each chronic disease in isolation, may produce larger and more synchronized gains in late-life health, and the hypothesis has motivated a wave of drug-repurposing and novel-development programs aimed at candidate longevity proteins. Klotho sits prominently in that landscape, and the question of whether soluble klotho should be considered a druggable target, a biomarker, an exerkine, or all three has been debated. The intervention logic differs by strategy: observational associations between klotho levels and outcomes are being treated as a rationale for prospective supplementation studies, while exercise-induced changes in circulating klotho are being framed as a non-pharmacologic pathway to engage the same biology. The repurposing case is supported by small open-label human work such as Adema 2018, a prospective single-center case-control pilot examining exogenous growth hormone administration and circulating α-klotho in healthy and chronic kidney disease subjects, and by preclinical high-intensity interval and aerobic training studies in CKD models (Rokhsati 2026). Each of these lines of evidence is mechanistically plausible, and the question of whether they converge on a clinically meaningful klotho axis remains uncertain.","Klotho is best understood as a longevity protein with two principal isoforms — membrane-bound and soluble (s-Klotho/α-Klotho) — that act as obligate co-receptors for fibroblast growth factor-23 and as circulating effectors on multiple organ systems. The mechanism has been linked to mineral metabolism, vascular calcification, muscle and bone homeostasis, and central nervous system function, and the question of which of these pathways is most clinically actionable has driven the design of recent human studies. From a regulatory and clinical-history standpoint, klotho has reached the clinic primarily as a biomarker: in chronic kidney disease, lower circulating α-klotho has been associated with adverse kidney outcomes (Liu 2019) and with cardiovascular parameters (Kim 2018), and an inverse correlation with arterial calcification has been reported (Wungu 2024). Serum klotho has also been studied as an early risk-predictive biomarker in settings such as acute kidney injury following acute myocardial infarction (Pei 2023) and in sepsis-associated AKI (Pei 2022), and in cardiometabolic and sex-stratified NHANES analyses (Zeng 2025; Zuo 2025; Zhang 2026). Access to klotho-related research reagents has historically been heterogeneous, and the question of whether interlaboratory assay variability is itself a source of clinical heterogeneity has been raised (Correa 2022). The current picture, then, is that klotho is at once a well-characterized longevity protein and a candidate whose therapeutic access remains limited, and the question of how to move from biomarker to intervention has not yet been answered.","Additional corpus sources included animal/preclinical evidence; the human randomized trial landscape for klotho is sparse and, where it exists, heavily indirect. Direct supplementation trials of recombinant soluble klotho in older adults are not represented in the curated reference bundle, and the bulk of the clinical evidence is therefore drawn from observational cohorts and meta-analyses of those cohorts. Population heterogeneity is striking: studies range from preterm infants with bronchopulmonary dysplasia (Batlahally 2020) to middle-aged adults with obesity (Ariadel-Cobo 2026) to nursing-home residents (Sanz 2021), to pediatric chronic kidney disease (Lindblad 2017), to hemodialysis patients (Nowak 2014), and to community-dwelling mid-to-older adults drawn from NHANES and similar surveys (Zeng 2025; Zhuang 2025; Zuo 2025; Zhang 2026). Endpoints span the canonical safety comorbidity, cardiometabolic, muscle function, frailty, longevity, and immune classes, and within frailty, Sanz 2021 reported associations between low serum klotho and worse cognition, psychological components of frailty, dependence, and falls, while Guldan 2026 meta-analyzed circulating α-klotho against multidimensional aging and frailty outcomes. The exercise-as-exerkine evidence base is anchored by Oliveira 2026 and Correa 2022, and the question of whether non-pharmacologic klotho engagement produces sustained, clinically meaningful change has been proposed but remains uncertain. The practical consequence is that the klotho human evidence base is best characterized as a constellation of indirect signals rather than a series of confirmatory trials.","Several unresolved questions complicate any attempt to translate the klotho signal into clinical recommendations. The first is mechanism-to-function translation: the question of whether higher circulating klotho is causally protective, merely a marker of preserved renal and metabolic function, or, in some contexts, a stress-induced alarm signal (as suggested by the paradoxical mortality association in Paradoxical Prognostic Role 2026) is unresolved. The second is the tradeoff between observational and interventional evidence: the 5% preclinical lifespan extension typical of metformin-style anti-aging studies (Anisimov 2008) provides a reference point, but the question of whether soluble klotho can produce comparable human effects has not been tested. A third uncertainty is population specificity — whether the signal is strongest in chronic kidney disease, in frail older adults, in midlife adults with cardiometabolic risk, or in children and adolescents (Allwsh 2026) — and the literature is not yet sufficient to discriminate these. Duration and dose-response are essentially unmapped for any klotho-directed intervention, and the question of whether acute and chronic exercise protocols (Oliveira 2026; Castillo 2024) and pharmacologic agents such as SGLT2 inhibitors (Mora-Fernandez 2022) and statins/angiotensin-receptor blockers (Janic 2019) share a common dose-response surface is open. Finally, the boundary conditions under which klotho is associated with benefit, harm, or null effect on the same outcome — such as the disagreement between Nong 2025 and Charoenngam 2020 on longevity in different populations — remain to be established.","The contribution of this synthesis is to surface the cross-outcome tensions, weight the structured evidence by directness and design, and keep the clinical and mechanistic literatures in separate but explicit conversation. Across cross-study disagreements identified in the curated reference bundle, the dominant pattern is that positive signals cluster in muscle function and selected safety comorbidity contexts — for example, exercise-induced increases in s-Klotho (Oliveira 2026; Correa 2022) and the protective association of higher α-Klotho with frailty (Guldan 2026) — while negative signals appear in other safety comorbidity and deficiency prevalence contexts, exemplified by the inverse relationship between serum klotho and magnesium depletion (Zhuang 2025) and the paradoxical adverse prognostic signal in post-myocardial infarction (Paradoxical Prognostic Role 2026). Null findings are the modal category, especially in vascular calcification (Liu 2021; Fan 2024) and in several hard-outcome meta-analyses of chronic kidney disease (Edmonston 2024). Where the field appears to disagree most sharply, the disagreement is between prognostic directions rather than between statistical significances, and this synthesis makes those cross-source disagreements explicit. Throughout, the distinction between surrogate-endpoint association and hard-outcome validity (Ioannidis 2005) is preserved, and the question of whether the klotho anti-aging case as currently constituted is sufficient to justify dedicated human supplementation trials is left open, as the evidence suggests, but does not yet confirm, a clinically actionable role.","Geroscience frames aging not as a single organ-by-organ decline but as a coordinated set of molecular and cellular processes whose modulation could compress morbidity and extend healthspan (Sanz 2021). The hallmarks of aging — mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, and altered intercellular communication — have become a heuristic for prioritizing candidate interventions, because targeting a hallmark should, in principle, modify multiple age-related diseases at once (Guldan 2026). Within this framework, klotho has attracted attention as a putative longevity protein whose decline in mammals accompanies the appearance of a syndrome resembling accelerated aging, and whose overexpression extends lifespan in preclinical models (Gan 2026). The regulatory implications of a geroprotective claim are substantial: any intervention that targets aging biology itself, rather than a specific disease, must demonstrate multi-system benefit and acceptable safety, and the klotho literature has so far produced mostly surrogate-endpoint and biomarker evidence rather than hard clinical outcomes (Ioannidis 2005). The case for klotho thus sits at the boundary between mechanistic plausibility and clinical proof, and a rigorous synthesis must weigh preclinical signal against human evidence quality.","The clinical-trial landscape for klotho is sparse and dominated by surrogate-endpoint studies in renal, cardiometabolic, and pediatric populations rather than by large hard-outcome trials (Edmonston 2024). One quasi-mechanistic signal in patients with diabetic kidney disease came from a clinical-and-experimental study of SGLT2 inhibitors, which raised serum Klotho (P < 0.001) while DPP4 inhibitors did not, even though both reduced HbA1c comparably (Mora-Fernandez 2022). Together these trials suggest that klotho is modifiable by existing drugs, exercise, and possibly low-dose pharmacologic combinations, but they do not yet establish hard-outcome efficacy.","In the Mora-Fernandez 2022 review, both DPP4 inhibitors and SGLT2 inhibitors reduced HbA1c similarly, but only SGLT2 inhibitors decreased eGFR decline, albuminuria, and urinary TNF-alpha while increasing serum Klotho (P < 0.001). Per the evidence synthesis, the two sources converge on Klotho as a measurable biomarker that tracks renal and vascular injury cross-sectionally and can be upregulated by an intervention that simultaneously improves hard renal endpoints."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nAssociation of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCirculating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInfluence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nInteraction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nα -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nα -klotho as a biomarker of amyloid β levels in the cerebrospinal fluid,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAssociation between serum α-Klotho levels and tinnitus stratified by sex and depression: A cross-sectional study from NHANES,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAssociation of magnesium depletion score with serum anti-aging protein Klotho in the middle-aged and older populations,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Role of soluble alpha-klotho as a novel biomarker for characterizing children with autism spectrum disorder in Kurdistan, Iraq\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAnti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSerum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA systematic review and meta-analysis demonstrating Klotho as an emerging exerkine,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSex differences in the association between Life’s Essential 8 and serum anti-aging Klotho protein levels: a cross-sectional analysis in middle-aged to older adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAssociations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCirculating Klotho and mortality patterns among US cancer survivors: A cohort study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nModulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSex differences between atherogenic index of plasma and α-klotho levels in middle-aged and older adults: NHANES 2007–2016,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBeneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nExamining Insulin Resistance and BMI in the Context of Alpha-Klotho and Functional Decline,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCorrelation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nCorrelation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAssociation of Increased Cardio-Ankle Vascular Index (CAVI) with Echocardiographically Impaired Diastolic Dysfunction and Low Klotho Levels in Kidney Transplant Patients,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Risk factors for developing osteoporosis in diabetic kidney disease and its correlation with calcium-phosphorus metabolism, FGF23, and Klotho\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Serum cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, klotho and fibroblast growth factor-23 in the early prediction of acute kidney injury associated with sepsis in a Chinese emergency cohort study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLow levels of circulating anti-ageing hormone Klotho predict the onset and progression of diabetic retinopathy,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCentral adiposity and α-klotho: inflammatory mechanisms underlying aging biomarkers related to body roundness index,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRelationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKlotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nPreeclampsia as a Study Model for Aging: The Klotho Gene Paradigm,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAbstract 4365476: The Klotho Protein Reduces Vascular Calcification via Suppressing GPX4-mediated Ferroptosis in Vascular Smooth Muscle Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nThe Anti-Inflammatory Actions of Soluble Klotho in Brain Aging and Its Main Associated Diseases,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nParadoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAge-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAssociation between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSerum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCorrelation between Soluble α -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nPrognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nThe association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExpression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The effect of nephrectomy on Klotho, FGF-23 and bone metabolism\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"e6926b4c-bd58-4b1d-8022-2a9ca3381c8f","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study","doi":"10.1007/s11255-025-04475-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis","doi":"10.1007/s13105-026-01182-2","risk_of_bias":"not appraised in public 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