{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"073c460c-0262-46c7-88e4-bc96b9c25668","name":"Research Synthesis: Chronic low-grade inflammation","doi":"10.17605/OSF.IO/8M5TJ","doi_status":"minted","osf_url":"https://osf.io/8m5tj/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_41226544390e4d8a/chain","content_hash":"sha256:ad23c969a1c16f57287abf3be5dd865cb2a51edb22b9fdbb2c5a29fcd30a4a71","provenance_passport":{"publication_id":"073c460c-0262-46c7-88e4-bc96b9c25668","submission_id":"1017658b-fd94-47c3-8318-8b274e570656","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:ad23c969a1c16f57287abf3be5dd865cb2a51edb22b9fdbb2c5a29fcd30a4a71","persistent_identifiers":{"doi":"10.17605/OSF.IO/8M5TJ","osf_url":"https://osf.io/8m5tj/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_41226544390e4d8a","dw_chain_url":"https://provenance.researka.org/artifacts/claim_41226544390e4d8a/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"073c460c-0262-46c7-88e4-bc96b9c25668","object_type":"publication","parent_object_id":"1017658b-fd94-47c3-8318-8b274e570656","title":"Research Synthesis: Chronic low-grade inflammation","body_markdown":"We conducted an AI-assisted structured evidence synthesis of 60 curated reference papers, applying a source-level audit trail that links every numeric claim to its source and flags cross-domain tensions across outcome classes (immune, longevity, cardiometabolic, contextual other).\n\nBibliometric output has matured (Jiang 2025) and clinical protocols are emerging (Lv 2023), yet the few human RCTs — including Li 2025b and Lazou-Ahren 2024 — vary in supplement, duration, and biomarker panel, limiting between-trial synthesis and precluding the surrogate-endpoint caution emphasized by Ioannidis 2005.\n\nAcross the corpus, the evidence supports inflammaging as a biologically grounded, biomarker-detectable phenomenon whose clinical translation remains incomplete: mechanistic plausibility coexists with mixed or sparse human RCT evidence, longevity-relevant cohorts (Ceolin 2025 vs Spray 2025) disagree in direction, and boundary conditions across populations, exposures, and supplement classes are not yet established.\n\n## Abstract\n\nThis paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims.\n\nThe evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\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\n## Introduction\n\nPopulation aging has become one of the defining demographic shifts of the twenty-first century, with the global share of people aged 60 years and older projected to rise sharply over the coming decades. This transition brings clinical and economic pressures that are now widely recognized, but it also reframes a more fundamental question: how can healthspan — the period of life spent in good health — be extended alongside lifespan, rather than treating each chronic disease of older age in isolation. The geroscience hypothesis has emerged in response, proposing that targeting the biological hallmarks of aging may simultaneously delay or attenuate multiple age-related conditions, including the low-grade, smoldering inflammation often termed inflammaging. Whether such a unifying intervention strategy is feasible, and which molecular targets deserve priority, remains a matter of active debate, and the question of whether inflammaging itself is a causal driver of age-related decline or merely a biomarker of cumulative damage has not been settled. The stakes are high because the burden of cardiometabolic disease, frailty, and cognitive decline in older adults continues to grow, and even modest gains in healthy aging would have substantial public-health implications.\n\nThe geroscience hypothesis rests on the premise that aging biology offers tractable, upstream intervention points that, if modified, could yield downstream benefits across organ systems. Two contrasting development pathways have shaped the current evidence base. The first is the repurposing of existing drugs with well-characterized safety profiles — most prominently metformin, originally approved for type 2 diabetes — into older-adult populations at risk of age-related disease. The second is the de novo development of novel geroprotectors targeting pathways such as mTOR, senescent-cell clearance, or inflammasome signaling. Both approaches face a common epistemic challenge: the gap between mechanistic plausibility, often established in cell or animal models, and clinical demonstration of benefit on hard endpoints in humans. Inflammaging sits at the center of this tension, as it is invoked both as a mechanistic explanation for why geroscience interventions might work and as a candidate endpoint on which those interventions might be evaluated. Evidence suggests that inflammation-modifying strategies may plausibly influence aging trajectories, but it remains uncertain whether reducing inflammaging is sufficient, necessary, or merely a correlate of slowing biological aging.\n\nThe inflammaging construct itself lacks a single agreed operational definition, which complicates any synthesis of the evidence. Across the available literature, inflammaging is variably described in terms of elevated circulating cytokines such as IL-6, acute-phase reactants including C-reactive protein, immune-cell phenotypic shifts, or composite biomarker indices such as the neutrophil-to-lymphocyte ratio, and a broad set of triggers has been proposed, ranging from senescent-cell accumulation and mitochondrial dysfunction to altered gut-barrier integrity and dysbiosis. Mechanistic studies cited in this domain include observations that PPAR-α downregulation may sustain monocyte inflammatory programs, that NRF1-driven innate immune dysregulation can amplify age-related inflammation, and that S100A8/A9 alarmins released from hematopoietic progenitors may propagate the response systemically. These mechanisms have been explored in cell-based, animal, and human cohort settings, but the predominant study design in the field is observational, and direct human randomized evidence addressing inflammaging as a primary endpoint remains comparatively sparse. Access to inflammaging biomarkers in clinical practice is further limited by the absence of a regulatory-grade consensus assay panel, which has slowed translation from research observation to intervention trials.\n\nThe human randomized trial landscape for inflammaging-modifying interventions is narrow but growing, and a few direct studies have begun to test whether nutrition- or microbiome-based strategies can shift inflammatory biomarkers in older adults. A randomized, double-blind, placebo-controlled trial of probiotics in adults over 70 years reported measurable effects on inflammaging-related immune readouts, while a two-year cocoa extract supplementation study in older US adults demonstrated a significant reduction in high-sensitivity C-reactive protein compared with placebo. Other randomized work has examined fasting, calorie restriction, mindfulness-based interventions, and balneotherapy, each with distinct biomarker panels and follow-up durations. Beyond these direct trials, the broader human evidence base is dominated by observational cohorts that link inflammaging-related indices to clinical phenotypes as varied as frailty, cardiovascular events, COVID-19 mortality, periodontal bone loss, cancer, and HIV-related comorbidity, with populations ranging from community-dwelling older adults to hospitalized patients and people living with chronic infection. This heterogeneity in design, population, and endpoint is itself a central feature of the literature, and the question of whether any single biomarker signature is portable across such diverse clinical contexts remains open.\n\nSeveral unresolved questions complicate the interpretation of the current evidence base. First, the boundary between mechanistic inflammaging signals and clinically meaningful hard outcomes — such as incident cardiovascular events, fractures, or mortality — is not consistently demonstrated, and a general methodological caution, Ioannidis 2005, reminds us that surrogate-endpoint associations do not guarantee hard-outcome validity. Second, the field's reading of inflammaging appears context-dependent: a positive association of inflammaging markers with clinical risk in one cohort, such as the higher short-term mortality linked to elevated neutrophil-to-lymphocyte ratio in hospitalized older COVID-19 patients, can coexist with null or even protective associations elsewhere, raising the question of whether inflammaging functions as a unidirectional driver or as a context-modulated response. Third, population specificity matters: evidence in forager-horticulturalist populations suggests inflammaging may be minimal, and sex-frailty paradox data indicate that the inflammatory burden of aging may differ qualitatively between men and women. Fourth, optimal dose, duration, and reversibility of any inflammaging-modifying intervention have not been established, and the question of whether short-term biomarker changes translate into sustained functional benefit remains unanswered.\n\nThe contribution of the present synthesis is to apply a structured evidence-weighting framework to the inflammaging literature, separating direct human randomized evidence from indirect observational and mechanistic work and making explicit the cross-outcome tensions that emerge when immune, cardiometabolic, longevity, and contextual endpoints are considered jointly. Where the field has historically treated inflammaging as a single phenomenon amenable to a single intervention logic, the available evidence instead supports a more cautious framing: positive signals in immune and contextual outcomes coexist with null findings in several adjacent domains, and direct RCT evidence remains limited in both number and duration. By cataloging these tensions and weighting study designs, populations, and endpoints separately, the synthesis aims to clarify what is currently known about inflammaging, what remains uncertain, and where future human trials would be most informative, while resisting the temptation to overstate the clinical case for inflammaging-targeted therapy as a generalizable anti-aging strategy.\n\n## Background\n\nThe background evidence for Chronic low-grade inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Lazou-Ahren 2024, Li 2025b are interpreted separately from mechanistic studies such as Netti 2026, Lin 2025, Aitella 2025, because these evidence roles answer different questions about aging biology and clinical translation.\n\nThe direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.\n\nAcross the retained sources, positive signals cluster around the immune and inflammation, contextual adjacent evidence outcome classes; null signals around the contextual adjacent evidence, immune and inflammation, longevity outcome classes; and negative or adverse signals around the immune and inflammation, longevity outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.\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\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-inflammaging-v06-DAILY-2026-06-24T17-12-56Z`.\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: 2026-06-24.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `inflammaging AND aging AND human`\n- `inflammaging AND older adults`\n- `inflammaging AND randomized controlled trial`\n- `chronic low-grade inflammation AND aging AND human`\n- `chronic low-grade inflammation AND older adults`\n- `chronic low-grade inflammation AND randomized controlled trial`\n- `aging inflammation AND aging AND human`\n- `aging inflammation AND older adults`\n- `aging inflammation AND randomized controlled trial`\n- `IL-6 AND aging AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses inflammaging.\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 362 records in the receipt-candidate union, 130 were classified as source candidates and 60 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 | 362 |\n| Classified source candidates | 130 |\n| No extractable claims | 111 |\n| None-only claim binding | 21 |\n| Mixed partial-or-none claim-binding candidates | 63 |\n| Partial-only claim-binding candidates | 20 |\n| Strict high-confidence sources | 17 |\n| Admitted final sources | 60 |\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, cognitive, contextual adjacent evidence, immune and inflammation, longevity, mechanism, mortality and survival, 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## Results\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=25; claims=804 | no extracted directional signal in 21/25 sources | 24 indirect; 1 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=21; claims=435 | no extracted directional signal in 13/21 sources | 2 direct; 15 indirect; 2 mechanistic; 2 review | limited corpus depth in this outcome class |\n| Longevity | n=5; claims=54 | no extracted directional signal in 3/5 sources | 4 indirect; 1 protocol | limited corpus depth in this outcome class |\n| Cardiometabolic | n=3; claims=67 | no extracted directional signal in 2/3 sources | 2 indirect; 1 review | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=2; claims=34 | unclear signal in 1/2 sources | 2 indirect | limited corpus depth in this outcome class |\n| Cognitive | n=1; claims=1 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Mechanism | n=1; claims=3 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=8 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Safety and Comorbidity | n=1; claims=3 | 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- Contextual Adjacent Evidence: n=25; claims=804; no extracted directional signal in 21/25 sources | directness: 24 indirect; 1 review; main limitation: no direct clinical anchor.\n- Immune and Inflammation: n=21; claims=435; no extracted directional signal in 13/21 sources | directness: 2 direct; 15 indirect; 2 mechanistic; 2 review; main limitation: directionally heterogeneous.\n- Longevity: n=5; claims=54; no extracted directional signal in 3/5 sources | directness: 4 indirect; 1 protocol; main limitation: no direct clinical anchor.\n- Cardiometabolic: n=3; claims=67; no extracted directional signal in 2/3 sources | directness: 2 indirect; 1 review; main limitation: no direct clinical anchor.\n- Skeletal, Fracture, and Bone: n=2; claims=34; no extracted directional signal in 1/2 sources | directness: 2 indirect; main limitation: no direct clinical anchor.\n- Cognitive: n=1; claims=1; no extracted directional signal in 1/1 sources | directness: 1 mechanistic; main limitation: no direct clinical anchor.\n\n### Cardiometabolic Outcomes\n\nAdditional corpus sources included animal/preclinical evidence; three sources populate the cardiometabolic outcome class, and none are positioned as a direct anti-aging clinical RCT in healthy adults. Cares 2026 is a systematic review of diet and exercise interventions in pediatric cancer survivors, framed around cardiometabolic disease risk and inflammaging biomarkers rather than longevity endpoints. Tizazu 2024 is an observational cohort in adults (canonical trial ID NCT03340935) examining how fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Xiong 2025 is a mechanistic cohort study in adults using advanced glycation end products to induce inflammaging in periodontal ligament fibroblasts via the RAGE/AKT/mTOR/glycolysis pathway. Across the corpus, the cardiometabolic evidence base combines a pediatric-survivor review, an adult fasting cohort, and a tissue-level mechanistic study, with no single trial anchoring a clinical inflammaging endpoint.\n\nAdditional corpus sources included animal/preclinical evidence; the quantitative yield is uneven across the three sources. Cares 2026 reports no p-values in the available excerpt, consistent with a narrative table-driven systematic review. No effect direction is recorded for Cares 2026 or Xiong 2025, and the effect direction for Tizazu 2024 is listed as unclear, so the cardiometabolic class as currently curated cannot support a directional synthesis statement.\n\nMechanistically, the cardiometabolic sources converge on inflammaging-relevant pathways even though the populations and exposures differ. Preclinical data from Xiong 2025 place the RAGE/AKT/mTOR/glycolysis axis in periodontal ligament fibroblasts, identifying a tissue substrate through which advanced glycation end products could propagate chronic inflammatory signaling relevant to cardiometabolic risk. Mechanistic human and observational data from Tizazu 2024 point to dendritic-cell compartment remodeling (mDCs versus pDCs) under fasting/calorie restriction, linking nutrient-sensing inputs to immunosenescence biomarkers. The Cares 2026 review layer sits above these mechanistic findings by aggregating diet-and-exercise interventions in a pediatric survivor population, where the same downstream inflammatory biomarkers are framed as cardiometabolic risk markers rather than as longevity endpoints.\n\nAdditional corpus sources included animal/preclinical evidence; within-corpus tensions in the cardiometabolic class reflect differences in population, exposure, and endpoint rather than direct numerical conflict. Cares 2026 frames inflammaging as a biomarker of cardiometabolic risk in pediatric cancer survivors exposed to diet/exercise interventions, while Tizazu 2024 frames it as an age-associated immune phenotype modulated by fasting/calorie restriction in adults; the two are not measuring the same outcome, so apparent disagreements are likely definitional. Xiong 2025 supplies a tissue-level mechanistic pathway that neither human source directly assays, leaving a translational gap between the RAGE/AKT/mTOR/glycolysis signal and the fasting-induced dendritic-cell changes. The current cardiometabolic synthesis therefore rests on complementary rather than competing evidence, and the anti-aging case in this outcome class remains incomplete pending a clinical RCT with a defined inflammaging endpoint.\n\n### Cognitive Outcomes\n\nThe cognitive evidence base in the curated inflammaging corpus is anchored by Aitella 2025, a mechanistic preclinical study framing rheumatoid arthritis and osteoporosis as prototypes of immunosenescence within osteoimmunology and detailing molecular pathways of inflammaging alongside targeted therapeutic strategies. The source centers on late-onset disease biology in adults rather than on a discrete cognitive endpoint, so population, design, dose, and follow-up numerics are not applicable; the contribution is at the pathway-mapping layer of the synthesis rather than at the quantitative endpoint layer.\n\nBecause Aitella 2025 is mechanistic and preclinical, no p-values, hazard ratios, odds ratios, sample sizes, or confidence intervals are reported in the source, and effect direction is null. The cognitive subsection therefore does not restate effect sizes from the evidence synthesis; instead, it anchors the mechanistic substrate (inflammaging-linked osteoimmunology) that the synthesis maps onto downstream cognitive endpoints reported in other curated evidence. Any quantitative cognitive claim in the discussion must be read as pathway-derived rather than as a direct cognitive RCT readout.\n\nMechanistically, the Aitella 2025 framework positions chronic low-grade inflammation and immunosenescence as upstream drivers that intersect bone, joint, and neural-aging biology, providing the human-readable substrate (\"preclinical data suggest\") that the synthesis uses to bridge osteoimmunology with inflammaging-related cognitive trajectories. The treat-to-target framing for selected patients over 60 years with low comorbidity burden is cited as a clinical extrapolation rather than as a tested cognitive intervention.\n\nWithin the cognitive outcome class, the corpus contains a single curated source, so within-corpus tensions are limited by design; the relevant contrast is internal to Aitella 2025, where the immunosenescence-prototype framing emphasizes shared inflammaging pathways while the targeted-therapies framing emphasizes disease-specific modulation. This internal contrast is surfaced as a standard academic tension between pathway-level and intervention-level inference rather than as a disagreement between independent cognitive trials.\n\n### Contextual Adjacent Evidence Outcomes\n\nThe contextual evidence base assembled for inflammaging is dominated by observational cohort and mechanistic designs, with no canonical randomized trial represented. The directness flag attached to every source in this outcome class is \"indirect,\" reflecting the absence of human RCT-grade efficacy endpoints.\n\nQuantitative signals were unevenly distributed across the contextual corpus, and a single source — Garcia-Gil 2026 — was the lone study with effect direction coded positive (P < 0.01, P < 0.001, P < 0.05). Most other sources carried null or unclear directional coding.\n\nMechanistically, the contextual evidence implicates several converging substrates. Together these substrates — skin, brain, gut, vasculature, hematopoietic niche — suggest that inflammaging is biologically diffuse rather than tissue-restricted, with preclinical data supplying the mechanistic plausibility that the indirect clinical correlations only partially recapitulate.\n\nAdditional corpus sources included animal/preclinical evidence; within-corpus tensions surface most visibly around Garcia-Gil 2026, the only positively coded source, which is in partial conflict with no fewer than 21 null-coded or unclear-coded contextual sources including Xu 2024, Wang 2024, Cordiano 2024, Villaume 2024, Nelson 2025, Skinner 2025, Li 2025, Mlynarska 2025, Huang 2025, Martin 2025, Xu 2026, Diego-Matos 2026, Mishra 2026, Filipek 2026, Zaongo 2026, Tan 2026, Yuan 2018, Bonora 2022, Horiba 2022, Zhang 2022, and Li 2022. These differences are partial rather than binary and are best read as boundary-condition signals: inflammaging's detectability appears model-, tissue-, and biomarker-dependent.\n\n### Immune and Inflammation Outcomes\n\nThe immune-outcome evidence base for inflammaging spans 20 curated studies ranging from double-blind randomized trials to preclinical tissue models, with end-of-trial biomarker endpoints rather than clinical events dominating the design. Across these trials, biomarker p-values cluster around inflammatory cytokines and acute-phase reactants rather than hard clinical endpoints.\n\nQuantitative inflammaging findings vary across the indirect observational cohorts, with most reporting a constellation of inflammatory biomarkers that include CRP, IL-6, fibrinogen, and neutrophil/lymphocyte indices. Paal 2025, focused on radiotherapy in prostate cancer, observed that several inflammaging-relevant parameters (CRP, albumin, fibrinogen, cholesterol, PLR, NLR) shifted significantly (P < 0.001, P = 0.041, P = 0.006, P = 0.032, P < 0.05) although one comparison returned P = 0.498 and another P = 0.152.\n\nMechanistically, inflammaging-linked biomarker shifts are anchored by preclinical and review-level evidence describing conserved molecular pathways. Aitella 2026 framed inflammaging alongside immunosenescence and neuro-immune aging in allergy cohorts treated with omalizumab or dupilumab as a mechanistic substrate.\n\nSeveral within-corpus tensions complicate the immune-outcome picture. By contrast, the direct human RCTs (Li 2025b, Lazou-Ahren 2024) operate at A1 directness whereas most of the null indirect cohorts (Ramuth 2026, Paal 2025, Liu 2026, Steele 2014, Santos 2024, Francavilla 2025, Moscucci 2025, Jiang 2025) sit at indirect directness, so direct-versus-indirect must be kept analytically separate when comparing effect direction. Francavilla 2025, Moscucci 2025, Aitella 2026, and Jiang 2025 further contextualize these biomarker findings in the post-COVID era and the cardiovascular risk profile of older women, where the magnitude and direction of inflammaging remain under characterization rather than established.\n\n### Immune and Inflammation Outcomes (Observational)\n\nTwo observational cohort studies anchor the immune-inflammation evidence base for inflammaging in this corpus. Guo 2025 profiled innate immune cell subtypes in adults and correlated these distributions with epigenetic clocks, inflammaging readouts, and downstream health outcomes. Both studies share an adult human population, a cross-sectional observational design, and immune-inflammation as the principal endpoint class, providing complementary tissue- and blood-based windows onto inflammaging biology.\n\nQuantitative findings are reported with a deliberately conservative statistical register. Yang 2025 reports transcript-level associations at P < 0.05 for the SPHK1-IRF7 sphingolipid-immune axis in aging meniscal tissue, with effect direction flagged as null in the curated record. Guo 2025 contributes no extractable p-values, and its effect direction is recorded as unclear, reflecting a hypothesis-generating rather than confirmatory posture. The combination of one source-traced P < 0.05 signal with one outcome whose directionality is not adjudicable means the immune-inflammation class is best summarized as directionally mixed, with one claim of age-associated epigenetic-immune dysregulation supported at P < 0.05 (Yang 2025) and a parallel claim (Guo 2025) awaiting clearer directional reporting.\n\nMechanistically, the two sources point toward convergent but non-identical inflammaging substrates. Yang 2025 frames inflammaging in a tissue-specific niche, in which epigenetic silencing of the SPHK1-IRF7 axis remodels sphingolipid-immune crosstalk within the aging meniscus, a peripheral but clinically relevant musculoskeletal compartment. Guo 2025, by contrast, situates inflammaging in the systemic innate-immune compartment, linking variations in innate immune cell subtypes to epigenetic-clock acceleration and to broader health outcomes via blood-based methylation readouts. Together, the mechanistic substrate underlying inflammaging in this corpus spans (i) tissue-resident sphingolipid-immune dysregulation and (ii) systemic innate-immune subtype remodeling correlated with biological-age estimators, indicating that the same label — inflammaging — captures distinct molecular layers depending on the compartment sampled.\n\nWithin-corpus tensions are most visible when the two immune-inflammation sources are read against the picked thesis, which reports a context-dependent profile with positive signals in immune and contextual-other domains, negative signals in immune and longevity domains, and null findings dominating contextual-other and immune outcomes. Yang 2025 carries a null effect-direction flag despite reaching P < 0.05, while Guo 2025 is reported with unclear effect direction and no p-values, illustrating the disagreement between statistical detectability and directional clarity noted in the integrating sentence. The two studies do not formally disagree on a numeric endpoint, but they disagree on the inferential weight that should be placed on transcript-level associations versus cell-subset correlations, a tension that the synthesis surfaces without invoking any pipeline-internal machinery. As currently constituted, the human observational evidence for inflammaging in this outcome class is incomplete, and any anti-aging claim built on these two sources should explicitly acknowledge the mixture of directionally null and directionally unclear findings alongside the P < 0.05 transcriptomic signal in Yang 2025.\n\n### Longevity Outcomes\n\nFive sources in the curated corpus addressed longevity-adjacent outcomes related to inflammaging, spanning observational cohorts and a registered D1 protocol. Giunta 2023 and Spray 2025 are observational cohort syntheses in adults addressing autonomic anti-inflammaging imbalance and cardiovascular inflammaging respectively.\n\nQuantitative findings concentrate in Ceolin 2025, where admission NLR was independently associated with increased long-term mortality risk and several inflammaging-related markers reached statistical significance: P < 0.001, P = 0.010, P = 0.002, P = 0.009, P = 0.049, with non-significant comparisons at P = 0.58, P = 0.223, and P = 0.075. The per-study endpoint evidence for these p-values is enumerated in the evidence synthesis (Per-Study Endpoint Evidence). Wrona 2024, Lv 2023, Giunta 2023, and Spray 2025 did not report primary p-values in the source record, and the Lv 2023 entry remains a protocol rather than a completed trial, so no quantitative mortality effect is yet available from that source.\n\nMechanistically, the longevity findings map onto inflammaging pathways through convergent substrate-level biology. In a clinical observational context, Ceolin 2025 implicates neutrophil-lymphocyte imbalance — a cellular readout of chronic low-grade inflammation — as a short-term mortality predictor in hospitalised older adults.\n\nWithin-corpus tensions cluster around Ceolin 2025, which carries a negative direction on longevity in contrast to the null direction reported by Lv 2023, Wrona 2024, and Spray 2025. Giunta 2023 contributes an unclear direction, consistent with the framing that interindividual variability in aging rate is itself a substrate of inflammaging. Read together, the sources indicate that the longevity signal in inflammaging research is concentrated in acute-vulnerability hospitalised cohorts (Ceolin 2025), while broader cohort syntheses (Wrona 2024, Spray 2025) and an as-yet-unexecuted intervention protocol (Lv 2023) do not yet supply a parallel positive human-RCT signal, leaving the boundary conditions for translation explicitly to be established.\n\n### Mechanism Outcomes\n\nThe mechanistic arm of the inflammaging corpus is anchored by a single preclinical source, Lin 2025, which examined corylin as a candidate modulator of inflammaging and pyroptosis in an in vitro model of diabetic periodontitis. The trial design is mechanistic in directness, with the population framed as adults and the work explicitly positioned as a preliminary in vitro study rather than a clinical RCT. This quantitative framing situates corylin as a candidate anti-inflammaging agent within a high-burden, age-relevant disease context. The endpoint architecture is pathway-focused, centered on pyroptosis and inflammaging readouts in a diabetic tissue milieu, rather than on a clinical functional or survival outcome.\n\nBecause Lin 2025 is the sole source assigned to the mechanism outcome class, no within-class quantitative synthesis (effect sizes, confidence intervals, or p-value aggregation) is possible at this stage of the corpus. The source is descriptive and pathway-framing rather than confirmatory, and the absence of reported p-values reflects its preliminary design. Mechanistically, the study positions corylin as a putative inhibitor of the inflammasome-pyroptosis axis, which is one of the canonical substrate pathways invoked in inflammaging biology. This mechanistic substrate is consistent with broader claims in the field that sustained low-grade activation of innate immune effectors contributes to age-related functional decline, but the source itself does not provide the human RCT or longitudinal cohort data needed to translate that substrate into a clinical anti-aging effect. The within-corpus evidentiary density for the mechanism class is therefore low, with one mechanistic source carrying the full outcome-class weight.\n\nThis dual-axis framing is consistent with the contemporary inflammaging model in which chronic metabolic stress and innate-immune activation reinforce one another across aging tissue compartments. Because the evidence is preclinical, the inference chain from bench to bedside must be drawn cautiously; the source is mechanistic, not clinical, and no human functional endpoint is reported. The within-corpus pathway map therefore resolves to a single corylin-pyroptosis node connected to a diabetic-periodontitis tissue context, without corroborating mechanistic human studies in the current source set. The mechanistic case for corylin in inflammaging is plausible at the substrate level but remains unverified at the clinical level within this corpus.\n\nWithin the outcome class, no within-corpus tensions arise because the mechanism class is represented by only one source (Lin 2025), and the cross-study disagreement map contains no same-outcome non-orthogonal pairs for this class. Consequently, disagreements in the mechanism class must be read from cross-class contrasts rather than from internal mechanism-vs-mechanism disagreement. By contrast, the immune and longevity outcome classes carry negative or null signals elsewhere in the corpus, which leaves the mechanism class to bear most of the integrative weight for the inflammaging thesis. This asymmetry is a boundary condition of the current synthesis rather than a substantive scientific disagreement, and it is acknowledged in the picked thesis statement, which notes that the inflammaging anti-aging case as currently constituted is incomplete. Readers should treat the mechanism findings in this section as hypothesis-generating, anchored in one preliminary in vitro study, and awaiting corroborating mechanistic human studies and clinical RCTs.\n\n### Mortality and Survival Outcomes\n\nThe single curated source bearing on mortality/survival in the inflammaging corpus is Wang 2025, an observational cohort study in adults that interrogated EGR1-ATF3 signaling in paravertebral muscle and reported transcriptomic significance at three thresholds (Wang 2025, P < 0.05; P < 0.01; P < 0.001). The source is annotated as indirect with respect to mortality survival, and no effect direction is recorded, meaning the source did not resolve whether modulation of the EGR1-ATF3 axis translated into a directional survival signal. Population, follow-up duration, and dose are not specified in the available source text, and so any quantitative extrapolation beyond the p-values themselves would exceed what the curated evidence supplies.\n\nThe source does not carry an effect size, hazard ratio, or odds ratio tied to mortality, and the canonical trial id field is empty, which constrains any inference to the transcriptomic stratum of the analysis. Because the only directly cited numerics are the three p-value bands, the mortality/survival synthesis rests on a single observational anchor rather than a pooled estimate.\n\nMechanistically, the Wang 2025 substrate is consistent with the broader inflammaging framework: EGR1-ATF3 signaling is positioned as a regulator of cell death and inflammaging within paravertebral muscle, which provides a human-cohort correlate to the cellular-senescence and SASP literature frequently invoked in inflammaging reviews. The mechanistic substrate underlying this functional finding is therefore observational human tissue coupled to pathway-level inference rather than a randomized intervention targeting hard survival endpoints. This places the mortality/survival evidence in the indirect tier, where any link to longevity remains inferential pending dedicated prospective follow-up.\n\nNo p-values, hazard ratios, or confidence intervals are reported in the source, so the strength of the association between CHIP-attributable clonal expansion and downstream comorbidity cannot be quantified from the curated excerpt.\n\nIn particular, the indirectness of the safety endpoint — a mechanistic and observational claim about comorbidity associations rather than a measured adverse-event rate — should be read against the broader pattern of mixed human evidence flagged in the picked thesis.\n\nBoth studies enrolled adult populations and used cohort designs without randomized allocation to anti-inflammatory or senolytic interventions.\n\nDuration of follow-up and intervention dose are not specified in the available sources.\n\n### Skeletal, Fracture, and Bone Outcomes\n\nLackner 2022 examined cardiac alterations following experimental hip fracture in adults, framing inflammaging as an independent risk factor for fracture-related morbidity (Lackner 2022).\n\nSurboyo 2026 evaluated inflammaging drivers in periodontal, periapical, and malignancy-associated disease, focusing on alveolar bone loss and repair in adults (Surboyo 2026).\n\nThe primary endpoint in Lackner 2022 centered on post-fracture cardiac sequelae, whereas Surboyo 2026 measured inflammatory cytokine expression in gingival tissue.\n\nQuantitative findings are limited. Surboyo 2026 provided no p-values in the source, and the effect direction was marked unclear, reflecting observational heterogeneity in cytokine-expression profiling across older adults with chronic periodontitis (Surboyo 2026). The detailed per-study endpoint values are catalogued in the evidence synthesis to avoid restating sparse numerics here. Both studies thus contribute qualitative rather than quantitative inflammaging evidence to the bone domain. No hazard ratios, odds ratios, or confidence intervals are reported in the available excerpts.\n\nMechanistically, both studies implicate age-associated chronic inflammation as a contributor to skeletal tissue compromise. Lackner 2022 positions inflammaging as an independent risk modifier for cardiac alterations after hip fracture, consistent with the canonical view that systemic low-grade inflammation amplifies post-fracture morbidity in older adults (Lackner 2022). Surboyo 2026 extends this mechanistic substrate to the oral cavity, citing evidence that older patients with chronic periodontitis display elevated gingival inflammatory cytokine expression, suggesting that inflammaging operates locally on alveolar bone remodeling (Surboyo 2026). Preclinical data referenced within these cohorts reinforce the link between senescent immune signaling and bone catabolism. The clinical RCT layer in this outcome class is absent, leaving mechanistic human studies and preclinical evidence as the dominant substrates.\n\nWithin-corpus tensions in the bone domain reflect the absence of consensus on inflammaging's directional contribution. Lackner 2022 reports a null effect direction, whereas Surboyo 2026 is marked unclear, so the two observational cohorts do not converge on a single sign of effect (Lackner 2022; Surboyo 2026). This disagreement parallels the broader pattern in the synthesis in which null and unclear findings dominate the contextual-other and immune outcome spaces. The lack of clinical RCT evidence in this outcome class leaves the boundary conditions under which inflammaging meaningfully modifies fracture or alveolar bone risk unresolved. Future work harmonizing cytokine panels and fracture endpoints would help adjudicate the directionality implied by these two studies.\n\nSkeletal, Fracture, and Bone remains a separate Results slice (n=2; claims=34; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.\n\n### Safety and Comorbidity Outcomes\n\nWithin the corpus, no second source anchors the mortality survival outcome class, so there is no within-class tension to surface; the cross-study disagreement map likewise contains no same-outcome non-orthogonal pairs for mortality survival. The integrating brief notes that null findings dominate the contextual other and immune outcome classes and that the inflammaging anti-aging case remains incomplete, with mechanistic plausibility coexisting alongside mixed or sparse human-RCT evidence. The study is observational in design, with the safety endpoint addressed indirectly rather than as a pre-specified adverse-event outcome, which shapes how its findings should be interpreted against any future interventional inflammaging trials (Martino 2026). The duration, dose, and follow-up schedule are not specified in the source, consistent with its role as a translational synthesis rather than a clinical trial report.\n\nMechanistically, Martino 2026 situates clonal haematopoiesis within the broader inflammaging framework, linking myeloid-skewed clonal expansion to chronic low-grade inflammation, cytokine milieu remodelling, and the biology of chronic lymphocytic leukaemia in the era of targeted therapy (Martino 2026). This mechanistic substrate supports a clinically actionable interpretation: individuals carrying CHIP clones may represent a sizeable, age-enriched population in whom inflammaging pathways are not merely theoretical but measurably contributing to non-haematological comorbidity, particularly atherosclerotic cardiovascular disease (Martino 2026). The human evidence base is observational rather than interventional, which is consistent with the absence of a dose or follow-up specification in the source.\n\nBecause only a single source contributes to this outcome class, within-corpus tensions on the safety endpoint are limited; however, the integration sentence notes that positive signals for inflammaging cluster in immune and contextual-other domains while null findings dominate the same domains, which has direct implications for how the safety evidence in Martino 2026 should be weighted (Martino 2026).\n\nSafety and Comorbidity remains a separate Results slice (n=1; claims=3; no extracted directional signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n## Cross-Domain Synthesis\n\nThe most consequential cross-outcome tension in this corpus is the divergence between mechanistic plausibility and the sparseness of direct human-RCT evidence on hard endpoints. The corpus contains exactly two RCTs with direct human evidence (Lazou-Ahren 2024, Li 2025b), and both are restricted to biomarker/immune endpoints — pro-inflammatory cytokine panels and hsCRP — rather than mortality, hospitalization, or healthspan. Li 2025b (a 2-year cocoa extract trial in older US adults) reports a significant hsCRP reduction (P = 0.008), while Lazou-Ahren 2024 (a probiotic RCT in adults > 70 years) reports an unclear effect direction with mixed p-values (some P < 0.05 alongside P = 0.22 and P = 0.092). Surrounding these two trials is an enormous indirect-evidence base: 50+ observational, preclinical, and review-level sources. The mechanistic claim — that dampening inflammaging should translate to longevity benefit — is bioplausible and is mechanistically reinforced by multiple reviews (Wrona 2024, Spray 2025, Mlynarska 2025), but it cannot be fused into a single causal sentence with the RCT-level evidence without hedging. The boundary condition is straightforward: the clinical-endpoint RCT literature is essentially absent, and any longevity claim rests on indirect, model-organism, or biomarker-level extrapolation. Resolving this would require a randomized trial with hard endpoints (mortality, major cardiovascular events, frailty incidence) sufficiently powered in older adults — a design that no current source provides.\n\nA second load-bearing tension runs between positive human-RCT biomarker signals and largely null observational findings on the same outcome class. Li 2025b's positive hsCRP signal (P = 0.008) sits alongside a wave of indirect observational work that reports null effects on inflammation-related biomarkers in older adults — Santos 2024 on long-term physical activity, Jiang 2025's bibliometric synthesis, Lee 2025 on plant-derived nanovesicles, and Lei 2025 on NRF1-mediated innate immune response, among others. The mechanism is likely an intervention-versus-natural-history asymmetry: short-to-medium-term RCTs and in vitro perturbations can move inflammatory readouts, while cross-sectional observational designs capture a noisy, confounded baseline where age, comorbidity, medication, and survival bias flatten the signal. The boundary condition is temporal and design-dependent — biomarker movement under active intervention does not equal biomarker change across natural aging. Resolution would require harmonized longitudinal cohorts with repeated-measures inflammatory panels and pre-registered thresholds.\n\nAnother tension, uniquely acute in this corpus, is the disagreement on whether inflammaging is even a robust, generalizable phenomenon in humans. The mechanistic reading here is that acute inflammatory triggers (infection, radiation, injury) produce transient, sometimes paradoxically protective immune remodeling that does not align with the slow, chronic inflammaging construct. The boundary condition is one of context: chronic low-grade inflammaging in community-dwelling older adults may behave very differently from acute inflammatory stress in hospitalized or treated populations. Resolution would require prospective cohorts that explicitly separate baseline inflammaging trajectory from acute inflammatory events, with the two never collapsed into a single exposure variable.\n\nAnother tension, central to the paper's overall argument, is the surrogate-endpoint versus hard-outcome gap, which the methodologically cautious reader must keep separate (Ioannidis 2005). The corpus's evidence is overwhelmingly concentrated on surrogate and contextual endpoints: in vitro Nrf2/HO-1 modulation (Garcia-Gil 2026), exoproteome complement deactivation (Mishra 2026), S100A8/A9 alarmins (Bonora 2022), NLR and PLR ratios (Ceolin 2025, Paal 2025), methylation-clock feature rectification (Skinner 2025), and peritumoral immune remodeling (Netti 2026). The few proxies for hard outcomes that do appear — Ceolin 2025's mortality endpoint, Wang 2025's EGR1-ATF3 mortality signal, Lackner 2022's hip-fracture cardiac alterations, Surboyo 2026's alveolar bone loss — are themselves indirect, observational, and largely null. The boundary condition is that improvements in any of these surrogate biomarkers, including hsCRP, IL-6, NLR, and SASP factors, are not equivalent to demonstrated gains in healthspan, disability-free survival, or mortality. Indeed, the same caution that Ioannidis 2005 articulated for surrogates in cardiovascular and metabolic trials applies here. What would resolve this is a trial designed with a hard clinical primary endpoint (e. For example, major adverse cardiovascular events, incident frailty, or mortality) and an inflammaging biomarker as a pre-specified secondary mediator, with formal mediation analysis linking the two — a design absent from this corpus.\n\nA fifth and final tension, often underweighted, is the cross-species generalizability of the inflammaging construct itself. The boundary condition is that inflammaging is plausibly a human-, environment-, and exposure-specific phenomenon rather than a pan-mammalian aging program. Resolving this would require harmonized wild and captive mammalian cohorts with the same inflammatory biomarker panel — a near-absent design in the current evidence base.\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.## Endpoint-Sensitivity Framework\n\nWe operationalize an Endpoint-Sensitivity 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 direct, 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 mechanism-vs-clinical, 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 the 60-paper inflammaging corpus, direct human RCT evidence for immune-biomarker modulation exists but is narrow in endpoint scope, while the broader inflammaging portfolio is dominated by indirect observational, mechanistic, and preclinical signals whose effect directions and outcome classes are genuinely mixed, so the inflammaging anti-aging case is best read as mechanistically plausible yet clinically underdetermined, not as a settled or refuted claim. The thesis is falsifiable: it would be refuted by replicated, hard-outcome RCTs (e. For example, mortality, incident frailty, cardiovascular events) showing consistent inflammaging-mediated benefit in pre-frail or older adults, with effect sizes that survive adjustment for baseline inflammation, sex, and comorbidity. The corpus supports a position stronger than \"context-dependent\" boilerplate: the convergent signal is that inflammaging biomarkers — CRP, IL-6, NLR, fibrinogen, sCD14, LPS — are reproducibly elevated in older and clinically vulnerable populations, but interventions that move these biomarkers have not yet been shown to move hard outcomes. We interpret the evidence as consistent with inflammaging as a measurable, modifiable biological state, while remaining cautious about claims of durable clinical translation. This distinction is the load-bearing reason the thesis is qualified rather than declarative.\n\nThreat 1: The direct RCT evidence base is too thin to ground durable claims. These two studies are the only source-anchored evidence where the design, endpoint, and direction meet the bar for direct human evidence on inflammaging biomarkers, and even they disagree on effect direction (unclear vs positive). A second reading of the corpus is therefore possible: the inflammaging anti-aging case may be no more than a small, inconsistent, biomarker-level literature, and any broader claim is overreach. We acknowledge that the body of direct human evidence is insufficient to claim either benefit or harm on hard clinical endpoints, and we treat the mechanistic consensus (Franceschi and others) as a hypothesis generator, not a conclusion.\n\nThreat 2: Cross-domain tensions are pervasive and risk spurious fusion. The corpus also contains null vs positive conflicts between Garcia-Gil 2026 (positive on contextual other, in vitro Nrf2/HO-1 modulation) and roughly twenty indirect observational and review sources reporting null contextual other effects (Mlynarska 2025, Mishra 2026, Yuan 2018, Bonora 2022, Horiba 2022, Zhang 2022, Li 2022, Xu 2024, Wang 2024, Cordiano 2024, Villaume 2024, Nelson 2025, Skinner 2025, Huang 2025, Martin 2025, Xu 2026, Diego-Matos 2026, Filipek 2026, Zaongo 2026, Tan 2026). Naive pooling across these designs would inflate certainty; one reading is that the field has not yet converged on what \"inflammaging reduction\" means across tissues and species. We therefore recommend that future syntheses stratify by design, tissue, and species rather than aggregate effect signs.\n\nThreat 3: The human longevity and mortality signal is genuinely mixed and likely population- and biomarker-specific. This mixture of directions is most parsimoniously explained as population specificity: acutely ill hospitalised older adults (Ceolin 2025) are not interchangeable with community-dwelling Bolivian foragers (Aronoff 2025) or with mechanistic preclinical models (Lin 2025 corylin, Yuan 2018 hAAT, Lee 2025 PgELNs). We interpret this as evidence that inflammaging is real and measurable, but that its clinical translation depends on baseline inflammatory load, comorbidity, and biological age. Translation to clinical practice therefore warrants further trials, not adoption.\n\nThreat 4: The mechanistic-versus-clinical pipeline has a major indirectness gap that the matrix flags repeatedly. The two direct RCTs (Lazou-Ahren 2024, Li 2025b) sit on immune outcomes, yet the corpus also includes mechanism-level claims about longevity, cardiometabolic risk, skeletal/bone outcomes, cognitive outcomes, and safety/comorbidity — all of which the matrix flags as mechanism vs clinical at severity 3. Surrogate-endpoint reasoning is precisely where the Ioannidis 2005 caution applies: a surrogate association does not guarantee hard-outcome validity. We interpret the recurrence of this gap as the single most important methodological limitation of the inflammaging literature, and we recommend that any future claim of clinical benefit be paired with explicit hard-endpoint adjudication (incident frailty, cardiovascular events, mortality) rather than biomarker movement alone.\n\nThreat 5: Endpoint, species, and age heterogeneity make a single effect estimate implausible. Cole 2026 in particular reports minimal evidence of inflammaging in naturalistic chimpanzee populations, which is interpretively important because it qualifies the universality of the inflammaging construct across the primate lineage. We therefore suggest that any future meta-analysis adopt a stratified-by-population design, since pooled effect sizes across such heterogeneous groups would have low interpretive value and could mislead clinical decision boundaries.\n\n**Resolution criteria:** The threats above would be settled by a small, deliberate set of study designs. First, a population-stratified prospective cohort enrolling acutely ill (Ceolin 2025 phenotype), community-dwelling, and forager-horticulturalist (Aronoff 2025 phenotype) groups with harmonised biomarker panels, to test the population-specificity hypothesis directly. Second, an ancillary mechanistic arm on a subset of trial participants linking biomarker movement to single-cell and epigenetic endpoints (Skinner 2025, Guo 2025) so that surrogate-to-hard-outcome inference (Ioannidis 2005) is no longer speculative. Until such trials are reported, the inflammaging anti-aging case remains to be determined, and the evidence supports inflammaging as a measurable state, not yet as a clinical target.\n\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\nThe curated corpus does not contain any long-term mortality or hard cardiovascular endpoint randomized trial of an inflammaging-targeted intervention in generally healthy community-dwelling older adults. As a result, any cross-paper claim that inflammaging modification prolongs survival or reduces hard events lacks an in-corpus RCT source and must be treated as hypothesis-generating, consistent with the surrogate-endpoint caution articulated in Ioannidis 2005.\n\nSeveral clinically relevant inflammaging claims in the corpus are supported by only a single source, leaving them unreplicated within this evidence base. Single-source claims of this kind cannot be checked for direction-of-effect stability and should be interpreted as illustrative rather than confirmed.\n\nThe enrolled populations skew toward narrow demographic and clinical strata, constraining external validity. Almost no source reports an inflammaging intervention in generally healthy mid-life adults free of chronic disease, so the headline findings should not be extrapolated to that population.\n\nAdditional corpus sources included animal/preclinical evidence; the endpoint scope of the corpus is heavily weighted toward circulating inflammatory biomarkers, in-vitro readouts, and tissue-level mechanistic markers rather than functional or patient-important outcomes. Directness is largely indirect or mechanistic: the immune class is dominated by indirect observational cohorts (e. For example, Ramuth 2026, Santos 2024, Wang 2021, Liu 2026), and the longevity class is largely populated by indirect, narrative, or protocol-stage sources (Wrona 2024, Spray 2025, Giunta 2023, Lv 2023). Consequently, inflammaging-biomarker effects reported in the corpus cannot be mapped onto the standard functional geriatric endpoints that clinicians use.\n\nThe gap between mechanistic plausibility and clinical evidence is particularly wide for several domain-relevant claims. Lin 2025 (in-vitro diabetic periodontitis), Aitella 2025 (preclinical rheumatoid arthritis and osteoporosis), Aitella 2026 (preclinical allergy biology), Netti 2026 (clear cell renal cell carcinoma peritumoral tissue), and Wang 2021 (monocyte PPAR-α downregulation) all generate mechanism-grade support for inflammaging but report no human clinical endpoint. Because the corpus supplies mechanistic and disease-specific indirect evidence but lacks general-population or hard-endpoint human RCT data, the clinic-ready translation of any inflammaging-targeted intervention is not supported by this evidence base.\n\n## Conclusion\n\nAcross the corpus, the 60 sources evaluated in this synthesis support an integrating position that the inflammaging construct, as currently operationalised, is mechanistically plausible but clinically incomplete: positive signals appear chiefly in immune and contextual biomarker outcomes (e. For example, Garcia-Gil 2026 and Aronoff 2025), negative signals cluster on immune and longevity outcomes (notably Paal 2025, Ceolin 2025), and null or mixed findings dominate the remaining outcome classes, with Cole 2026, Steele 2014, and Li 2022 returning non-significant results on key comparators. These findings, layered atop 163 non-orthogonal cross-domain tensions, indicate that the inflammaging anti-aging case as currently constituted remains to be confirmed in adequately powered trials with pre-registered longevity or functional endpoints.\n\nAdditional corpus sources included animal/preclinical evidence; what the current evidence does and does not support for clinical practice requires careful boundary-drawing. For drugs, compounds, or supplements with putative anti-inflammaging properties — including metformin, doxycycline (Li 2022), alpha-1 antitrypsin (Yuan 2018), vitamin E-loaded dialysers (Sepe 2019), pomegranate extract (Cordiano 2024), fucoxanthin combinations (Garcia-Gil 2026), and 2-O-methylmagnolol (Huang 2025b) — the appropriate clinical posture is that off-label geroprotective use remains to be confirmed pending further trials with hard endpoints, and any such use outside of registered protocols cannot currently be justified by the evidence base.\n\nA defensible next study should pre-specify\nwhich endpoint layer it intends to test, align intervention exposure with\nthat endpoint, and report functional or safety tradeoffs with the same\nvisibility as benefit signals. Agreement across mechanistic, intermediate,\nfunctional, and hard-clinical layers would support stronger inference than\nany isolated signal; disagreement across those layers should be treated as\na design problem rather than averaged into a single geroprotective claim.\n\n## What This Synthesis Adds\n\nThis synthesis maps 60 included sources on Inflammaging across 10 outcome classes and 163 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 60 curated reference papers, the evidence base for inflammaging shows a context-dependent profile. Positive signals appear in: immune, contextual other. Negative signals appear in: immune, longevity. Null findings dominate: contextual other, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The inflammaging 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 Paal 2025 and Aronoff 2025 on immune and inflammation (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Cares 2026, Alp 2025, Aronoff 2025) emphasize convergent signals on Inflammaging. 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 | 5 | negative, null, unclear | conflict-resolution gap |\n| cardiometabolic | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |\n| cognitive | 0 | 1 | null | direct interventional hard-endpoint gap |\n| mechanism | 0 | 1 | null | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 25 | null, positive, unclear | conflict-resolution gap |\n| immune and inflammation | 2 | 17 | mixed, negative, null, positive, unclear | conflict-resolution gap |\n| immune and inflammation | 0 | 2 | null, unclear | direct interventional hard-endpoint gap |\n| mortality and survival | 0 | 1 | null | direct interventional hard-endpoint gap |\n| safety and comorbidity | 0 | 1 | null | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 0 | 2 | null, unclear | 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 5 indirect sources; direction profile: negative, null, unclear |\n| P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |\n| P3 | cognitive: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | mechanism: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P5 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 25 indirect sources; direction profile: null, positive, unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Inflammaging 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## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Lazou-Ahren 2024; tier=A1; directness=direct; endpoint=immune; direction=unclear; representative statistic=P = 0.01.\n- Li 2025b; tier=A1; directness=direct; endpoint=immune; direction=positive; representative statistic=P = 0.008.\n- Cares 2026; tier=B1; directness=review; endpoint=cardiometabolic; direction=null.\n- Alp 2025; tier=B1; directness=review; endpoint=immune; direction=null.\n- Aronoff 2025; tier=B1; directness=review; endpoint=immune; direction=positive; representative statistic=P < 0.01.\n- Li 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.\n- Paal 2025; tier=B2; directness=indirect; endpoint=immune; direction=negative; representative statistic=P < 0.001.\n- Garcia-Gil 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.001.\n- Steele 2014; tier=B2; directness=indirect; endpoint=immune; direction=null; representative statistic=P = 0.052.\n- Ceolin 2025; tier=B2; directness=indirect; endpoint=longevity; direction=negative; representative statistic=P < 0.001.\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- Additional corpus sources included animal/preclinical evidence; Lazou-Ahren 2024: outcome=immune; directness=direct; tier=A1; direction=unclear; claims=31.\n- Li 2025b: outcome=immune; directness=direct; tier=A1; direction=positive; claims=6.\n- Cares 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=null; claims=31.\n- Alp 2025: outcome=immune; directness=review; tier=B1; direction=null; claims=4.\n- Aronoff 2025: outcome=immune; directness=review; tier=B1; direction=positive; claims=2.\n- Li 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=344.\n- Paal 2025: outcome=immune; directness=indirect; tier=B2; direction=negative; claims=88.\n- Garcia-Gil 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=positive; claims=86.\n- Steele 2014: outcome=immune; directness=indirect; tier=B2; direction=null; claims=57.\n- Ceolin 2025: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=49.\n- Cole 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=46.\n- Ramuth 2026: outcome=immune; directness=indirect; tier=B2; direction=null; claims=45.\n- Mishra 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=39.\n- Bonora 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38.\n- Li 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38.\n- Wang 2021: outcome=immune; directness=indirect; tier=B2; direction=null; claims=37.\n- Xu 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=37.\n- Lackner 2022: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=31.\n- Tizazu 2024: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=29.\n- Arosio 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=27.\n- Santos 2024: outcome=immune; directness=indirect; tier=B2; direction=null; claims=27.\n- Diego-Matos 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26.\n- Zhang 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=25.\n- Lei 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=23.\n- Sepe 2019: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=21.\n- Huang 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.\n- Nelson 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.\n- Yuan 2018: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16.\n- Horiba 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- Yang 2025: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=14.\n- Cordiano 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13.\n- Liu 2026: outcome=immune; directness=indirect; tier=B2; direction=null; claims=13.\n- Martin 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12.\n- Guo 2025: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=10.\n- Huang 2025b: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=9.\n- Mlynarska 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=9.\n- Wang 2025: outcome=mortality survival; directness=indirect; tier=B2; direction=null; claims=8.\n- Xiong 2025: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=7.\n- Xu 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4.\n- Jiang 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=3.\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- Additional corpus sources included animal/preclinical evidence; severity 5 disagreement: Paal 2025 vs Aronoff 2025; Paal 2025 reports negative effect on immune; Aronoff 2025 reports positive on the same outcome — direct conflict\n- Severity 4 null vs negative: Lv 2023 vs Ceolin 2025; Ceolin 2025 (negative on longevity) vs Lv 2023 (null on longevity) — partial conflict\n- Severity 4 null vs negative: Wrona 2024 vs Ceolin 2025; Ceolin 2025 (negative on longevity) vs Wrona 2024 (null on longevity) — partial conflict\n- Severity 4 null vs negative: Santos 2024 vs Paal 2025; Paal 2025 (negative on immune) vs Santos 2024 (null on immune) — partial conflict\n- Severity 4 null vs negative: Paal 2025 vs Zhang 2025; Paal 2025 (negative on immune) vs Zhang 2025 (null on immune) — partial conflict\n- Severity 4 null vs negative: Paal 2025 vs Jiang 2025; Paal 2025 (negative on immune) vs Jiang 2025 (null on immune) — partial conflict\n- Severity 4 null vs negative: Paal 2025 vs Francavilla 2025; Paal 2025 (negative on immune) vs Francavilla 2025 (null on immune) — partial conflict\n- Severity 4 null vs negative: Paal 2025 vs Lee 2025; Paal 2025 (negative on immune) vs Lee 2025 (null on immune) — partial conflict\n\n## References\n\n- **Li 2022.** _Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases._ Antioxidants, 2022. DOI: 10.3390/antiox11122413. PMID: 36552622.\n- **Paal 2025.** _Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation._ World Journal of Urology, 2025. DOI: 10.1007/s00345-024-05409-z. PMID: 39692768.\n- **Garcia-Gil 2026.** _Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes._ Antioxidants, 2026. DOI: 10.3390/antiox15050599. PMID: 42193222.\n- **Steele 2014.** _Contribution of Intestinal Barrier Damage, Microbial Translocation and HIV-1 Infection Status to an Inflammaging Signature._ PLoS ONE, 2014. DOI: 10.1371/journal.pone.0097171. PMID: 24819230.\n- **Ceolin 2025.** _Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability._ Immunity & Ageing: I & A, 2025. DOI: 10.1186/s12979-025-00548-2. PMID: 41462275.\n- **Cole 2026.** _Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations._ American Journal of Biological Anthropology, 2026. DOI: 10.1002/ajpa.70211. PMID: 41657073.\n- **Ramuth 2026.** _New insights into the association between cardiometabolic index with metabolic profile, nutritional status, and inflammaging in older adults._ Frontiers in Aging, 2026. DOI: 10.3389/fragi.2025.1699767. PMID: 41602164.\n- **Mishra 2026.** _Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging._ Nature Aging, 2026. DOI: 10.1038/s43587-026-01107-0. PMID: 41974968.\n- **Li 2025.** _Bottom-up engineering of the nucleus pulposus using a photocrosslinkable decellularized matrix hydrogel attenuates inflammaging and enhances microtissue-mediated regeneration._ Materials Today Bio, 2025. DOI: 10.1016/j.mtbio.2025.102347. PMID: 41104045.\n- **Bonora 2022.** _Hematopoietic progenitor cell liabilities and alarmins S100A8/A9‐related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults._ Aging Cell, 2022. DOI: 10.1111/acel.13545. PMID: 35166014.\n- **Xu 2026.** _The alteration of bile acids and gut microbiota is associated with intestinal barrier dysfunction and inflammaging in human._ Frontiers in Aging, 2026. DOI: 10.3389/fragi.2026.1741360. PMID: 42064446.\n- **Wang 2021.** _Programmed PPAR-α downregulation induces inflammaging by suppressing fatty acid catabolism in monocytes._ iScience, 2021. DOI: 10.1016/j.isci.2021.102766. PMID: 34286232.\n- **Lazou-Ahren 2024.** _Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial._ Probiotics and Antimicrobial Proteins, 2024. DOI: 10.1007/s12602-024-10310-7. PMID: 38896223.\n- **Cares 2026.** _Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review._ Advances in Nutrition, 2026. DOI: 10.1016/j.advnut.2026.100605. PMID: 41692128.\n- **Lackner 2022.** _Cardiac alterations following experimental hip fracture - inflammaging as independent risk factor._ Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.895888. PMID: 36131923.\n- **Tizazu 2024.** _Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging._ Aging Medicine, 2024. DOI: 10.1002/agm2.12342. PMID: 39234195.\n- **Santos 2024.** _Long-Term Physical Activity Mitigates Inflammaging Progression in Older Adults Amidst the COVID-19 Pandemic._ International Journal of Environmental Research and Public Health, 2024. DOI: 10.3390/ijerph21111425. PMID: 39595692.\n- **Arosio 2025.** _Inflammaging and the sex-frailty paradox._ Aging Clinical and Experimental Research, 2025. DOI: 10.1007/s40520-025-03181-7. PMID: 41055841.\n- **Diego-Matos 2026.** _Gut-heart immuno-metabolic disruption associated with inflammaging and subclinical coronary artery disease in people with HIV on antiretroviral therapy._ Immunity & Ageing: I & A, 2026. DOI: 10.1186/s12979-026-00566-8. PMID: 42046076.\n- **Zhang 2025.** _Protective effects of Rosa roxburghii Tratt. extract against UVB-induced inflammaging through inhibiting the IL-17 pathway._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-92559-8. PMID: 40064976.\n- **Netti 2026.** _Molecular Remodeling of Peritumoral Tissue in Clear Cell Renal Cell Carcinoma: Insights into Inflammaging and Prognostic Markers._ Cancers, 2026. DOI: 10.3390/cancers18030414. PMID: 41681886.\n- **Lei 2025.** _NRF1-mediated innate immune response drives inflammaging._ Nature Communications, 2025. DOI: 10.1038/s41467-025-66368-6. PMID: 41381492.\n- **Sepe 2019.** _Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging._ BMC Nephrology, 2019. DOI: 10.1186/s12882-019-1585-6. PMID: 31729973.\n- **Nelson 2025.** _The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation._ JCI Insight, 2025. DOI: 10.1172/jci.insight.187271. PMID: 40036082.\n- **Huang 2025.** _Spatiotemporal mapping reveals Ccl8 hi macrophages as key drivers of testicular inflammaging._ Clinical and Translational Medicine, 2025. DOI: 10.1002/ctm2.70527. PMID: 41251087.\n- **Yuan 2018.** _Anti‐inflammaging effects of human alpha‐1 antitrypsin._ Aging Cell, 2018. DOI: 10.1111/acel.12694. PMID: 29045001.\n- **Yang 2025.** _Epigenetic silencing of SPHK1-IRF7 axis drives inflammaging in age-related meniscus degeneration via sphingolipid-immune dysregulation._ Journal of Orthopaedic Surgery and Research, 2025. DOI: 10.1186/s13018-025-06518-0. PMID: 41419949.\n- **Horiba 2022.** _IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin._ JID Innovations, 2022. DOI: 10.1016/j.xjidi.2022.100112. PMID: 35521044.\n- **Cordiano 2024.** _Pomegranate ( Punica granatum L.) Extract Effects on Inflammaging._ Molecules, 2024. DOI: 10.3390/molecules29174174. PMID: 39275022.\n- **Liu 2026.** _Interferon-related inflammaging links epigenetic age acceleration to multimorbidity._ Cell Genomics, 2026. DOI: 10.1016/j.xgen.2026.101218. PMID: 41999740.\n- **Martin 2025.** _Age-related nigral downregulation of the Parkinson’s risk factor FAM49B primes human microglia for inflammaging._ NPJ Aging, 2025. DOI: 10.1038/s41514-025-00296-z. PMID: 41419490.\n- **Guo 2025.** _Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes._ Advanced Science, 2025. DOI: 10.1002/advs.202505922. PMID: 40862296.\n- **Huang 2025b.** _2-O-methylmagnolol mitigates the generation of reactive oxidative stress and inflammaging in human gingival epithelial cells and fibroblasts with advanced glycation end products stimulation._ Journal of Dental Sciences, 2025. DOI: 10.1016/j.jds.2025.04.022. PMID: 40654450.\n- **Mlynarska 2025.** _Inflammaging and Senescence-Driven Extracellular Matrix Remodeling in Age-Associated Cardiovascular Disease._ Biomolecules, 2025. DOI: 10.3390/biom15101452. PMID: 41154680.\n- **Wang 2025.** _Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging._ Biological Research, 2025. DOI: 10.1186/s40659-025-00634-1. PMID: 40722201.\n- **Xiong 2025.** _Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway._ Acta Odontologica Scandinavica, 2025. DOI: 10.2340/aos.v84.44581. PMID: 40839341.\n- **Li 2025b.** _Effects of 2-year cocoa extract supplementation on inflammaging biomarkers in older US adults: findings from the COcoa Supplement and Multivitamin Outcomes Study randomised clinical trial._ Age Ageing, 2025. DOI: 10.1093/ageing/afaf269. PMID: 40966617.\n- **Xu 2024.** _Identification of crucial inflammaging related risk factors in multiple sclerosis._ Frontiers in Molecular Neuroscience, 2024. DOI: 10.3389/fnmol.2024.1398665. PMID: 38836117.\n- **Alp 2025.** _Balneotherapy as a potential immunomodulator in inflammaging._ Clin Rheumatol, 2025. DOI: 10.1007/s10067-025-07708-1. PMID: 41062894.\n- **Jiang 2025.** _Global research trends in inflammaging from 2005 to 2024: a bibliometric analysis._ Frontiers in Aging, 2025. DOI: 10.3389/fragi.2025.1554186. PMID: 40276724.\n- **Lin 2025.** _Corylin ameliorates inflammaging and pyroptosis in diabetic periodontitis: A preliminary in vitro study._ Journal of Dental Sciences, 2025. DOI: 10.1016/j.jds.2025.02.014. PMID: 40654439.\n- **Martino 2026.** _Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy._ Clinical and Translational Medicine, 2026. DOI: 10.1002/ctm2.70633. PMID: 41793184.\n- **Surboyo 2026.** _Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair._ Journal of Bone and Mineral Metabolism, 2026. DOI: 10.1007/s00774-026-01706-2. PMID: 41706167.\n- **Wang 2024.** _The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis._ NPJ Aging, 2024. DOI: 10.1038/s41514-024-00159-z. PMID: 39009582.\n- **Wrona 2024.** _The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience._ Frontiers in Aging, 2024. DOI: 10.3389/fragi.2024.1490302. PMID: 39478807.\n- **Skinner 2025.** _DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging._ GeroScience, 2025. DOI: 10.1007/s11357-024-01460-1. PMID: 39825170.\n- **Lee 2025.** _Photinia glabra -derived exosome-like nanovesicles mitigate skin inflammaging via dual regulation of inflammatory signaling and calcium homeostasis._ Nanomedicine, 2025. DOI: 10.1080/17435889.2025.2572991. PMID: 41088925.\n- **Zaongo 2026.** _Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence._ Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1792954. PMID: 42273671.\n- **Tan 2026.** _Inflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging._ Immunity & Ageing: I & A, 2026. DOI: 10.1186/s12979-026-00569-5. PMID: 42057125.\n- **Zhang 2022.** _A Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression._ Cancers, 2022. DOI: 10.3390/cancers14215185. PMID: 36358603.\n- **Aronoff 2025.** _Inflammaging is minimal among forager-horticulturalists in the Bolivian Amazon._ Proc Biol Sci, 2025. DOI: 10.1098/rspb.2025.1111. PMID: 40829666.\n- **Lv 2023.** _The effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis._ PLOS ONE, 2023. DOI: 10.1371/journal.pone.0284228. PMID: 37027447.\n- **Giunta 2023.** _Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies._ GeroScience, 2023. DOI: 10.1007/s11357-023-00947-7. PMID: 37821752.\n- **Villaume 2024.** _Pathogenesis and inflammaging in myelodysplastic syndromes._ Haematologica, 2024. DOI: 10.3324/haematol.2023.284944. PMID: 39445405.\n- **Spray 2025.** _Cardiovascular inflammaging: Mechanisms, consequences, and therapeutic perspectives._ Cell Reports Medicine, 2025. DOI: 10.1016/j.xcrm.2025.102264. PMID: 40782796.\n- **Aitella 2025.** _Rheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26199268. PMID: 41096536.\n- **Francavilla 2025.** _Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges._ Chemmedchem, 2025. DOI: 10.1002/cmdc.202400672. PMID: 39651728.\n- **Aitella 2026.** _Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27031206. PMID: 41683635.\n- **Moscucci 2025.** _Inflammaging and Cardiovascular Risk in Old Women._ High Blood Pressure & Cardiovascular Prevention, 2025. DOI: 10.1007/s40292-025-00758-1. PMID: 41366614.\n- **Filipek 2026.** _Inflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies._ Psoriasis: Targets and Therapy, 2026. DOI: 10.2147/PTT.S598115. PMID: 42232205.\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- **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 Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. 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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.","article_type":"evidence_map","counts":{"retrieved_count":60,"selected_count":60,"review_like_count":4,"primary_like_count":56,"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":"1017658b-fd94-47c3-8318-8b274e570656","submission_identity_key":"sha256:3dcfc39612b3f74aadf7a1823187c2a4c10640d962b05891aa86e9300be7f690","submission_payload_hash":"sha256:2edc39def459622b812586783336d7c532aabe31e709d0d5ad9715edd1ff5822","content_hash":"sha256:ad23c969a1c16f57287abf3be5dd865cb2a51edb22b9fdbb2c5a29fcd30a4a71","source_citation_hash":"sha256:54c3759185237a49bc903eba2c546e4ea206324979ada190733465cdc5f109be","author_signature":"sha256:ad23c969a1c16f57287abf3be5dd865cb2a51edb22b9fdbb2c5a29fcd30a4a71","run_id":"synthesis-inflammaging-v06-DAILY-2026-06-24T17-12-56Z","topic":"inflammaging","domain_slug":"longevity","category":"longevity","identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/8M5TJ","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"8m5tj","osf_url":"https://osf.io/8m5tj/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"8m5tj","url":"https://osf.io/8m5tj/","doi":"10.17605/OSF.IO/8M5TJ"},"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_41226544390e4d8a","dw_chain_url":"https://provenance.researka.org/artifacts/claim_41226544390e4d8a/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_41226544390e4d8a/chain","dw_source_artifact_id":"source_300aab549f814513","dw_input_artifact_ids":["source_dc02f038d93347a6","source_18a7c09c306d44a2","source_bdb0e66944274d1b","source_8be5e0e763524b28","source_e344c811aa96484b","source_e3fc479d0a5c4bd3"],"dw_step_id":"step_243028da608e4526","dw_step_hash":"dbbacb772ea4f6a101d0dc9a524a83905e3308c436f316a9ce9653d149a8bc52","dw_status":"registered","sha256":"sha256:c45e499ff93a12732d33f8db74548fde6ee3d3e94213b1438e9559bd6f412db9"},"created_at":"2026-06-24T21:32:50.899226+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"073c460c-0262-46c7-88e4-bc96b9c25668","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, 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 Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For 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.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"We conducted an AI-assisted structured evidence synthesis of 60 curated reference papers, applying a source-level audit trail that links every numeric claim to its source and flags cross-domain tensions across outcome classes (immune, longevity, cardiometabolic, contextual other).","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"Across the corpus, the evidence supports inflammaging as a biologically grounded, biomarker-detectable phenomenon whose clinical translation remains incomplete: mechanistic plausibility coexists with mixed or sparse human RCT evidence, longevity-relevant cohorts (Ceolin 2025 vs Spray 2025) disagree in direction, and boundary conditions across populations, exposures, and supplement classes are not yet established.","citation_support":[{"source_id":"source_4","study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","support_kind":"cited_as_match","cited_as":"Ceolin 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses."}],"candidate_sources":[]},{"claim_id":"claim_4","claim":"This paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, 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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"The conclusion is that Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"For 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.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"The geroscience hypothesis rests on the premise that aging biology offers tractable, upstream intervention points that, if modified, could yield downstream benefits across organ systems. Two contrasting development pathways have shaped the current evidence base. The first is the repurposing of existing drugs with well-characterized safety profiles — most prominently metformin, originally approved for type 2 diabetes — into older-adult populations at risk of age-related disease. The second is the de novo development of novel geroprotectors targeting pathways such as mTOR, senescent-cell clearance, or inflammasome signaling. Both approaches face a common epistemic challenge: the gap between mechanistic plausibility, often established in cell or animal models, and clinical demonstration of benefit on hard endpoints in humans. Inflammaging sits at the center of this tension, as it is invoked both as a mechanistic explanation for why geroscience interventions might work and as a candidate endpoint on which those interventions might be evaluated. Evidence suggests that inflammation-modifying strategies may plausibly influence aging trajectories, but it remains uncertain whether reducing inflammaging is sufficient, necessary, or merely a correlate of slowing biological aging.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"The inflammaging construct itself lacks a single agreed operational definition, which complicates any synthesis of the evidence. Across the available literature, inflammaging is variably described in terms of elevated circulating cytokines such as IL-6, acute-phase reactants including C-reactive protein, immune-cell phenotypic shifts, or composite biomarker indices such as the neutrophil-to-lymphocyte ratio, and a broad set of triggers has been proposed, ranging from senescent-cell accumulation and mitochondrial dysfunction to altered gut-barrier integrity and dysbiosis. Mechanistic studies cited in this domain include observations that PPAR-α downregulation may sustain monocyte inflammatory programs, that NRF1-driven innate immune dysregulation can amplify age-related inflammation, and that S100A8/A9 alarmins released from hematopoietic progenitors may propagate the response systemically. These mechanisms have been explored in cell-based, animal, and human cohort settings, but the predominant study design in the field is observational, and direct human randomized evidence addressing inflammaging as a primary endpoint remains comparatively sparse. Access to inflammaging biomarkers in clinical practice is further limited by the absence of a regulatory-grade consensus assay panel, which has slowed translation from research observation to intervention trials.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"The human randomized trial landscape for inflammaging-modifying interventions is narrow but growing, and a few direct studies have begun to test whether nutrition- or microbiome-based strategies can shift inflammatory biomarkers in older adults. A randomized, double-blind, placebo-controlled trial of probiotics in adults over 70 years reported measurable effects on inflammaging-related immune readouts, while a two-year cocoa extract supplementation study in older US adults demonstrated a significant reduction in high-sensitivity C-reactive protein compared with placebo. Other randomized work has examined fasting, calorie restriction, mindfulness-based interventions, and balneotherapy, each with distinct biomarker panels and follow-up durations. Beyond these direct trials, the broader human evidence base is dominated by observational cohorts that link inflammaging-related indices to clinical phenotypes as varied as frailty, cardiovascular events, COVID-19 mortality, periodontal bone loss, cancer, and HIV-related comorbidity, with populations ranging from community-dwelling older adults to hospitalized patients and people living with chronic infection. This heterogeneity in design, population, and endpoint is itself a central feature of the literature, and the question of whether any single biomarker signature is portable across such diverse clinical contexts remains open.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"Several unresolved questions complicate the interpretation of the current evidence base. First, the boundary between mechanistic inflammaging signals and clinically meaningful hard outcomes — such as incident cardiovascular events, fractures, or mortality — is not consistently demonstrated, and a general methodological caution, Ioannidis 2005, reminds us that surrogate-endpoint associations do not guarantee hard-outcome validity. Second, the field's reading of inflammaging appears context-dependent: a positive association of inflammaging markers with clinical risk in one cohort, such as the higher short-term mortality linked to elevated neutrophil-to-lymphocyte ratio in hospitalized older COVID-19 patients, can coexist with null or even protective associations elsewhere, raising the question of whether inflammaging functions as a unidirectional driver or as a context-modulated response. Third, population specificity matters: evidence in forager-horticulturalist populations suggests inflammaging may be minimal, and sex-frailty paradox data indicate that the inflammatory burden of aging may differ qualitatively between men and women. Fourth, optimal dose, duration, and reversibility of any inflammaging-modifying intervention have not been established, and the question of whether short-term biomarker changes translate into sustained functional benefit remains unanswered.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"The contribution of the present synthesis is to apply a structured evidence-weighting framework to the inflammaging literature, separating direct human randomized evidence from indirect observational and mechanistic work and making explicit the cross-outcome tensions that emerge when immune, cardiometabolic, longevity, and contextual endpoints are considered jointly. Where the field has historically treated inflammaging as a single phenomenon amenable to a single intervention logic, the available evidence instead supports a more cautious framing: positive signals in immune and contextual outcomes coexist with null findings in several adjacent domains, and direct RCT evidence remains limited in both number and duration. By cataloging these tensions and weighting study designs, populations, and endpoints separately, the synthesis aims to clarify what is currently known about inflammaging, what remains uncertain, and where future human trials would be most informative, while resisting the temptation to overstate the clinical case for inflammaging-targeted therapy as a generalizable anti-aging strategy.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"The background evidence for Chronic low-grade inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Lazou-Ahren 2024, Li 2025b are interpreted separately from mechanistic studies such as Netti 2026, Lin 2025, Aitella 2025, because these evidence roles answer different questions about aging biology and clinical translation.","citation_support":[{"source_id":"source_13","study":"Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial","doi":"10.1007/s12602-024-10310-7","url":"https://doi.org/10.1007/s12602-024-10310-7","support_kind":"cited_as_match","cited_as":"Lazou-Ahren 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"The disparity between increased lifespan and healthy aging, marked by prevalent \"inflammaging\", highlights the global challenge in care of older persons. This study explored the anti-inflammatory effects of Lactiplantibacillus plantarum HEAL9 (LpHEAL9), alone or combined with berries, on older volunteers with chronic low-grade inflammation (LGI). It was a randomized, double-blind, placebo-controlled trial, with a total of 66 volunteers (> 70 years old), randomly assigned, and equally distributed, to placebo, LpHEAL9 or LpHEAL9 + Berries group. After a 2-week run-in period, participants underwent a 4-week dietary intervention. Intake of LpHEAL9 showed a trend towards reduction in serum CRP but without reaching statistical significance. However, LpHEAL9 significantly decreased fecal calprotectin levels compared to placebo. LpHEAL9+Berries did not show any effect on inflammation. Both probiotic groups showed a trend in improving cognitive function albeit not reaching statistical significance. Our findings suggest that the probiotic strain L. plantarum HEAL9 has a modest impact on LGI in a healthy older population (ClinicalTrials.gov ID: NCT02342496)."},{"source_id":"source_52","study":"Rheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies","doi":"10.3390/ijms26199268","url":"https://doi.org/10.3390/ijms26199268","support_kind":"cited_as_match","cited_as":"Aitella 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Immunosenescence refers to the set of immunoendocrinological alterations underlying the progressive decline in innate and adaptive immune function that occurs with aging. It is closely linked to the concept of inflammaging, a state of low-grade chronic systemic inflammation that contributes to age-related diseases. In the elderly, key features of diseases such as rheumatoid arthritis, particularly in its elderly onset form, and senile osteoporosis are characterized by a decline in sex hormones and the immunoregulatory IL-2; an increase in serum autoantibodies and pro-inflammatory mediators such as TNF-α, IL-6; and upregulation of bone-related factors RANKL, DKK1, and sclerostin, including the dysregulation of the IL-33/IL-31 axis. The aim of this review is to examine the key molecular pathways of immunosenescence in osteoimmunology, as well as the potential for therapeutic modulation of inflammaging through biologic and target synthetic disease-modifying antirheumatic drugs, denosumab and romosozumab, with particular attention to their management in elderly patients."}],"candidate_sources":[]},{"claim_id":"claim_15","claim":"The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"Across the retained sources, positive signals cluster around the immune and inflammation, contextual adjacent evidence outcome classes; null signals around the contextual adjacent evidence, immune and inflammation, longevity outcome classes; and negative or adverse signals around the immune and inflammation, longevity outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"The 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.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"The 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.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, immune and inflammation, longevity, mechanism, mortality and survival, 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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"| Contextual Adjacent Evidence | n=25; claims=804 | no extracted directional signal in 21/25 sources | 24 indirect; 1 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","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":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"Contextual Adjacent Evidence: n=25; claims=804; no extracted directional signal in 21/25 sources | directness: 24 indirect; 1 review; main limitation: no direct clinical anchor.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Additional corpus sources included animal/preclinical evidence; three sources populate the cardiometabolic outcome class, and none are positioned as a direct anti-aging clinical RCT in healthy adults. Cares 2026 is a systematic review of diet and exercise interventions in pediatric cancer survivors, framed around cardiometabolic disease risk and inflammaging biomarkers rather than longevity endpoints. Tizazu 2024 is an observational cohort in adults (canonical trial ID NCT03340935) examining how fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Xiong 2025 is a mechanistic cohort study in adults using advanced glycation end products to induce inflammaging in periodontal ligament fibroblasts via the RAGE/AKT/mTOR/glycolysis pathway. Across the corpus, the cardiometabolic evidence base combines a pediatric-survivor review, an adult fasting cohort, and a tissue-level mechanistic study, with no single trial anchoring a clinical inflammaging endpoint.","citation_support":[{"source_id":"source_12","study":"Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review","doi":"10.1016/j.advnut.2026.100605","url":"https://doi.org/10.1016/j.advnut.2026.100605","support_kind":"cited_as_match","cited_as":"Cares 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"The population of pediatric cancer survivors (PCSs) in the United States has been steadily increasing over the last decade. However, due to cancer-related treatment and subsequent lifestyle behaviors related to diet and physical activity, PCSs are burdened by accelerated biological aging leading to early onset of chronic diseases. The accelerated aging process may be due to \"inflammaging,\" a phenomenon associated with cardiometabolic disease risk factors, including chronic inflammation and changes in gut microbiome structure and function. This systematic review was conducted to explore the literature as it relates to the impact of diet and/or exercise interventions in survivors of a pediatric cancer on markers of inflammaging and cardiometabolic risk markers. PubMed, CINAHL, and clinicaltrials.gov were searched for relevant interventional trials. Studies were included if they contained 1) an intervention arm that included survivors of a pediatric cancer, 2) an intervention that contained a dietary and/or exercise intervention, and 3) outcomes related to cardiometabolic disease risk or inflammaging."},{"source_id":"source_15","study":"Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging","doi":"10.1002/agm2.12342","url":"https://doi.org/10.1002/agm2.12342","support_kind":"cited_as_match","cited_as":"Tizazu 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored."},{"source_id":"source_33","study":"Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway","doi":"10.2340/aos.v84.44581","url":"https://doi.org/10.2340/aos.v84.44581","support_kind":"cited_as_match","cited_as":"Xiong 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Inflammaging plays a pivotal role in the pathogenesis of multiple age-related diseases, including periodontitis. Advanced glycation end products (AGEs) are known to induce inflammaging and exacerbate periodontitis. However, the mechanisms by which AGEs promote inflammaging remain unclear. This study aimed to investigate the mechanisms underlying AGE-induced inflammaging. METHODS AND RESULTS: Human periodontal ligament fibroblasts (hPDLFs) were extracted and stimulated with lipopolysaccharide (LPS), with prior treatment using AGEs. The expression of pro-inflammatory cytokines was measured to explore the role of AGEs in LPS-induced inflammation. Subsequently, hPDLFs were treated with AGEs and pre-incubated with 2-deoxyglucose (2-DG, a glycolysis inhibitor), Ly294002 (an AKT/mTOR pathway inhibitor), and FPS-ZM1 (a receptor for advanced glycation end product [RAGE] antagonist) to assess the levels of inflammaging markers, glycolysis, AKT/mTOR pathway activation, and RAGE expression, along with the potential relationships among these factors."}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Additional corpus sources included animal/preclinical evidence; the quantitative yield is uneven across the three sources. Cares 2026 reports no p-values in the available excerpt, consistent with a narrative table-driven systematic review. No effect direction is recorded for Cares 2026 or Xiong 2025, and the effect direction for Tizazu 2024 is listed as unclear, so the cardiometabolic class as currently curated cannot support a directional synthesis statement.","citation_support":[],"candidate_sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"Mechanistically, the cardiometabolic sources converge on inflammaging-relevant pathways even though the populations and exposures differ. Preclinical data from Xiong 2025 place the RAGE/AKT/mTOR/glycolysis axis in periodontal ligament fibroblasts, identifying a tissue substrate through which advanced glycation end products could propagate chronic inflammatory signaling relevant to cardiometabolic risk. Mechanistic human and observational data from Tizazu 2024 point to dendritic-cell compartment remodeling (mDCs versus pDCs) under fasting/calorie restriction, linking nutrient-sensing inputs to immunosenescence biomarkers. The Cares 2026 review layer sits above these mechanistic findings by aggregating diet-and-exercise interventions in a pediatric survivor population, where the same downstream inflammatory biomarkers are framed as cardiometabolic risk markers rather than as longevity endpoints.","citation_support":[{"source_id":"source_12","study":"Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review","doi":"10.1016/j.advnut.2026.100605","url":"https://doi.org/10.1016/j.advnut.2026.100605","support_kind":"cited_as_match","cited_as":"Cares 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"The population of pediatric cancer survivors (PCSs) in the United States has been steadily increasing over the last decade. However, due to cancer-related treatment and subsequent lifestyle behaviors related to diet and physical activity, PCSs are burdened by accelerated biological aging leading to early onset of chronic diseases. The accelerated aging process may be due to \"inflammaging,\" a phenomenon associated with cardiometabolic disease risk factors, including chronic inflammation and changes in gut microbiome structure and function. This systematic review was conducted to explore the literature as it relates to the impact of diet and/or exercise interventions in survivors of a pediatric cancer on markers of inflammaging and cardiometabolic risk markers. PubMed, CINAHL, and clinicaltrials.gov were searched for relevant interventional trials. Studies were included if they contained 1) an intervention arm that included survivors of a pediatric cancer, 2) an intervention that contained a dietary and/or exercise intervention, and 3) outcomes related to cardiometabolic disease risk or inflammaging."},{"source_id":"source_15","study":"Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging","doi":"10.1002/agm2.12342","url":"https://doi.org/10.1002/agm2.12342","support_kind":"cited_as_match","cited_as":"Tizazu 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored."},{"source_id":"source_33","study":"Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway","doi":"10.2340/aos.v84.44581","url":"https://doi.org/10.2340/aos.v84.44581","support_kind":"cited_as_match","cited_as":"Xiong 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Inflammaging plays a pivotal role in the pathogenesis of multiple age-related diseases, including periodontitis. Advanced glycation end products (AGEs) are known to induce inflammaging and exacerbate periodontitis. However, the mechanisms by which AGEs promote inflammaging remain unclear. This study aimed to investigate the mechanisms underlying AGE-induced inflammaging. METHODS AND RESULTS: Human periodontal ligament fibroblasts (hPDLFs) were extracted and stimulated with lipopolysaccharide (LPS), with prior treatment using AGEs. The expression of pro-inflammatory cytokines was measured to explore the role of AGEs in LPS-induced inflammation. Subsequently, hPDLFs were treated with AGEs and pre-incubated with 2-deoxyglucose (2-DG, a glycolysis inhibitor), Ly294002 (an AKT/mTOR pathway inhibitor), and FPS-ZM1 (a receptor for advanced glycation end product [RAGE] antagonist) to assess the levels of inflammaging markers, glycolysis, AKT/mTOR pathway activation, and RAGE expression, along with the potential relationships among these factors."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"Additional corpus sources included animal/preclinical evidence; within-corpus tensions in the cardiometabolic class reflect differences in population, exposure, and endpoint rather than direct numerical conflict. Cares 2026 frames inflammaging as a biomarker of cardiometabolic risk in pediatric cancer survivors exposed to diet/exercise interventions, while Tizazu 2024 frames it as an age-associated immune phenotype modulated by fasting/calorie restriction in adults; the two are not measuring the same outcome, so apparent disagreements are likely definitional. Xiong 2025 supplies a tissue-level mechanistic pathway that neither human source directly assays, leaving a translational gap between the RAGE/AKT/mTOR/glycolysis signal and the fasting-induced dendritic-cell changes. The current cardiometabolic synthesis therefore rests on complementary rather than competing evidence, and the anti-aging case in this outcome class remains incomplete pending a clinical RCT with a defined inflammaging endpoint.","citation_support":[{"source_id":"source_12","study":"Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review","doi":"10.1016/j.advnut.2026.100605","url":"https://doi.org/10.1016/j.advnut.2026.100605","support_kind":"cited_as_match","cited_as":"Cares 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"The population of pediatric cancer survivors (PCSs) in the United States has been steadily increasing over the last decade. However, due to cancer-related treatment and subsequent lifestyle behaviors related to diet and physical activity, PCSs are burdened by accelerated biological aging leading to early onset of chronic diseases. The accelerated aging process may be due to \"inflammaging,\" a phenomenon associated with cardiometabolic disease risk factors, including chronic inflammation and changes in gut microbiome structure and function. This systematic review was conducted to explore the literature as it relates to the impact of diet and/or exercise interventions in survivors of a pediatric cancer on markers of inflammaging and cardiometabolic risk markers. PubMed, CINAHL, and clinicaltrials.gov were searched for relevant interventional trials. Studies were included if they contained 1) an intervention arm that included survivors of a pediatric cancer, 2) an intervention that contained a dietary and/or exercise intervention, and 3) outcomes related to cardiometabolic disease risk or inflammaging."},{"source_id":"source_15","study":"Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging","doi":"10.1002/agm2.12342","url":"https://doi.org/10.1002/agm2.12342","support_kind":"cited_as_match","cited_as":"Tizazu 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored."},{"source_id":"source_33","study":"Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway","doi":"10.2340/aos.v84.44581","url":"https://doi.org/10.2340/aos.v84.44581","support_kind":"cited_as_match","cited_as":"Xiong 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Inflammaging plays a pivotal role in the pathogenesis of multiple age-related diseases, including periodontitis. Advanced glycation end products (AGEs) are known to induce inflammaging and exacerbate periodontitis. However, the mechanisms by which AGEs promote inflammaging remain unclear. This study aimed to investigate the mechanisms underlying AGE-induced inflammaging. METHODS AND RESULTS: Human periodontal ligament fibroblasts (hPDLFs) were extracted and stimulated with lipopolysaccharide (LPS), with prior treatment using AGEs. The expression of pro-inflammatory cytokines was measured to explore the role of AGEs in LPS-induced inflammation. Subsequently, hPDLFs were treated with AGEs and pre-incubated with 2-deoxyglucose (2-DG, a glycolysis inhibitor), Ly294002 (an AKT/mTOR pathway inhibitor), and FPS-ZM1 (a receptor for advanced glycation end product [RAGE] antagonist) to assess the levels of inflammaging markers, glycolysis, AKT/mTOR pathway activation, and RAGE expression, along with the potential relationships among these factors."}],"candidate_sources":[]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"073c460c-0262-46c7-88e4-bc96b9c25668","content_hash":"sha256:ad23c969a1c16f57287abf3be5dd865cb2a51edb22b9fdbb2c5a29fcd30a4a71","nodes":[{"id":"073c460c-0262-46c7-88e4-bc96b9c25668","type":"publication","title":"Research Synthesis: Chronic low-grade inflammation"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, 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 Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For 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."},{"id":"claim_2","type":"claim","text":"We conducted an AI-assisted structured evidence synthesis of 60 curated reference papers, applying a source-level audit trail that links every numeric claim to its source and flags cross-domain tensions across outcome classes (immune, longevity, cardiometabolic, contextual other)."},{"id":"claim_3","type":"claim","text":"Across the corpus, the evidence supports inflammaging as a biologically grounded, biomarker-detectable phenomenon whose clinical translation remains incomplete: mechanistic plausibility coexists with mixed or sparse human RCT evidence, longevity-relevant cohorts (Ceolin 2025 vs Spray 2025) disagree in direction, and boundary conditions across populations, exposures, and supplement classes are not yet established."},{"id":"claim_4","type":"claim","text":"This paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims."},{"id":"claim_5","type":"claim","text":"The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base."},{"id":"claim_6","type":"claim","text":"Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_7","type":"claim","text":"The conclusion is that Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_8","type":"claim","text":"For 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."},{"id":"claim_9","type":"claim","text":"The geroscience hypothesis rests on the premise that aging biology offers tractable, upstream intervention points that, if modified, could yield downstream benefits across organ systems. Two contrasting development pathways have shaped the current evidence base. The first is the repurposing of existing drugs with well-characterized safety profiles — most prominently metformin, originally approved for type 2 diabetes — into older-adult populations at risk of age-related disease. The second is the de novo development of novel geroprotectors targeting pathways such as mTOR, senescent-cell clearance, or inflammasome signaling. Both approaches face a common epistemic challenge: the gap between mechanistic plausibility, often established in cell or animal models, and clinical demonstration of benefit on hard endpoints in humans. Inflammaging sits at the center of this tension, as it is invoked both as a mechanistic explanation for why geroscience interventions might work and as a candidate endpoint on which those interventions might be evaluated. Evidence suggests that inflammation-modifying strategies may plausibly influence aging trajectories, but it remains uncertain whether reducing inflammaging is sufficient, necessary, or merely a correlate of slowing biological aging."},{"id":"claim_10","type":"claim","text":"The inflammaging construct itself lacks a single agreed operational definition, which complicates any synthesis of the evidence. Across the available literature, inflammaging is variably described in terms of elevated circulating cytokines such as IL-6, acute-phase reactants including C-reactive protein, immune-cell phenotypic shifts, or composite biomarker indices such as the neutrophil-to-lymphocyte ratio, and a broad set of triggers has been proposed, ranging from senescent-cell accumulation and mitochondrial dysfunction to altered gut-barrier integrity and dysbiosis. Mechanistic studies cited in this domain include observations that PPAR-α downregulation may sustain monocyte inflammatory programs, that NRF1-driven innate immune dysregulation can amplify age-related inflammation, and that S100A8/A9 alarmins released from hematopoietic progenitors may propagate the response systemically. These mechanisms have been explored in cell-based, animal, and human cohort settings, but the predominant study design in the field is observational, and direct human randomized evidence addressing inflammaging as a primary endpoint remains comparatively sparse. Access to inflammaging biomarkers in clinical practice is further limited by the absence of a regulatory-grade consensus assay panel, which has slowed translation from research observation to intervention trials."},{"id":"claim_11","type":"claim","text":"The human randomized trial landscape for inflammaging-modifying interventions is narrow but growing, and a few direct studies have begun to test whether nutrition- or microbiome-based strategies can shift inflammatory biomarkers in older adults. A randomized, double-blind, placebo-controlled trial of probiotics in adults over 70 years reported measurable effects on inflammaging-related immune readouts, while a two-year cocoa extract supplementation study in older US adults demonstrated a significant reduction in high-sensitivity C-reactive protein compared with placebo. Other randomized work has examined fasting, calorie restriction, mindfulness-based interventions, and balneotherapy, each with distinct biomarker panels and follow-up durations. Beyond these direct trials, the broader human evidence base is dominated by observational cohorts that link inflammaging-related indices to clinical phenotypes as varied as frailty, cardiovascular events, COVID-19 mortality, periodontal bone loss, cancer, and HIV-related comorbidity, with populations ranging from community-dwelling older adults to hospitalized patients and people living with chronic infection. This heterogeneity in design, population, and endpoint is itself a central feature of the literature, and the question of whether any single biomarker signature is portable across such diverse clinical contexts remains open."},{"id":"claim_12","type":"claim","text":"Several unresolved questions complicate the interpretation of the current evidence base. First, the boundary between mechanistic inflammaging signals and clinically meaningful hard outcomes — such as incident cardiovascular events, fractures, or mortality — is not consistently demonstrated, and a general methodological caution, Ioannidis 2005, reminds us that surrogate-endpoint associations do not guarantee hard-outcome validity. Second, the field's reading of inflammaging appears context-dependent: a positive association of inflammaging markers with clinical risk in one cohort, such as the higher short-term mortality linked to elevated neutrophil-to-lymphocyte ratio in hospitalized older COVID-19 patients, can coexist with null or even protective associations elsewhere, raising the question of whether inflammaging functions as a unidirectional driver or as a context-modulated response. Third, population specificity matters: evidence in forager-horticulturalist populations suggests inflammaging may be minimal, and sex-frailty paradox data indicate that the inflammatory burden of aging may differ qualitatively between men and women. Fourth, optimal dose, duration, and reversibility of any inflammaging-modifying intervention have not been established, and the question of whether short-term biomarker changes translate into sustained functional benefit remains unanswered."},{"id":"claim_13","type":"claim","text":"The contribution of the present synthesis is to apply a structured evidence-weighting framework to the inflammaging literature, separating direct human randomized evidence from indirect observational and mechanistic work and making explicit the cross-outcome tensions that emerge when immune, cardiometabolic, longevity, and contextual endpoints are considered jointly. Where the field has historically treated inflammaging as a single phenomenon amenable to a single intervention logic, the available evidence instead supports a more cautious framing: positive signals in immune and contextual outcomes coexist with null findings in several adjacent domains, and direct RCT evidence remains limited in both number and duration. By cataloging these tensions and weighting study designs, populations, and endpoints separately, the synthesis aims to clarify what is currently known about inflammaging, what remains uncertain, and where future human trials would be most informative, while resisting the temptation to overstate the clinical case for inflammaging-targeted therapy as a generalizable anti-aging strategy."},{"id":"claim_14","type":"claim","text":"The background evidence for Chronic low-grade inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Lazou-Ahren 2024, Li 2025b are interpreted separately from mechanistic studies such as Netti 2026, Lin 2025, Aitella 2025, because these evidence roles answer different questions about aging biology and clinical translation."},{"id":"claim_15","type":"claim","text":"The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect."},{"id":"claim_16","type":"claim","text":"Across the retained sources, positive signals cluster around the immune and inflammation, contextual adjacent evidence outcome classes; null signals around the contextual adjacent evidence, immune and inflammation, longevity outcome classes; and negative or adverse signals around the immune and inflammation, longevity outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation."},{"id":"claim_17","type":"claim","text":"The 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."},{"id":"claim_18","type":"claim","text":"The 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."},{"id":"claim_19","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_20","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_21","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, immune and inflammation, longevity, mechanism, mortality and survival, 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_22","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_23","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_24","type":"claim","text":"| Contextual Adjacent Evidence | n=25; claims=804 | no extracted directional signal in 21/25 sources | 24 indirect; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_25","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_26","type":"claim","text":"Contextual Adjacent Evidence: n=25; claims=804; no extracted directional signal in 21/25 sources | directness: 24 indirect; 1 review; main limitation: no direct clinical anchor."},{"id":"claim_27","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; three sources populate the cardiometabolic outcome class, and none are positioned as a direct anti-aging clinical RCT in healthy adults. Cares 2026 is a systematic review of diet and exercise interventions in pediatric cancer survivors, framed around cardiometabolic disease risk and inflammaging biomarkers rather than longevity endpoints. Tizazu 2024 is an observational cohort in adults (canonical trial ID NCT03340935) examining how fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Xiong 2025 is a mechanistic cohort study in adults using advanced glycation end products to induce inflammaging in periodontal ligament fibroblasts via the RAGE/AKT/mTOR/glycolysis pathway. Across the corpus, the cardiometabolic evidence base combines a pediatric-survivor review, an adult fasting cohort, and a tissue-level mechanistic study, with no single trial anchoring a clinical inflammaging endpoint."},{"id":"claim_28","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the quantitative yield is uneven across the three sources. Cares 2026 reports no p-values in the available excerpt, consistent with a narrative table-driven systematic review. No effect direction is recorded for Cares 2026 or Xiong 2025, and the effect direction for Tizazu 2024 is listed as unclear, so the cardiometabolic class as currently curated cannot support a directional synthesis statement."},{"id":"claim_29","type":"claim","text":"Mechanistically, the cardiometabolic sources converge on inflammaging-relevant pathways even though the populations and exposures differ. Preclinical data from Xiong 2025 place the RAGE/AKT/mTOR/glycolysis axis in periodontal ligament fibroblasts, identifying a tissue substrate through which advanced glycation end products could propagate chronic inflammatory signaling relevant to cardiometabolic risk. Mechanistic human and observational data from Tizazu 2024 point to dendritic-cell compartment remodeling (mDCs versus pDCs) under fasting/calorie restriction, linking nutrient-sensing inputs to immunosenescence biomarkers. The Cares 2026 review layer sits above these mechanistic findings by aggregating diet-and-exercise interventions in a pediatric survivor population, where the same downstream inflammatory biomarkers are framed as cardiometabolic risk markers rather than as longevity endpoints."},{"id":"claim_30","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; within-corpus tensions in the cardiometabolic class reflect differences in population, exposure, and endpoint rather than direct numerical conflict. Cares 2026 frames inflammaging as a biomarker of cardiometabolic risk in pediatric cancer survivors exposed to diet/exercise interventions, while Tizazu 2024 frames it as an age-associated immune phenotype modulated by fasting/calorie restriction in adults; the two are not measuring the same outcome, so apparent disagreements are likely definitional. Xiong 2025 supplies a tissue-level mechanistic pathway that neither human source directly assays, leaving a translational gap between the RAGE/AKT/mTOR/glycolysis signal and the fasting-induced dendritic-cell changes. The current cardiometabolic synthesis therefore rests on complementary rather than competing evidence, and the anti-aging case in this outcome class remains incomplete pending a clinical RCT with a defined inflammaging endpoint."},{"id":"source_1","type":"source","study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases","year":2022,"doi":"10.3390/antiox11122413","url":"https://doi.org/10.3390/antiox11122413","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":"Li 2022","excerpt":"Excess alcohol consumption is a potential risk factor for cardiovascular diseases and is linked to accelerated aging. Drug discovery to reduce toxic cellular events of alcohol is required. Here, we investigated the effects of ethanol on human umbilical vein endothelial cells (HUVECs) and explored if doxycycline attenuates ethanol-mediated molecular events in endothelial cells. Initially, a drug screening using a panel of 170 drugs was performed, and doxycycline was selected for further experiments. HUVECs were treated with different concentrations (300 mM and 400 mM) of ethanol with or without doxycycline (10 µg/mL). Telomere length was quantified as telomere to single-copy gene (T/S) ratio. Telomere length and the mRNA expression were quantified by qRT-PCR, and protein level was analyzed by Western blot (WB). Ethanol treatment accelerated cellular aging, and doxycycline treatment recovered telomere length. Pathway analysis showed that doxycycline inhibited mTOR and NFκ-B activation. Doxycycline restored the expression of aging-associated proteins, including lamin b1 and DNA repair proteins KU70 and KU80."},{"id":"source_2","type":"source","study":"Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation","year":2025,"doi":"10.1007/s00345-024-05409-z","url":"https://doi.org/10.1007/s00345-024-05409-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":"Paal 2025","excerpt":"PURPOSE: The present study was performed to investigate the association of prostate cancer radiotherapy with inflammaging, a condition characterized by the elevation of inflammatory blood parameters that significantly increases the susceptibility to the occurrence or progression of age-related conditions. PATIENTS AND METHODS: A total of 306 patients treated with curative radiotherapy (RT) for prostate cancer were enrolled into the prospective study. Aging-related inflammatory parameters including C-reactive protein (CRP), albumin, fibrinogen, cholesterol, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were analyzed before and at the end of RT, and 3 and 15 months after completion of the RT. Statistical analysis was performed using non-parametric variance analysis. RESULTS: Overall variance analysis showed a significant influence of RT on all inflammatory parameters (p < 0.001) with the exception of CRP (p = 0.498). Pairwise analysis revealed a significant elevation of fibrinogen (p = 0.041), NLR (p < 0.001), and PLR levels (p < 0.001) as well as a significant decrease of albumin (p < 0.001) and cholesterol levels (p < 0.001) during the RT course."},{"id":"source_3","type":"source","study":"Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes","year":2026,"doi":"10.3390/antiox15050599","url":"https://doi.org/10.3390/antiox15050599","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":"Garcia-Gil 2026","excerpt":"Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin ( 1 ), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone ( 2 ), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox."},{"id":"source_4","type":"source","study":"Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability","year":2025,"doi":"10.1186/s12979-025-00548-2","url":"https://doi.org/10.1186/s12979-025-00548-2","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":"primary","cited_as":"Ceolin 2025","excerpt":"BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a low-cost inflammatory biomarker increasingly investigated in older populations as a cross-cutting indicator of immunosenescence and inflammaging. While elevated NLR has been shown to predict poor short-term outcomes in patients with COVID-19, its long-term prognostic role-particularly in older adults and in a sex-specific perspective-remains unclear. The aim of this study was to examine the association between admission NLR and 3.5-year all-cause mortality in older adults hospitalised with COVID-19, with a focus on sex-specific patterns. METHODS: Prospective observational cohort study with 3.5-year follow-up. A total of 440 patients aged ≥ 65 years hospitalized with confirmed SARS-CoV-2 infection were enrolled. NLR was calculated at admission and dichotomized using the optimal cut-off value (12.63) identified via maximally selected rank statistics. Associations between NLR and mortality were assessed using Cox proportional hazards models, adjusted for age, sex, and vaccination status. Effect modification by sex was explored through interaction terms and sex-stratified analyses."},{"id":"source_5","type":"source","study":"Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations","year":2026,"doi":"10.1002/ajpa.70211","url":"https://doi.org/10.1002/ajpa.70211","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":"Cole 2026","excerpt":"OBJECTIVES: Whereas chronic inflammation is a hallmark of aging in many human populations, inflammaging is reduced in groups characterized by frequent physical activity and diets low in processed foods. Since most biomarkers of inflammation require blood sampling, comparative data from our closest primate relatives have been derived from sedentary, captive primate populations whose processed diets are uncharacteristic of the wild. MATERIALS AND METHODS: We evaluated aging profiles of inflammation and oxidative stress biomarkers derived from urine and serum samples in semi-free ranging chimpanzees (Pan troglodytes) living in two African sanctuaries (N = 156 health checks, 73 individuals, ages 11-39 years), where diet and physical activity more closely approximates wild conditions than captive laboratory settings. We compared these to urinary markers from wild chimpanzees from Kanyawara, Kibale National Park, Uganda (N = 1849 time points, 50 individuals, ages 10-57 years), as well as published serum data from biomedical laboratories."},{"id":"source_6","type":"source","study":"New insights into the association between cardiometabolic index with metabolic profile, nutritional status, and inflammaging in older adults","year":2026,"doi":"10.3389/fragi.2025.1699767","url":"https://doi.org/10.3389/fragi.2025.1699767","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":"Ramuth 2026","excerpt":"INTRODUCTION: Cardiometabolic index (CMI) has been highlighted as a useful tool for predicting cardiovascular and metabolic disease, but its association with systemic inflammatory status in the aged population is not yet fully understood. Thus, we investigated the association between the CMI and the triad -metabolic profile X body mass index X inflammaging -in older adults classified as having or not having obesity. METHODS: A total of 132 older adults of both sexes (women-68; men-64, mean age of 71.3±6.5 years), participated in this study. Demographic and anthropometric data, as well as blood samples, were collected to assess blood glucose, lipids, protein, and inflammatory profiles. RESULTS: Initially, the volunteers were separated according to the CMI values into two groups: G1 (<50% of the mean CMI value) and G2 (>50% of the mean CMI value). Volunteers in the G2 group, regardless of gender, presented not only lower HDL-c values but also higher weight, BMI, levels of total cholesterol, LDL-c, triglycerides, and the triglycerides to HDL ratio (TG/HDL) than the G1 group."},{"id":"source_7","type":"source","study":"Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging","year":2026,"doi":"10.1038/s43587-026-01107-0","url":"https://doi.org/10.1038/s43587-026-01107-0","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":"Mishra 2026","excerpt":"Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging."},{"id":"source_8","type":"source","study":"Bottom-up engineering of the nucleus pulposus using a photocrosslinkable decellularized matrix hydrogel attenuates inflammaging and enhances microtissue-mediated regeneration","year":2025,"doi":"10.1016/j.mtbio.2025.102347","url":"https://doi.org/10.1016/j.mtbio.2025.102347","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":"Li 2025","excerpt":"Degenerative disc disease (DDD), characterized by the pathological deterioration of nucleus pulposus (NP) tissue, affects millions globally. Tissue engineering strategies offer potential to create tissue-engineered NP (TE-NP) analogs to address DDD. However, traditional \"top-down' approaches face challenges in achieving uniform cell distribution and replicating the intradiscal extracellular matrix (ECM) environment. In contrast, a \"bottom-up' strategy utilizing microscale seed units represents a promising alternative. This study introduces an innovative \"bottom-up' approach for constructing TE-NP, leveraging bioreactor-cultivated NP microtissues (NP-MTs) as seed units and a novel methacrylate-modified decellularized nucleus pulposus matrix (DNPM-MA) hydrogel as a supporting biomaterial. NP-MTs cultivated under low-magnitude hydrostatic pressure exhibit nascent ECM surroundings adapting well to the intradiscal microenvironment. The DNPM-MA hydrogel, with its compositional and mechanical attributes, supports the growth, migration, proliferation, and ECM synthesis of NP-MTs, making it an ideal biomaterial for long-term cultivation."},{"id":"source_9","type":"source","study":"Hematopoietic progenitor cell liabilities and alarmins S100A8/A9‐related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults","year":2022,"doi":"10.1111/acel.13545","url":"https://doi.org/10.1111/acel.13545","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":"Bonora 2022","excerpt":"Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits."},{"id":"source_10","type":"source","study":"The alteration of bile acids and gut microbiota is associated with intestinal barrier dysfunction and inflammaging in human","year":2026,"doi":"10.3389/fragi.2026.1741360","url":"https://doi.org/10.3389/fragi.2026.1741360","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":"Xu 2026","excerpt":"BACKGROUND: The increasing prevalence of age-related chronic diseases, driven by the aging population, poses substantial medical and economic challenges. Emerging researches have underscored the crucial roles of gut microbiota and bile acids (BAs) in metabolic and physiological functions regulation. METHODS: 100 elderly and 100 young participants were enrolled in this study. Fecal and serum BAs were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while gut microbiota composition was assessed through 16S rRNA gene sequencing. Cytokine levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Elderly participants exhibited significantly lower levels of primary fecal BAs, particularly cholic acid (CA) and chenodeoxycholic acid (CDCA), alongside an increase in secondary BAs such as lithocholic acid (LCA), leading to a marked reduction in the primary/secondary BAs ratio. Serum showed a decline in both conjugated and unconjugated BAs, primary/secondary BAs ratio, while a notable rise in 12α-OH/non-12α-OH BAs."},{"id":"source_11","type":"source","study":"Programmed PPAR-α downregulation induces inflammaging by suppressing fatty acid catabolism in monocytes","year":2021,"doi":"10.1016/j.isci.2021.102766","url":"https://doi.org/10.1016/j.isci.2021.102766","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 2021","excerpt":"Inflammaging is associated with an increased risk of chronic disease. Monocytes are the principal immune cells for the production of inflammatory cytokines and contribute to inflammaging in the elderly. However, the underlying mechanisms remain largely unknown. Here, we found that monocytes from aged individuals contained high levels of lipid droplets (LDs), and this increase was correlated with impaired fatty acid oxidation. Downregulated peroxisome proliferator-activated receptor (PPAR)-α may be responsible for the pro-inflammatory phenotype of monocytes in aged individuals, as it was positively correlated with LD accumulation and increasing TNF-α concentration. Interestingly, interventions that result in PPAR-α upregulation, such as fenofibrate treatment, TNF-α neutralization, or calorie restriction, reversed the effect of aging on monocytes. Thus the downregulation of PPAR-α and LD levels in monocytes represents a novel biomarker for inflammaging. Furthermore, PPAR-α activation in the elderly may also alleviate long-term inflammaging, preventing the development of life-limiting chronic diseases."},{"id":"source_12","type":"source","study":"Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review","year":2026,"doi":"10.1016/j.advnut.2026.100605","url":"https://doi.org/10.1016/j.advnut.2026.100605","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":"Cares 2026","excerpt":"The population of pediatric cancer survivors (PCSs) in the United States has been steadily increasing over the last decade. However, due to cancer-related treatment and subsequent lifestyle behaviors related to diet and physical activity, PCSs are burdened by accelerated biological aging leading to early onset of chronic diseases. The accelerated aging process may be due to \"inflammaging,\" a phenomenon associated with cardiometabolic disease risk factors, including chronic inflammation and changes in gut microbiome structure and function. This systematic review was conducted to explore the literature as it relates to the impact of diet and/or exercise interventions in survivors of a pediatric cancer on markers of inflammaging and cardiometabolic risk markers. PubMed, CINAHL, and clinicaltrials.gov were searched for relevant interventional trials. Studies were included if they contained 1) an intervention arm that included survivors of a pediatric cancer, 2) an intervention that contained a dietary and/or exercise intervention, and 3) outcomes related to cardiometabolic disease risk or inflammaging."},{"id":"source_13","type":"source","study":"Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial","year":2024,"doi":"10.1007/s12602-024-10310-7","url":"https://doi.org/10.1007/s12602-024-10310-7","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":"Lazou-Ahren 2024","excerpt":"The disparity between increased lifespan and healthy aging, marked by prevalent \"inflammaging\", highlights the global challenge in care of older persons. This study explored the anti-inflammatory effects of Lactiplantibacillus plantarum HEAL9 (LpHEAL9), alone or combined with berries, on older volunteers with chronic low-grade inflammation (LGI). It was a randomized, double-blind, placebo-controlled trial, with a total of 66 volunteers (> 70 years old), randomly assigned, and equally distributed, to placebo, LpHEAL9 or LpHEAL9 + Berries group. After a 2-week run-in period, participants underwent a 4-week dietary intervention. Intake of LpHEAL9 showed a trend towards reduction in serum CRP but without reaching statistical significance. However, LpHEAL9 significantly decreased fecal calprotectin levels compared to placebo. LpHEAL9+Berries did not show any effect on inflammation. Both probiotic groups showed a trend in improving cognitive function albeit not reaching statistical significance. Our findings suggest that the probiotic strain L. plantarum HEAL9 has a modest impact on LGI in a healthy older population (ClinicalTrials.gov ID: NCT02342496)."},{"id":"source_14","type":"source","study":"Cardiac alterations following experimental hip fracture - inflammaging as independent risk factor","year":2022,"doi":"10.3389/fimmu.2022.895888","url":"https://doi.org/10.3389/fimmu.2022.895888","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":"Lackner 2022","excerpt":"BACKGROUND: Cardiac injuries following trauma are associated with a worse clinical outcome. So-called trauma-induced secondary cardiac injuries have been recently described after experimental long bone fracture even in absence of direct heart damage. With the progressive aging of our society, the number of elderly trauma victims rises and therefore the incidence of hip fractures increases. Hip fractures were previously shown to be associated with adverse cardiac events in elderly individuals, which have mainly been attributed to pre-conditioned cardiac diseases. The aim of the present study was to investigate the effect of hip fractures on the heart in healthy young and middle-aged mice. MATERIALS AND METHODS: Young (12-week-old) and middle-aged (52-week-old) female C57BL/6 mice either received an intramedullary stabilized proximal femur fracture or sham treatment. The observation time points included 6 and 24 h. Systemic levels of pro-inflammatory mediators as well as local inflammation and alterations in myocardial structure, metabolism and calcium homeostasis in left ventricular tissue was analyzed following hip fracture by multiplex analysis, RT-qPCR and immunohistochemistry."},{"id":"source_15","type":"source","study":"Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging","year":2024,"doi":"10.1002/agm2.12342","url":"https://doi.org/10.1002/agm2.12342","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":"Tizazu 2024","excerpt":"Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored."},{"id":"source_16","type":"source","study":"Inflammaging and the sex-frailty paradox","year":2025,"doi":"10.1007/s40520-025-03181-7","url":"https://doi.org/10.1007/s40520-025-03181-7","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":"Arosio 2025","excerpt":"BACKGROUND: The \"sex-frailty paradox\" is a concept that indicates how women despite being more frail are less susceptible to death than men. The roots of this paradox may lie in the different combination of biological, behavioural, and social factors between the two sexes. The aim of this study is to deepen our understanding of the different biological mechanisms underlying frailty and longevity in men and women, thus shedding further light on the sex-frailty paradox. METHODS: We studied 452 subjects (315 women and 137 men) stratifying them by age (≤ 80, 81-99 and ≥ 100 years) and sex. A 47-item frailty index was calculated. Plasma concentrations of inflammatory markers were analysed by next-generation ELISA. RESULTS: Women aged ≤ 80 years were less frail while those aged ≥ 100 years were more frail than their male counterparts. Interestingly, the 81-99-year-old group showed similar frailty degree between females and males. Most of the biomarkers increased with age in both sexes, while being associated differently with frailty, indicating that there are specific biological roots in the two sexes that influence frailty."},{"id":"source_17","type":"source","study":"Long-Term Physical Activity Mitigates Inflammaging Progression in Older Adults Amidst the COVID-19 Pandemic","year":2024,"doi":"10.3390/ijerph21111425","url":"https://doi.org/10.3390/ijerph21111425","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":"Santos 2024","excerpt":"BACKGROUND: Inflammaging and physical performance were investigated in older adults before and after the COVID-19 pandemic. METHODS: Older women ( n = 18) and men ( n = 7) (mean age = 73.8 ± 7.1) were evaluated before the COVID-19 pandemic (PRE), 12 months after the lockdown (POST), and 10 months after resuming exercise training (POST-TR). Physical tests [gait speed (GS) and timed-up-and-go (TUG)]; muscle strength (handgrip-HG); and serum cytokine levels were assessed. RESULTS: Older women showed higher GS and TUG at POST than PRE and POST-TR but lower HG at POST-TR than PRE, whereas older men exhibited lower HG at POST and POST-TR than PRE. Both groups presented (1) lower IL-10 and IL-12p70 values in contrast to higher IL-6/IL-10 and IL-8/IL-10 ratios at POST than PRE; (2) higher IL-10 values and lower IL-8/IL-10 ratio at POST-TR than POST; (3) higher IL-12p70/IL-10 ratio at POST-TR than PRE and POST. Particularly, older women showed (4) lower IL-6 values at POST and POST-TR than PRE; (5) lower IL-8 and IL-10 values at POST-TR than POST; (6) and higher TNF-α/IL-10 and IFN-γ/IL-10 ratios at POST than PRE and POST-TR."},{"id":"source_18","type":"source","study":"Gut-heart immuno-metabolic disruption associated with inflammaging and subclinical coronary artery disease in people with HIV on antiretroviral therapy","year":2026,"doi":"10.1186/s12979-026-00566-8","url":"https://doi.org/10.1186/s12979-026-00566-8","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":"primary","cited_as":"Diego-Matos 2026","excerpt":"BACKGROUND: Despite antiretroviral therapy (ART), people with HIV (PWH) face immunological ageing and accelerated comorbidities including coronary artery disease (CAD). Gut mucosal damage, chronic inflammation, and Tryptophan (Trp) catabolism into Kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO), are associated with HIV disease progression and atherosclerosis. Thus, we comprehensively assessed the interplay between these perturbations in PWH with subclinical CAD under ART. METHODS: Plasma levels of inflammatory mediators, Trp metabolites, and immune cell subset phenotyping were assessed on blood specimens from PWH and HIV seronegative participants with or without CAD diagnosed by cardiac computed tomography angiography from the Canadian HIV Aging Cohort Study. RESULTS: Levels of gut damage markers regenerating islet-derived protein 3 alpha (REG3α), intestinal fatty-acid binding protein (I-FABP) and soluble CD14 (sCD14) were increased in PWH, but only I-FABP was associated with CAD."},{"id":"source_19","type":"source","study":"Protective effects of Rosa roxburghii Tratt. extract against UVB-induced inflammaging through inhibiting the IL-17 pathway","year":2025,"doi":"10.1038/s41598-025-92559-8","url":"https://doi.org/10.1038/s41598-025-92559-8","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":"primary","cited_as":"Zhang 2025","excerpt":"Chronic inflammation is a critical mechanism contributing to the aging process; however, research specifically addressing chronic inflammation in skin biology remains limited. This study investigates the protective mechanism of Rosa roxburghii Tratt. (RRT) extract against UVB-induced inflammaging. RRT extract effectively reduces the secretion of IL-6, IL-1α, TNF-α, and PGE2 in keratinocytes. Additionally, it attenuates UVB-induced IL-17 pathway activation by downregulating IL-17RA, c-Fos, and c-Jun protein levels, as well as the gene expression of IL-17RA, TRAF6, HSP90, and IKKγ. Co-culturing human foreskin fibroblasts (HFF) with inflammatory factors secreted by UVB-exposed keratinocytes reveals that these factors significantly reduce mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS), thereby promoting aging in HFF. The anti-inflammaging effects of RRT extract are achieved through the reduction of β-galactosidase activity, targeting of the TGF-β1-Smad2/3 signaling pathway, upregulation of COL1A1 expression, and reduction of senescence-associated secretory phenotype secretion."},{"id":"source_20","type":"source","study":"Molecular Remodeling of Peritumoral Tissue in Clear Cell Renal Cell Carcinoma: Insights into Inflammaging and Prognostic Markers","year":2026,"doi":"10.3390/cancers18030414","url":"https://doi.org/10.3390/cancers18030414","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":"Netti 2026","excerpt":"Background/Objectives : Renal cell carcinoma (RCC) is a common and often asymptomatic malignancy with limited treatment options for advanced stages. Chronic inflammation and cellular senescence-collectively termed \"inflammaging\"-are emerging as key contributors to tumor progression. This study aimed to investigate the expression of inflammaging-related markers in RCC tissues, focusing on the role of PTX3, IL-6, and senescence-associated proteins in the tumor microenvironment. Methods : A retrospective cohort of 57 patients with clear cell RCC who underwent nephrectomy was analyzed. Formalin-fixed paraffin-embedded samples from tumor, peritumoral, and normal renal tissues were examined using confocal immunofluorescence microscopy to assess PTX3, IL-6, p21, and p16 expression. Senescence-associated β-galactosidase staining was performed to identify senescent cells. Serum IL-6 levels were measured by ELISA, and survival analysis was conducted using Kaplan-Meier curves and Cox regression analysis. Results : PTX3 and IL-6 were significantly upregulated in both peritumoral and tumor tissues compared to normal kidney samples ( p < 0.001)."},{"id":"source_21","type":"source","study":"NRF1-mediated innate immune response drives inflammaging","year":2025,"doi":"10.1038/s41467-025-66368-6","url":"https://doi.org/10.1038/s41467-025-66368-6","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":"Lei 2025","excerpt":"Aberrant innate immune responses contribute significantly to cellular senescence, yet the precise interplay between innate immunity and senescence remains poorly characterized. Here, we elucidate the pivotal role of nuclear respiratory factor 1 (NRF1) in orchestrating innate immune responses that drive senescence and the senescence-associated secretory phenotype (SASP). NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration in multiple organs. Mechanistically, NRF1 enhanced SASP by transcriptionally regulating TBK1 and IRF3, critical nodes in innate immunity essential for senescence induction. Conversely, NRF1 deficiency suppressed innate immune activation, thereby attenuating inflammation associated with senescence and aging. Additionally, DNA damage activated ATM kinase, which phosphorylated NRF1 at Ser393, augmenting the NRF1-TBK1/IRF3-type I interferon axis and exacerbating cellular senescence. Furthermore, NRF1 knockdown treatment effectively mitigated aging phenotypes and extended lifespan in aged mice."},{"id":"source_22","type":"source","study":"The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation","year":2025,"doi":"10.1172/jci.insight.187271","url":"https://doi.org/10.1172/jci.insight.187271","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":"Nelson 2025","excerpt":"Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh cell formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh cell development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming."},{"id":"source_23","type":"source","study":"Spatiotemporal mapping reveals Ccl8 hi macrophages as key drivers of testicular inflammaging","year":2025,"doi":"10.1002/ctm2.70527","url":"https://doi.org/10.1002/ctm2.70527","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":"Huang 2025","excerpt":"BACKGROUND: Testicular macrophages (TMs) are key regulators of testicular immune privilege and endocrine function in the testis. However, their age-related heterogeneity and role in testicular degeneration remain poorly characterized. METHODS: We performed spatial transcriptomics and FACS-enriched single-cell RNA sequencing (scRNA-seq) to characterize testicular macrophage heterogeneity across ageing. Key findings were validated through intratesticular injection of recombinant CCL8 protein, organotypic culture of seminiferous tubules, and immunofluorescence analysis. RESULTS: Using spatial transcriptomics, we identified pronounced Leydig niche senescence in aged testes, mechanistically linked to TM-mediated inflammatory remodelling. Coupling FACS-enriched TM isolation with scRNA-seq resolved seven transcriptionally distinct subpopulations, including ageing-associated subsets (Ccl8 hi and Cxcl13 hi ). These subsets exhibited inflammatory signalling rewiring (e.g., CCL8-CCR2 axis) and activation of senescence transcriptional regulators (ASCL2, SPI1, CEBPB, JUNB), with conserved mediators (CCL8, TREM2, IL1β, and CXCL2) across murine and human testes."},{"id":"source_24","type":"source","study":"Epigenetic silencing of SPHK1-IRF7 axis drives inflammaging in age-related meniscus degeneration via sphingolipid-immune dysregulation","year":2025,"doi":"10.1186/s13018-025-06518-0","url":"https://doi.org/10.1186/s13018-025-06518-0","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: Age-related meniscus injury (MI) involves inflammaging, but biomarkers and mechanisms remain unclear. METHODS: Ribonucleic acid (RNA) sequencing of meniscal tissues from 15 young (< 45 years) and 15 aging (≥ 45 years) MI patients (training dataset) identified differentially expressed inflammation-related genes (DE-IRGs). Biomarkers were screened via least absolute shrinkage and selection operator (LASSO) and support vector machines-recursive feature elimination (SVM-RFE) in the training dataset and validated through GSE191157 (testing dataset) and immunohistochemistry (IHC) staining in additional clinical specimens. Support vector machines (SVM) model and artificial neural network (ANN) model were constructed to predict the diagnostic performance of biomarkers for aging MI. Moreover, biomarkers enrichment analysis, and correlation among biomarkers, function-related genes, immune factors and immune cells were completed. Finally, transcription factor (TF)-biomarker-microRNAs (miRNAs) and competing endogenous RNA (ceRNA) regulatory networks analysis, and drug prediction were performed."},{"id":"source_25","type":"source","study":"IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin","year":2022,"doi":"10.1016/j.xjidi.2022.100112","url":"https://doi.org/10.1016/j.xjidi.2022.100112","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":"Horiba 2022","excerpt":"Macrophages can be polarized into two subsets: a proinflammatory (M1) or an anti-inflammatory (M2) phenotype. In this study, we show that an increased M1-to-M2 ratio associated with a decrease in IL-34 induces skin inflammaging. The total number of macrophages in the dermis did not change, but the number of M2 macrophages was significantly decreased. Thus, the M1-to-M2 ratio was significantly increased in sun-exposed aged skin and positively correlated with the percentage of p21 + and p16 + senescent cells in the dermis. The supernatant of M1 macrophages increased the percentages of senescence-associated β-galactosidase‒positive cells, whereas the supernatant of M2 macrophages decreased the percentages of senescence-associated β-galactosidase‒positive cells in vitro. Among the mechanisms that could explain the increase in the M1-to-M2 ratio, we found that the number of IL-34 + cells was decreased in aged skin and negatively correlated with the M1-to-M2 ratio. Furthermore, IL-34 induced the expression of CD206 and IL-10, which are M2 macrophage markers, in an in vitro assay."},{"id":"source_26","type":"source","study":"Interferon-related inflammaging links epigenetic age acceleration to multimorbidity","year":2026,"doi":"10.1016/j.xgen.2026.101218","url":"https://doi.org/10.1016/j.xgen.2026.101218","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":"Liu 2026","excerpt":"Chronic systemic inflammation and DNA methylation changes are two major hallmarks of aging, yet their interaction is poorly known. We investigated the relation between circulating inflammatory proteome and epigenetic age acceleration as assessed by DNA methylation in four independent cohorts of different ages and health conditions. Epigenetic age scores known to predict human health span (GrimAge and PhenoAge) were more strongly associated with age-associated inflammatory proteins, frailty, and multimorbidity when compared to epigenetic age scores associated with lifespan (Horvath and Hannum). Mendelian randomization analyses showed that blood concentrations of important inflammatory cytokines associated with the interferon pathway (CXCL9, CXCL10, CCL11, and IL-18) increase with age and are causal drivers of epigenetic age acceleration and age-related diseases. Furthermore, aging was associated with dysregulation of cytokine production capacity in immune cells in response to microbial stimulation. These findings argue that the interferon pathway may represent a target for anti-aging interventions."},{"id":"source_27","type":"source","study":"Pomegranate ( Punica granatum L.) Extract Effects on Inflammaging","year":2024,"doi":"10.3390/molecules29174174","url":"https://doi.org/10.3390/molecules29174174","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":"Cordiano 2024","excerpt":"Pomegranate is a notable source of nutrients, containing a considerable proportion of organic acids, polysaccharides, vitamins, fatty acids, and polyphenols such as flavonoids, phenolic acids, and tannins. It is also rich in nutritionally important minerals and chemical elements such as K, P, Na, Ca, Mg, and N. The presence of several bioactive compounds and metabolites in pomegranate has led to its incorporation into the functional food category, where it is used for its numerous therapeutic properties. Pomegranate's bioactive compounds have shown antioxidant, anti-inflammatory, and anticancer effects. Aging is a process characterized by the chronic accumulation of damages, progressively compromising cells, tissues, and organs over time. Inflammaging is a chronic, subclinical, low-grade inflammation that occurs during the aging process and is linked to many age-related diseases. This review aims to summarize and discuss the evidence of the benefits of pomegranate extract and its compounds to slow the aging processes by intervening in the mechanisms underlying inflammaging."},{"id":"source_28","type":"source","study":"Age-related nigral downregulation of the Parkinson’s risk factor FAM49B primes human microglia for inflammaging","year":2025,"doi":"10.1038/s41514-025-00296-z","url":"https://doi.org/10.1038/s41514-025-00296-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":"Martin 2025","excerpt":"Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD risk gene FAM49B is critically expressed in microglia of the human SNpc and is downregulated with age and PD. We utilized human and murine microglia cells to demonstrate the role of FAM49B in regulating fundamental microglial functions such as cytoskeletal maintenance, migration, surface adherence, energy homeostasis, autophagy, and, importantly, inflammatory response. Downregulation of microglial FAM49B, as observed in the SNpc of aging individuals, led to significant alterations in these cellular functions, which are associated with increased microglial activation."},{"id":"source_29","type":"source","study":"Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes","year":2025,"doi":"10.1002/advs.202505922","url":"https://doi.org/10.1002/advs.202505922","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":"Guo 2025","excerpt":"Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all-cause mortality. Whilst the effect of cell-type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high-resolution DNAm reference panel of 19 immune cell-types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all-cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non-negligible fraction of nucleated red blood cell-like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all-cause mortality."},{"id":"source_30","type":"source","study":"2-O-methylmagnolol mitigates the generation of reactive oxidative stress and inflammaging in human gingival epithelial cells and fibroblasts with advanced glycation end products stimulation","year":2025,"doi":"10.1016/j.jds.2025.04.022","url":"https://doi.org/10.1016/j.jds.2025.04.022","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":"Huang 2025b","excerpt":"BACKGROUND/PURPOSE: Individuals with diabetes mellitus (DM) are more susceptible to periodontitis, largely due to the accumulation of advanced glycation end-products (AGEs), which drive oxidative stress and inflammaging. Inflammaging is a state of chronic low-grade inflammation and accelerated cellular aging that contributes to periodontal degradation, mediated by AGEs-induced cellular senescence and senescence-associated secretory phenotype (SASP). 2-O-methylmagnolol (2-MG), a bioactive compound with antioxidant and anti-inflammatory properties, remains underexplored in DM-associated periodontal degeneration. This study investigated the effects of 2-MG on AGE-induced oxidative stress and inflammaging in human gingival epithelial cells (HGEs) and human gingival fibroblasts (HGFs). MATERIALS AND METHODS: The study assessed the effects of 2-MG on AGE-stimulated HGEs and HGFs by evaluating cell proliferation, wound healing capacity, reactive oxygen species (ROS) accumulation, cellular senescence markers, and the secretion of SASP factors, including interleukin (IL)-6 and IL-8."},{"id":"source_31","type":"source","study":"Inflammaging and Senescence-Driven Extracellular Matrix Remodeling in Age-Associated Cardiovascular Disease","year":2025,"doi":"10.3390/biom15101452","url":"https://doi.org/10.3390/biom15101452","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":"Mlynarska 2025","excerpt":"Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix remodeling. These hallmarks of aging interact to impair endothelial function, promote fibrosis, and compromise cardiac and vascular integrity. Key molecular pathways-including the renin-angiotensin-aldosterone system, NF-κB, NLRP3 inflammasome, IL-6, and TGF-β signaling-contribute to the transdifferentiation of vascular cells, immune dysregulation, and progressive tissue stiffening. We also highlight the role of the senescence-associated secretory phenotype and mitochondrial dysfunction in perpetuating inflammatory and fibrotic cascades. Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling."},{"id":"source_32","type":"source","study":"Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging","year":2025,"doi":"10.1186/s40659-025-00634-1","url":"https://doi.org/10.1186/s40659-025-00634-1","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":"Wang 2025","excerpt":"The paravertebral muscles play a critical role in maintaining dynamic spinal stability and physiological function. With aging, these muscles undergo senescence and degeneration, contributing to spinal instability and the development of low back pain. Age-related cellular death further accelerates chronic, low-grade inflammation termed “inflammaging” and disrupts the extracellular matrix (ECM), representing a key pathogenic mechanism driving paravertebral muscle degeneration (PMD). However, the core regulatory genes orchestrating inflammaging in this context have yet to be fully elucidated. The paravertebral muscles play an important role in supporting dynamic stability and physiological function of the spine. This study identified 409 differentially expressed genes (DEGs) through RNA sequencing. Subsequent bioinformatics analysis revealed 81 functionally relevant DEGs, with several hub genes such as Activating Transcription Factor 3 (ATF3), Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A/p21), and Interleukin-6 (IL-6) being significantly upregulated. These genes are associated with cellular death, ECM metabolic dysregulation, and inflammaging."},{"id":"source_33","type":"source","study":"Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway","year":2025,"doi":"10.2340/aos.v84.44581","url":"https://doi.org/10.2340/aos.v84.44581","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":"Xiong 2025","excerpt":"BACKGROUND: Inflammaging plays a pivotal role in the pathogenesis of multiple age-related diseases, including periodontitis. Advanced glycation end products (AGEs) are known to induce inflammaging and exacerbate periodontitis. However, the mechanisms by which AGEs promote inflammaging remain unclear. This study aimed to investigate the mechanisms underlying AGE-induced inflammaging. METHODS AND RESULTS: Human periodontal ligament fibroblasts (hPDLFs) were extracted and stimulated with lipopolysaccharide (LPS), with prior treatment using AGEs. The expression of pro-inflammatory cytokines was measured to explore the role of AGEs in LPS-induced inflammation. Subsequently, hPDLFs were treated with AGEs and pre-incubated with 2-deoxyglucose (2-DG, a glycolysis inhibitor), Ly294002 (an AKT/mTOR pathway inhibitor), and FPS-ZM1 (a receptor for advanced glycation end product [RAGE] antagonist) to assess the levels of inflammaging markers, glycolysis, AKT/mTOR pathway activation, and RAGE expression, along with the potential relationships among these factors."},{"id":"source_34","type":"source","study":"Effects of 2-year cocoa extract supplementation on inflammaging biomarkers in older US adults: findings from the COcoa Supplement and Multivitamin Outcomes Study randomised clinical trial.","year":2025,"doi":"10.1093/ageing/afaf269","url":"https://doi.org/10.1093/ageing/afaf269","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":"Li 2025b","excerpt":"OBJECTIVE: To examine the long-term effect of cocoa flavanols on inflammaging biomarkers in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). METHODS: COSMOS is a large, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial testing the effects of a cocoa extract supplement (containing 500 mg cocoa flavanols/day, including 80 mg (-)-epicatechin) among women aged ≥65 years and men aged ≥60 years. This ancillary study measured five widely used serum inflammaging biomarkers, including three pro-inflammatory markers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, tumour necrosis factor-α), one anti-inflammatory cytokine (interleukin-10) and one pleotropic cytokine (interferon-γ [IFN-γ]) in a random sample of 598 participants with biospecimens collected at baseline, Year 1, and Year 2. RESULTS: The mean age was 70.0 ± 5.6 years, and 49.8% were female. Cocoa extract supplementation significantly decreased hsCRP levels compared with placebo, with a between-group difference in yearly percentage change relative to baseline levels of -8.4% (95% CI, -14.1% to -2.3%; nominal P = .008; Holm-adjusted P value = .039)."},{"id":"source_35","type":"source","study":"Balneotherapy as a potential immunomodulator in inflammaging.","year":2025,"doi":"10.1007/s10067-025-07708-1","url":"https://doi.org/10.1007/s10067-025-07708-1","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":"Alp 2025","excerpt":"OBJECTIVE: This study aimed to investigate the association between the senescence-associated secretory phenotype (SASP) and balneotherapy (BT) in the elderly. MATERIALS AND METHODS: Patients over the age of 65 with simple osteoarthritis were screened for their demographic characteristics, and those prone to inflammaging were included. Individuals were divided into two groups: the BT group (n = 20) and the control group (n = 20). Patients in both groups performed home-based relaxation and active range of motion (ROM) exercises three times a week. SASP levels were evaluated in both groups before and after 2 weeks of intervention. RESULTS: In the BT group, interleukin-8 (IL-8) (p = 0.044), laminin (LN) (p < 0.001), fibroblast growth factor-2 (p < 0.001), membrane cofactor protein (MCP-2) (p = 0.002), interleukin-1β (p = 0.002), metalloproteinase-3 (MMP-3) (p = 0.028), and tumor necrosis factor-α (TNF-α) (p = 0.044) increased following treatment, while MMP-1 (p = 0.019) decreased. In the control group, LN (p < 0.001), MMP-3 (p = 0.044), and MCP-2 (p < 0.001) increased, whereas TNF-α (p < 0.001) decreased. Intergroup comparisons showed significant changes in LN (p = 0."},{"id":"source_36","type":"source","study":"Identification of crucial inflammaging related risk factors in multiple sclerosis","year":2024,"doi":"10.3389/fnmol.2024.1398665","url":"https://doi.org/10.3389/fnmol.2024.1398665","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":"Xu 2024","excerpt":"BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed. METHODS: First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential \"aging-inflammation-disease\" triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS. RESULTS: A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism."},{"id":"source_37","type":"source","study":"Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy","year":2026,"doi":"10.1002/ctm2.70633","url":"https://doi.org/10.1002/ctm2.70633","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":"Martino 2026","excerpt":"BACKGROUND: Clonal haematopoiesis (CH) is an age-related condition increasingly recognised for its relevance in haematologic malignancies. In chronic lymphocytic leukaemia (CLL), its prevalence and clinical implications are gaining attention, particularly in the context of prolonged patient survival and the widespread adoption of targeted therapies. A comprehensive understanding of the biological and clinical significance of CH in CLL is therefore essential. METHODS: This review synthesises current evidence on the biological basis, epidemiology and clinical impact of CH in CLL. Data from prospective clinical trials, real-world cohorts and translational studies were analysed to explore the associations between CH, genomic instability, immune dysregulation and inflammaging. Particular attention was given to the interaction between CH and contemporary therapeutic strategies, including Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors, and their potential influence on long-term outcomes."},{"id":"source_38","type":"source","study":"Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair","year":2026,"doi":"10.1007/s00774-026-01706-2","url":"https://doi.org/10.1007/s00774-026-01706-2","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":"primary","cited_as":"Surboyo 2026","excerpt":"BACKGROUND: Aging significantly impacts bone metabolism through altered osteoblast/osteoclast dynamics, reduced stem cell regeneration, and chronic inflammaging. This narrative review explores how these age-related changes influence alveolar bone loss and regeneration in the oral cavity. METHODS: The review investigates key mechanisms-including immunosenescence and inflammasome activation-across three specific pathological contexts: (1) periodontitis, (2) periapical bone resorption, and (3) malignancy-associated osteolysis. Preclinical and clinical evidence were integrated to analyze the bone-immune equilibrium. RESULTS: Aging was found to skew the immune environment, exacerbating bone destruction. The review identifies emerging immunomodulatory strategies to rejuvenate bone healing, such as targeting senescent cells (senolytics) and inflammatory cytokines to modulate the immune microenvironment. CONCLUSION: Addressing the unique challenges of the aging population is critical for regenerative dentistry. Future research must bridge current gaps to translate immunomodulatory insights into clinical therapies for improving alveolar bone regeneration in older patients."},{"id":"source_39","type":"source","study":"Global research trends in inflammaging from 2005 to 2024: a bibliometric analysis","year":2025,"doi":"10.3389/fragi.2025.1554186","url":"https://doi.org/10.3389/fragi.2025.1554186","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":"Jiang 2025","excerpt":"BACKGROUND: Inflammaging, defined as chronic low-grade inflammation associated with aging, is considered a key factor in many age-related diseases. Despite growing research, comprehensive assessments of trends and focuses on this field over the past 2 decades remain lacking. OBJECTIVE: To comprehensively analyze literature development trends, scientific priorities, and their evolution in the field of inflammaging from 2005 to 2024 using bibliometric analysis. METHODS: Academic literature on inflammaging was retrieved from the Web of Science Core Collection. CiteSpace software was used as the bibliometric tool to analyze annual publication trends, contributing countries/regions, leading research institutions, primary journals, and keyword co-occurrence, including clustering and burst analysis in this field. RESULTS: The study included 1,800 eligible articles, demonstrating a consistent growth in research publications over the past 20 years. The United States and Italy were the principal contributors. The University of Bologna had the highest publication. Professor Claudio Franceschi has been a leading figure in this field."},{"id":"source_40","type":"source","study":"Corylin ameliorates inflammaging and pyroptosis in diabetic periodontitis: A preliminary in vitro study","year":2025,"doi":"10.1016/j.jds.2025.02.014","url":"https://doi.org/10.1016/j.jds.2025.02.014","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":"Lin 2025","excerpt":"BACKGROUND/PURPOSE: Diabetic periodontitis (DP) is a severe oral disease characterized by hyperinflammation and impaired wound healing, with inflammaging and pyroptosis playing key roles in its pathogenesis. Corylin, an isoflavone compound, has shown promising anti-inflammatory and anti-pyroptotic properties, but its specific effects on DP remain largely unexplored. This study aimed to evaluate the effects of Corylin on inflammaging and pyroptosis in an in vitro model of DP, potentially offering novel insights into therapeutic strategies for this challenging condition. MATERIALS AND METHODS: This in vitro study evaluated the effects of Corylin on inflammaging and pyroptosis in human gingival fibroblasts (HGFs) exposed to advanced glycation end products (AGEs) to mimic the diabetic environment. We then examined the reactive oxygen species (ROS) generation and wound healing ability in the cells. To assess the inflammaging, we probed into cell senescence activity and senescence marker p16 as well as its senescence associated secretory phenotype (SASP) such as interleukins (IL)-6 and IL-8."},{"id":"source_41","type":"source","study":"Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence","year":2026,"doi":"10.3389/fimmu.2026.1792954","url":"https://doi.org/10.3389/fimmu.2026.1792954","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":"Zaongo 2026","excerpt":"Colorectal cancer (CRC) is one of the most commonly occurring malignancies worldwide, with incidence and mortality rising sharply in older adults. While aging is increasingly recognized as a key risk factor for CRC, the fundamental immunological mechanisms which underlie this risk remain incompletely understood. Two interconnected processes, namely inflammaging and immunosenescence, appear central to this association. On the one hand, inflammaging, which is characterized by chronic low-grade inflammation in older individuals, fosters a tumor-promoting microenvironment through oxidative stress, genomic instability, and persistent cytokine activation. On the other hand, immunosenescence diminishes immune surveillance, reducing the clearance of premalignant cells and weakening responses to tumor progression and therapy. Together, these processes create an immunological framework that predisposes the aging colon to malignant transformation. This review synthesizes current knowledge of the cellular and mechanistic impacts of inflammaging and immunosenescence in CRC pathogenesis, highlighting their roles in shaping disease susceptibility in the elderly."},{"id":"source_42","type":"source","study":"Inflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging","year":2026,"doi":"10.1186/s12979-026-00569-5","url":"https://doi.org/10.1186/s12979-026-00569-5","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":"Tan 2026","excerpt":"BACKGROUND: Healthy aging is increasingly challenged by inflammaging, a chronic, low‑grade inflammatory state primarily exacerbated by gut microbiota dysbiosis and declining immune function. Persistent digestive and systemic inflammation, along with immunosenescence, contributes to multiple age‑related diseases. Micronutrients regulate key components of immune system and support the composition and function of the gut microbiota, underscoring their emerging role as modulators of inflammaging. MAIN BODY: This narrative review synthesizes current evidence insights on how micronutrients regulate cellular and molecular drivers of inflammaging, with emphasis on immune function and gut microbiota imbalance. Adequate intakes of vitamins A, B‑complex, C, D, E, and K, together with trace elements (zinc, selenium, magnesium, iron, and copper), supports both innate and adaptive immune response, genomic and epigenetic stability, mitochondrial efficiency, telomere integrity, and immune regulation."},{"id":"source_43","type":"source","study":"DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging","year":2025,"doi":"10.1007/s11357-024-01460-1","url":"https://doi.org/10.1007/s11357-024-01460-1","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":"Skinner 2025","excerpt":"Biological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands of CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first and next generations and clarify the logic by which these clocks systematically exclude biomarkers of aging and age-related disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability."},{"id":"source_44","type":"source","study":"Photinia glabra -derived exosome-like nanovesicles mitigate skin inflammaging via dual regulation of inflammatory signaling and calcium homeostasis","year":2025,"doi":"10.1080/17435889.2025.2572991","url":"https://doi.org/10.1080/17435889.2025.2572991","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":"Lee 2025","excerpt":"AIMS: Chronic low-grade inflammation accelerates skin aging, termed inflammaging. This study investigates whether Photinia glabra- derived exosome-like nanovesicles (PgELNs) can alleviate inflammaging by modulating inflammatory signaling and calcium homeostasis. MATERIALS AND METHODS: PgELNs were isolated using tangential flow filtration and characterized by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Human keratinocytes (HaCaT) were stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) to model inflammaging. PgELN uptake, cell viability, senescence markers, cytokine expression, tight junction proteins, and calcium levels were assessed via flow cytometry, quantitative Real-Time Polymerase Chain Reaction (RT-PCR), immunoblotting, and transcriptomic profiling. RESULTS: PgELNs were efficiently internalized without cytotoxicity. In stimulated cells, PgELNs reduced proinflammatory cytokines, senescence-associated secretory phenotype (SASP) markers, and restored IL-10 and tight junction proteins."},{"id":"source_45","type":"source","study":"Inflammaging is minimal among forager-horticulturalists in the Bolivian Amazon.","year":2025,"doi":"10.1098/rspb.2025.1111","url":"https://doi.org/10.1098/rspb.2025.1111","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":"Aronoff 2025","excerpt":"An increase in chronic systemic inflammation in later life, termed inflammaging, is implicated in health risk. However, it is unclear whether inflammaging develops in all human populations, or if it is the product of environmental mismatch. We assessed inflammaging in Tsimane forager-horticulturalists of the Bolivian Amazon, using serum cytokines in a primarily cross-sectional sample (1134 samples from n = 714 individuals, age 39-94, 51.3% female). IL-6 was positively associated with age ( β = 0.013, p < 0.01). However, other pro-inflammatory markers, including IL-1β and TNF-α, did not increase with age ( β = -0.005 and β = -0.001, respectively). We then compared the Moseten, a neighbouring population that has experienced greater market integration (423 samples from n = 380 individuals, age 39-85, 48.2% female). The Moseten also showed a positive age association for IL-6 that attenuated at later ages (age β = 0.025, p < 0.01; age 2 β = -0.001, p < 0.05). Further, IL-1β and TNF-α were both positively associated with age ( β = 0.021, p < 0.05 and β = 0.011, p < 0.01, respectively)."},{"id":"source_46","type":"source","study":"The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis","year":2024,"doi":"10.1038/s41514-024-00159-z","url":"https://doi.org/10.1038/s41514-024-00159-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":"Wang 2024","excerpt":"Osteoarthritis (OA) is the most common form of arthritis and accounts for nearly $140 billion in annual healthcare expenditures only in the United States. Obesity, aging, and joint injury are major risk factors for OA development and progression, but the mechanisms contributing to pathology remain unclear. Emerging evidence suggests that cellular dysregulation and inflammation in joint tissues, including intra-articular adipose tissue depots, may contribute to disease severity. In particular, the infrapatellar fat pad (IFP), located in the knee joint, which provides a protective cushion for joint loading, also secretes multiple endocrine factors and inflammatory cytokines (inflammaging) that can regulate joint physiology and disease. Correlates of cartilage degeneration and OA-associated disease severity include inflammation and fibrosis of IFP in model organisms and human studies. In this article, we discuss recent progress in understanding the roles and regulation of intra-articular fat tissue in regulating joint biology and OA."},{"id":"source_47","type":"source","study":"The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience","year":2024,"doi":"10.3389/fragi.2024.1490302","url":"https://doi.org/10.3389/fragi.2024.1490302","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":"Wrona 2024","excerpt":"As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function."},{"id":"source_48","type":"source","study":"A Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression","year":2022,"doi":"10.3390/cancers14215185","url":"https://doi.org/10.3390/cancers14215185","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 2022","excerpt":"Cancer is a disease of aging, but most studies on cancer are in young but not aged animal models, and cancer clinical trials are rarely performed in older adults. Recognition of the connections between aging and cancer and improvement of treatment for elderly cancer patients has become one of the most critical medical issues with the global increase in the elderly population. Mouse models are essential experimental tools for understanding the molecular mechanisms of complex processes and related gene pathways of biological aging. However, few mouse models can be used to understand the role of aging in cancer development and the underlying mechanisms. One of the hallmarks of aging is chronic inflammation, often called inflammaging. This is our rationale for examining the role of aging-related inflammation in prostate cancer, a major aging malignancy. We have now developed a novel method to generate age-related cancer models in mice to better understand how age impacts cancer initiation and progression in the natural aging process. We discuss its application to elucidate some of the contributing mechanisms."},{"id":"source_49","type":"source","study":"Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies","year":2026,"doi":"10.3390/ijms27031206","url":"https://doi.org/10.3390/ijms27031206","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":"Aitella 2026","excerpt":"With the global increase in population aging, allergic diseases in older adults are becoming an increasingly relevant clinical and public health challenge. Age-related molecular and cellular alterations significantly affect the pathophysiology, clinical manifestations, diagnosis, and management of major allergic diseases in the elderly. This review focuses on immunosenescence in major allergic conditions, including asthma, chronic urticaria and angioedema, dermatitis, food and drug allergies, and hymenoptera venom hypersensitivity. Particular emphasis is placed on molecular mechanisms underlying immune aging, such as inflammaging, dysregulation of innate and adaptive immune responses, epithelial barrier dysfunction, microbiota alterations, neuro-immune interactions, and age-related comorbidities. Sex-related differences in immune responses are also addressed, together with current diagnostic and therapeutic strategies, including the opportunities and limitations of biologic therapies in aging populations."},{"id":"source_50","type":"source","study":"Inflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies","year":2026,"doi":"10.2147/PTT.S598115","url":"https://doi.org/10.2147/PTT.S598115","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":"Filipek 2026","excerpt":"Psoriasis is a common chronic dermatological disease, affecting approximately 1-3% of the global population, and is associated with numerous comorbidities, impaired quality of life, and reduced life expectancy compared with the general population. The pathogenesis of psoriasis is complex and multifactorial, involving genetic susceptibility, external environmental factors, and immune system dysregulation. Psoriasis is perceived as a systemic disorder associated with a systemic inflammatory condition. In psoriasis, a chronically activated immune response results in the expression of numerous pro-inflammatory mediators, which enhance and sustain the inflammatory feedback loop, thereby exacerbating cell senescence. Senescent cells adopt a hypersecretory state called senescence-associated secretory phenotype (SASP). Multiple SASP-related mediators are dysregulated in psoriasis, including pro-inflammatory cytokines, chemokines, growth factors, proteases and regulators, soluble or shed receptors and ligands, some of which may serve as biomarkers or therapeutic targets."},{"id":"source_51","type":"source","study":"Cardiovascular inflammaging: Mechanisms, consequences, and therapeutic perspectives","year":2025,"doi":"10.1016/j.xcrm.2025.102264","url":"https://doi.org/10.1016/j.xcrm.2025.102264","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":"Spray 2025","excerpt":"Both aging and systemic inflammation are major risk factors for cardiovascular disease. This review summarizes the interrelationship of aging and inflammation-known as inflammaging-and the consequences for cardiovascular health. We discuss mechanisms including epigenetic modification, mitochondrial dysfunction, cellular senescence, and gut dysbiosis, many of which are themselves interrelated. Increasing understanding of inflammaging provides an array of biomarkers, some of which are now recommended in international guidelines. We also discuss therapeutic strategies aiming to modify the process of inflammaging and improve cardiovascular disease outcomes, either with immunomodulating agents or with therapies targeted at specific mechanisms, such as senolytics, telomerase activators, and pre- and probiotic supplementation. We conclude that inflammaging is a key part of cardiovascular aging and provides encouraging opportunities for new therapies."},{"id":"source_52","type":"source","study":"Rheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies","year":2025,"doi":"10.3390/ijms26199268","url":"https://doi.org/10.3390/ijms26199268","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":"Aitella 2025","excerpt":"Immunosenescence refers to the set of immunoendocrinological alterations underlying the progressive decline in innate and adaptive immune function that occurs with aging. It is closely linked to the concept of inflammaging, a state of low-grade chronic systemic inflammation that contributes to age-related diseases. In the elderly, key features of diseases such as rheumatoid arthritis, particularly in its elderly onset form, and senile osteoporosis are characterized by a decline in sex hormones and the immunoregulatory IL-2; an increase in serum autoantibodies and pro-inflammatory mediators such as TNF-α, IL-6; and upregulation of bone-related factors RANKL, DKK1, and sclerostin, including the dysregulation of the IL-33/IL-31 axis. The aim of this review is to examine the key molecular pathways of immunosenescence in osteoimmunology, as well as the potential for therapeutic modulation of inflammaging through biologic and target synthetic disease-modifying antirheumatic drugs, denosumab and romosozumab, with particular attention to their management in elderly patients."},{"id":"source_53","type":"source","study":"Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges","year":2025,"doi":"10.1002/cmdc.202400672","url":"https://doi.org/10.1002/cmdc.202400672","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":"Francavilla 2025","excerpt":"Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress."},{"id":"source_54","type":"source","study":"Inflammaging and Cardiovascular Risk in Old Women","year":2025,"doi":"10.1007/s40292-025-00758-1","url":"https://doi.org/10.1007/s40292-025-00758-1","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":"Moscucci 2025","excerpt":"Inflammaging is a chronic, low-grade inflammation that accompanies aging and contributes to the development of age-related diseases. Recent research has increasingly focused on its impact in women, recognizing that aging and inflammatory processes differ between sexes. Estrogens, known for their anti-inflammatory effects, offer protection during reproductive years. However, their decline during menopause and the climacteric period is linked to increased inflammation and a higher risk of chronic diseases such as osteoporosis, cardiovascular disease, and arthritis. X-linked immune-related genes play a critical role in immune system regulation. Epigenetic changes associated with aging can affect the expression of inflammation-related genes, with hormonal and genetic differences contributing to sex-specific responses. Women generally exhibit stronger immune responses than men, which can enhance infection resistance but also increase susceptibility to autoimmune diseases and inflammaging. Lifestyle factors, including diet and physical activity, significantly influence inflammation. Due to metabolic differences, women may respond differently to these interventions."},{"id":"source_55","type":"source","study":"Pathogenesis and inflammaging in myelodysplastic syndromes","year":2024,"doi":"10.3324/haematol.2023.284944","url":"https://doi.org/10.3324/haematol.2023.284944","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":"Villaume 2024","excerpt":"Myelodysplastic syndromes (MDS) are a genetically complex and phenotypically diverse set of clonal hematologic neoplasms that occur with increasing frequency with age. MDS has long been associated with systemic inflammatory conditions and disordered inflammatory signaling is implicated in MDS pathogenesis. A rise in sterile inflammation occurs with ageing and the term \"inflammaging\" has been coined by to describe this phenomenon. This distinct form of sterile inflammation has an unknown role in in the pathogenesis of myeloid malignancies despite shared correlations with age and ageing-related diseases. More recent is a discovery that many cases of MDS arise from clonal hematopoiesis of indeterminate potential (CHIP), an age associated, asymptomatic pre-disease state. The interrelationship between ageing, inflammation and clonal CHIP is complex and likely bidirectional with causality between inflammaging and CHIP potentially instrumental to understanding MDS pathogenesis. Here we review the concept of inflammaging and MDS pathogenesis and explore their causal relationship by introducing a novel framing mechanism of \"pre-clonal inflammaging\" and \"clonal inflammaging\"."},{"id":"source_56","type":"source","study":"The effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis","year":2023,"doi":"10.1371/journal.pone.0284228","url":"https://doi.org/10.1371/journal.pone.0284228","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":"Lv 2023","excerpt":"BACKGROUND: Inflammaging, a chronic low-grade inflammation, is considered as the basis of age-related diseases. Mindfulness is involved in protecting telomeres, whose shortening causes aging. This paper reports a protocol for the meta-analysis and systematic review to bond the causality between the mindfulness practices and inflammaging responses according to the data collected from the relevant observational studies. METHODS AND ANALYSIS: The published studies during 2006-2023 will be identified from PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and ProQuest Dissertation & Theses Global. The retrieved records will be screened independently by two researchers, and the relevant data will be extracted after reaching an agreement. The eligible studies will be analyzed with both of a meta-analysis and a narrative review. The risk of bias will be evaluated according to the Cochrane assessment for risk of biases. In the meta-analysis, random models will be applied to evaluate the effectiveness of mindfulness-based interventions on inflammaging due to the variation among studies."},{"id":"source_57","type":"source","study":"Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies","year":2023,"doi":"10.1007/s11357-023-00947-7","url":"https://doi.org/10.1007/s11357-023-00947-7","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":"Giunta 2023","excerpt":"Inflammaging refers to the age-related low grade, sterile, chronic, systemic, and long-lasting subclinical, proinflammatory status, currently recognized as the main risk factor for development and progression of the most common age-related diseases (ARDs). Extensive investigations were focused on a plethora of proinflammatory stimuli that can fuel inflammaging, underestimating and partly neglecting important endogenous anti-inflammaging mechanisms that could play a crucial role in such age-related proinflammatory state. Studies on autonomic nervous system (ANS) functions during aging highlighted an imbalance toward an overactive sympathetic nervous system (SNS) tone, promoting proinflammatory conditions, and a diminished parasympathetic nervous system (PNS) activity, playing anti-inflammatory effects mediated by the so called cholinergic anti-inflammatory pathway (CAP). At the molecular level, CAP is characterized by signals communicated via the vagus nerve (with the possible involvement of the splenic nerves) through acetylcholine release to downregulate the inflammatory actions of macrophages, key players of inflammaging."},{"id":"source_58","type":"source","study":"Contribution of Intestinal Barrier Damage, Microbial Translocation and HIV-1 Infection Status to an Inflammaging Signature","year":2014,"doi":"10.1371/journal.pone.0097171","url":"https://doi.org/10.1371/journal.pone.0097171","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":"Steele 2014","excerpt":"BACKGROUND: Systemic inflammation is a characteristic of both HIV-1 infection and aging (\"inflammaging\"). Intestinal epithelial barrier damage (IEBD) and microbial translocation (MT) contribute to HIV-associated inflammation, but their impact on inflammaging remains unclear. METHODS: Plasma biomarkers for IEBD (iFABP), MT (LPS, sCD14), T-cell activation (sCD27), and inflammation (hsCRP, IL-6) were measured in 88 HIV-1 uninfected (HIV(neg)) and 83 treated, HIV-1-infected (HIV(pos)) adults from 20-100 years old. RESULTS: Age positively correlated with iFABP (r = 0.284, p = 0.008), sCD14 (r = 0.646, p = <0.0001) and LPS (r = 0.421, p = 0.0002) levels in HIV(neg) but not HIV(pos) subjects. Age also correlated with sCD27, hsCRP, and IL-6 levels regardless of HIV status. Middle-aged HIV(pos) subjects had elevated plasma biomarker levels similar to or greater than those of elderly HIV(neg) subjects with the exception of sCD14. Clustering analysis described an inflammaging phenotype (IP) based on iFABP, sCD14, sCD27, and hsCRP levels in HIV(neg) subjects over 60 years of age."},{"id":"source_59","type":"source","study":"Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging","year":2019,"doi":"10.1186/s12882-019-1585-6","url":"https://doi.org/10.1186/s12882-019-1585-6","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":"Sepe 2019","excerpt":"BACKGROUND: Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation. METHODS: We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period."},{"id":"source_60","type":"source","study":"Anti‐inflammaging effects of human alpha‐1 antitrypsin","year":2018,"doi":"10.1111/acel.12694","url":"https://doi.org/10.1111/acel.12694","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":"Yuan 2018","excerpt":"Inflammaging plays an important role in most age-related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha-1 antitrypsin (hAAT) has immune-regulatory, anti-inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti-inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT-expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti-aging effect of hAAT, we monitored the expression of aging-associated genes and found that aging-induced expressions of Relish (NF-ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA-seq analysis revealed that innate immunity genes regulated by NF-kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines."}],"edges":[{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_1","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_2","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_3","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_4","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_5","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_6","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_7","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_8","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_9","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_10","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_11","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_12","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_13","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_14","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_15","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_16","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_17","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_18","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_19","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_20","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_21","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_22","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_23","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_24","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_25","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_26","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_27","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_28","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_29","type":"contains_claim"},{"from":"073c460c-0262-46c7-88e4-bc96b9c25668","to":"claim_30","type":"contains_claim"}],"screening":{"identified":60,"screened":60,"excluded":0,"included":60,"included_or_retained":60,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"60 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":"073c460c-0262-46c7-88e4-bc96b9c25668","screening":{"identified":60,"screened":60,"excluded":0,"included":60,"included_or_retained":60,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"60 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 Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, 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 Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For 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.","Across the corpus, the evidence supports inflammaging as a biologically grounded, biomarker-detectable phenomenon whose clinical translation remains incomplete: mechanistic plausibility coexists with mixed or sparse human RCT evidence, longevity-relevant cohorts (Ceolin 2025 vs Spray 2025) disagree in direction, and boundary conditions across populations, exposures, and supplement classes are not yet established.","The conclusion is that Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The geroscience hypothesis rests on the premise that aging biology offers tractable, upstream intervention points that, if modified, could yield downstream benefits across organ systems. Two contrasting development pathways have shaped the current evidence base. The first is the repurposing of existing drugs with well-characterized safety profiles — most prominently metformin, originally approved for type 2 diabetes — into older-adult populations at risk of age-related disease. The second is the de novo development of novel geroprotectors targeting pathways such as mTOR, senescent-cell clearance, or inflammasome signaling. Both approaches face a common epistemic challenge: the gap between mechanistic plausibility, often established in cell or animal models, and clinical demonstration of benefit on hard endpoints in humans. Inflammaging sits at the center of this tension, as it is invoked both as a mechanistic explanation for why geroscience interventions might work and as a candidate endpoint on which those interventions might be evaluated. Evidence suggests that inflammation-modifying strategies may plausibly influence aging trajectories, but it remains uncertain whether reducing inflammaging is sufficient, necessary, or merely a correlate of slowing biological aging.","The inflammaging construct itself lacks a single agreed operational definition, which complicates any synthesis of the evidence. Across the available literature, inflammaging is variably described in terms of elevated circulating cytokines such as IL-6, acute-phase reactants including C-reactive protein, immune-cell phenotypic shifts, or composite biomarker indices such as the neutrophil-to-lymphocyte ratio, and a broad set of triggers has been proposed, ranging from senescent-cell accumulation and mitochondrial dysfunction to altered gut-barrier integrity and dysbiosis. Mechanistic studies cited in this domain include observations that PPAR-α downregulation may sustain monocyte inflammatory programs, that NRF1-driven innate immune dysregulation can amplify age-related inflammation, and that S100A8/A9 alarmins released from hematopoietic progenitors may propagate the response systemically. These mechanisms have been explored in cell-based, animal, and human cohort settings, but the predominant study design in the field is observational, and direct human randomized evidence addressing inflammaging as a primary endpoint remains comparatively sparse. Access to inflammaging biomarkers in clinical practice is further limited by the absence of a regulatory-grade consensus assay panel, which has slowed translation from research observation to intervention trials.","The human randomized trial landscape for inflammaging-modifying interventions is narrow but growing, and a few direct studies have begun to test whether nutrition- or microbiome-based strategies can shift inflammatory biomarkers in older adults. A randomized, double-blind, placebo-controlled trial of probiotics in adults over 70 years reported measurable effects on inflammaging-related immune readouts, while a two-year cocoa extract supplementation study in older US adults demonstrated a significant reduction in high-sensitivity C-reactive protein compared with placebo. Other randomized work has examined fasting, calorie restriction, mindfulness-based interventions, and balneotherapy, each with distinct biomarker panels and follow-up durations. Beyond these direct trials, the broader human evidence base is dominated by observational cohorts that link inflammaging-related indices to clinical phenotypes as varied as frailty, cardiovascular events, COVID-19 mortality, periodontal bone loss, cancer, and HIV-related comorbidity, with populations ranging from community-dwelling older adults to hospitalized patients and people living with chronic infection. This heterogeneity in design, population, and endpoint is itself a central feature of the literature, and the question of whether any single biomarker signature is portable across such diverse clinical contexts remains open.","Several unresolved questions complicate the interpretation of the current evidence base. First, the boundary between mechanistic inflammaging signals and clinically meaningful hard outcomes — such as incident cardiovascular events, fractures, or mortality — is not consistently demonstrated, and a general methodological caution, Ioannidis 2005, reminds us that surrogate-endpoint associations do not guarantee hard-outcome validity. Second, the field's reading of inflammaging appears context-dependent: a positive association of inflammaging markers with clinical risk in one cohort, such as the higher short-term mortality linked to elevated neutrophil-to-lymphocyte ratio in hospitalized older COVID-19 patients, can coexist with null or even protective associations elsewhere, raising the question of whether inflammaging functions as a unidirectional driver or as a context-modulated response. Third, population specificity matters: evidence in forager-horticulturalist populations suggests inflammaging may be minimal, and sex-frailty paradox data indicate that the inflammatory burden of aging may differ qualitatively between men and women. Fourth, optimal dose, duration, and reversibility of any inflammaging-modifying intervention have not been established, and the question of whether short-term biomarker changes translate into sustained functional benefit remains unanswered.","The contribution of the present synthesis is to apply a structured evidence-weighting framework to the inflammaging literature, separating direct human randomized evidence from indirect observational and mechanistic work and making explicit the cross-outcome tensions that emerge when immune, cardiometabolic, longevity, and contextual endpoints are considered jointly. Where the field has historically treated inflammaging as a single phenomenon amenable to a single intervention logic, the available evidence instead supports a more cautious framing: positive signals in immune and contextual outcomes coexist with null findings in several adjacent domains, and direct RCT evidence remains limited in both number and duration. By cataloging these tensions and weighting study designs, populations, and endpoints separately, the synthesis aims to clarify what is currently known about inflammaging, what remains uncertain, and where future human trials would be most informative, while resisting the temptation to overstate the clinical case for inflammaging-targeted therapy as a generalizable anti-aging strategy.","The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.","The 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.","Additional corpus sources included animal/preclinical evidence; within-corpus tensions in the cardiometabolic class reflect differences in population, exposure, and endpoint rather than direct numerical conflict. Cares 2026 frames inflammaging as a biomarker of cardiometabolic risk in pediatric cancer survivors exposed to diet/exercise interventions, while Tizazu 2024 frames it as an age-associated immune phenotype modulated by fasting/calorie restriction in adults; the two are not measuring the same outcome, so apparent disagreements are likely definitional. Xiong 2025 supplies a tissue-level mechanistic pathway that neither human source directly assays, leaving a translational gap between the RAGE/AKT/mTOR/glycolysis signal and the fasting-induced dendritic-cell changes. The current cardiometabolic synthesis therefore rests on complementary rather than competing evidence, and the anti-aging case in this outcome class remains incomplete pending a clinical RCT with a defined inflammaging endpoint."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nDoxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular Diseases,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRadiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMorin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNeutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMinimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"New insights into the association between cardiometabolic index with metabolic profile, nutritional status, and inflammaging in older adults\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBottom-up engineering of the nucleus pulposus using a photocrosslinkable decellularized matrix hydrogel attenuates inflammaging and enhances microtissue-mediated regeneration,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHematopoietic progenitor cell liabilities and alarmins S100A8/A9‐related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe alteration of bile acids and gut microbiota is associated with intestinal barrier dysfunction and inflammaging in human,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nProgrammed PPAR-α downregulation induces inflammaging by suppressing fatty acid catabolism in monocytes,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDiet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCardiac alterations following experimental hip fracture - inflammaging as independent risk factor,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFasting and calorie restriction modulate age‐associated immunosenescence and inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging and the sex-frailty paradox,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLong-Term Physical Activity Mitigates Inflammaging Progression in Older Adults Amidst the COVID-19 Pandemic,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGut-heart immuno-metabolic disruption associated with inflammaging and subclinical coronary artery disease in people with HIV on antiretroviral therapy,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nProtective effects of Rosa roxburghii Tratt. extract against UVB-induced inflammaging through inhibiting the IL-17 pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMolecular Remodeling of Peritumoral Tissue in Clear Cell Renal Cell Carcinoma: Insights into Inflammaging and Prognostic Markers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNRF1-mediated innate immune response drives inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpatiotemporal mapping reveals Ccl8 hi macrophages as key drivers of testicular inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEpigenetic silencing of SPHK1-IRF7 axis drives inflammaging in age-related meniscus degeneration via sphingolipid-immune dysregulation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nIL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInterferon-related inflammaging links epigenetic age acceleration to multimorbidity,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPomegranate ( Punica granatum L.) Extract Effects on Inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAge-related nigral downregulation of the Parkinson’s risk factor FAM49B primes human microglia for inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n2-O-methylmagnolol mitigates the generation of reactive oxidative stress and inflammaging in human gingival epithelial cells and fibroblasts with advanced glycation end products stimulation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging and Senescence-Driven Extracellular Matrix Remodeling in Age-Associated Cardiovascular Disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTargeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAdvanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of 2-year cocoa extract supplementation on inflammaging biomarkers in older US adults: findings from the COcoa Supplement and Multivitamin Outcomes Study randomised clinical trial.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBalneotherapy as a potential immunomodulator in inflammaging.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nIdentification of crucial inflammaging related risk factors in multiple sclerosis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGlobal research trends in inflammaging from 2005 to 2024: a bibliometric analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCorylin ameliorates inflammaging and pyroptosis in diabetic periodontitis: A preliminary in vitro study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPhotinia glabra -derived exosome-like nanovesicles mitigate skin inflammaging via dual regulation of inflammatory signaling and calcium homeostasis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging is minimal among forager-horticulturalists in the Bolivian Amazon.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Cardiovascular inflammaging: Mechanisms, consequences, and therapeutic perspectives\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInflammaging and Cardiovascular Risk in Old Women,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPathogenesis and inflammaging in myelodysplastic syndromes,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAutonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Contribution of Intestinal Barrier Damage, Microbial Translocation and HIV-1 Infection Status to an Inflammaging Signature\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nVitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAnti‐inflammaging effects of human alpha‐1 antitrypsin,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":"073c460c-0262-46c7-88e4-bc96b9c25668","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Doxycycline Attenuated Ethanol-Induced Inflammaging in Endothelial Cells: Implications in Alcohol-Mediated Vascular 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