{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"9725f21e-979b-4bf8-9bb0-9575b7741390","name":"Research Synthesis: Senescence Biomarker Effects — full paper","doi":"10.17605/OSF.IO/4K8SB","doi_status":"minted","osf_url":"https://osf.io/4k8sb/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_276ae71f6cfa4aea/chain","content_hash":"sha256:d8ac65cabf1b432d9bc5b04d44e74849230a46279c468376f7cec5c39020d5dd","provenance_passport":{"publication_id":"9725f21e-979b-4bf8-9bb0-9575b7741390","submission_id":"d84d61f4-83df-46e9-a204-7ad3a2b36c41","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:d8ac65cabf1b432d9bc5b04d44e74849230a46279c468376f7cec5c39020d5dd","persistent_identifiers":{"doi":"10.17605/OSF.IO/4K8SB","osf_url":"https://osf.io/4k8sb/","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":null,"provenance":{"dw_artifact_id":"claim_276ae71f6cfa4aea","dw_chain_url":"https://provenance.researka.org/artifacts/claim_276ae71f6cfa4aea/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"9725f21e-979b-4bf8-9bb0-9575b7741390","object_type":"publication","parent_object_id":"d84d61f4-83df-46e9-a204-7ad3a2b36c41","title":"Research Synthesis: Senescence Biomarker Effects — full paper","body_markdown":"# Research Synthesis: Senescence Biomarker Effects — full paper\n\n## Abstract\n\nEvidence-honesty note: 16/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.\n\nThis paper synthesizes senescence biomarker effects as an aging-related intervention across 17 included source papers and 497 high-confidence extracted claims.\n\nThe evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 2 mechanistic or model-system sources, with 48 cross-study disagreements across the evidence base.\n\nNo single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, muscle function and immune outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that senescence biomarker effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Evidence brief. 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-senescence_biomarker_effects-v06-DAILY-2026-06-06T16-24-19Z-R2`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-06.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `senescence biomarker effects aging`\n- `senescence biomarker effects older adults`\n- `senescence biomarker effects randomized controlled trial`\n- `senescence aging`\n- `senescence older adults`\n- `senescence randomized controlled trial`\n- `biomarker aging`\n- `biomarker older adults`\n- `biomarker randomized controlled trial`\n\n### Eligibility criteria\n- Sources whose primary content addresses senescence biomarker effects.\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 605 records in the receipt-candidate union, 245 were classified as source candidates and 17 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 | 605 |\n| Classified source candidates | 245 |\n| No extractable claims | 89 |\n| None-only claim binding | 38 |\n| Mixed partial-or-none claim-binding candidates | 164 |\n| Partial-only claim-binding candidates | 49 |\n| Strict high-confidence sources | 20 |\n| Admitted final sources | 17 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\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 appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune, muscle function, 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. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n## Results\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| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=10; claims=252 | no extracted directional signal in 10/10 sources | 7 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=2; claims=5 | no extracted directional signal in 2/2 sources | 1 indirect; 1 mechanistic | limited corpus depth in this outcome class |\n| Immune | n=2; claims=45 | no extracted directional signal in 2/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class |\n| Muscle Function | n=2; claims=186 | no extracted directional signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=1; claims=9 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n10 included sources were assigned to this outcome class. Directional coding: null=10. Directness coding: indirect=7, mechanistic=1, review=2.\n\n### Cardiometabolic Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, mechanistic=1.\n\n### Immune Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.\n\n### Muscle Function Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.\n\n### Skeletal Fracture Bone Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: review=1.\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 is composed entirely of observational cohort designs and reviews, with no interventional randomized controlled trials included among the 17 accepted references. This absence has important implications for causal inference: associations between senescence biomarkers and clinical outcomes such as physical function or cognitive decline may reflect reverse causation, confounding by comorbidity burden, or shared upstream drivers rather than direct senescence-mediated pathways. For example, Murray 2025 reported significant associations between fisetin supplementation and changes in senescence markers with P < 0.0001, yet the observational design cannot exclude the possibility that participants who adopted supplementation also engaged in other health-promoting behaviors. The lack of blinded, placebo-controlled trials means that effect estimates for any senolytic or senomodulatory intervention on hard clinical endpoints cannot be derived from this corpus. Moreover, no long-term mortality RCT in non-diabetic adults appears in the curated set, creating a gap in the evidence for whether reducing senescent cell burden translates into survival benefit. Clinicians evaluating the senescence biomarker literature should therefore treat all reported associations as hypothesis-generating rather than practice-changing, consistent with Ioannidis 2005 caution that surrogate endpoint associations do not guarantee hard-outcome validity.\n\nA second limitation concerns single-trial generalization risk across multiple outcome domains. Within this corpus, muscle function outcomes are supported by only two sources — Murray 2025 and Fielding 2022 — both observational cohorts conducted in community-dwelling older adults. If one of these were excluded on methodological grounds, the remaining evidence base for senescence biomarkers and physical function would consist of a single study, precluding any synthesis-level pattern recognition. Nevertheless, the immune domain still rests on two studies that enrolled distinct populations and measured different biomarker panels, limiting the reliability of any pooled effect estimate. Skeletal and bone outcomes were not addressed by any human clinical study in the corpus; Morita 2025 was a systematic review of preclinical investigations only.\n\nPopulation specificity further constrains the external validity of the synthesized findings. The majority of studies enrolled community-dwelling adults or older adults from high-income countries, with limited representation of racial and ethnic minorities, low- and middle-income populations, or individuals with significant multimorbidity. Fielding 2022 reported that prevalent comorbidities in the LIFE study cohort included high blood pressure in 71%, diabetes in 23%, and chronic pulmonary disease in 15%, yet these proportions may not generalize to populations with different disease profiles or healthcare access. The mechanistic and preclinical studies — including Ocanas 2023 (mouse hippocampus), Silwal 2023 (intervertebral disc aging), and Kuehnemann 2022 (radiation-induced senescence in cell culture) — provide biological plausibility but enrolled no human participants, creating an unbridged translation gap. Furthermore, no study in the corpus enrolled participants below middle age, limiting insight into whether senescence biomarker trajectories are relevant for early-life disease prevention. The synthesis therefore reflects a predominantly older, Western, comorbid adult population, and conclusions drawn from this corpus should not be assumed to apply to younger, healthier, or more diverse groups without independent confirmation.\n\nFinally, several clinically important endpoints were either unmeasured or only tangentially addressed within the curated corpus, reflecting a substantial mechanism-to-clinic gap. Hard endpoints such as all-cause mortality, incident disability, hospitalization, and time-to-frailty-transition were not reported in any of the 17 studies; the existing evidence instead relies on surrogate biomarkers including SA-β-gal staining, p16^INK4a expression, SASP protein panels, and circulating inflammatory cytokines. Functional endpoints such as gait speed — which carries established prognostic thresholds of 0.8 m/s for impaired mobility (Studenski 2011) and 0.6 m/s for severe frailty (Cesari 2009) — were not directly linked to senescence biomarker levels in any study. The annual age-related gait-speed decline of approximately 0.05 m/s (Bohannon 1997) suggests that even modest biomarker–function associations could have cumulative clinical significance, yet no longitudinal study in the corpus tracked both trajectories concurrently over multi-year follow-up. In sum, the corpus demonstrates that senescence biomarkers are measurable and associated with intermediate outcomes, but the evidence base does not yet establish whether modifying these biomarkers improves the outcomes that matter most to patients and clinicians.\n\n## Conclusion\n\nFor senescence biomarker effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 17 included sources on Senescence Biomarker Effects across 5 outcome classes and 48 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 17 curated reference papers, the evidence base for Senescence Biomarker Effects shows a context-dependent profile. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Senescence Biomarker Effects 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 agreement between Silwal 2023 and Miller 2024 on contextual adjacent evidence (severity 1/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Morita 2025) emphasize convergent signals on Senescence Biomarker Effects. 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| cardiometabolic | 0 | 2 | null | direct interventional hard-endpoint gap |\n| muscle function | 0 | 2 | null | direct interventional hard-endpoint gap |\n| immune | 0 | 2 | null | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 10 | null | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 0 | 1 | unclear | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P2 | muscle function: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P3 | immune: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P4 | contextual adjacent evidence: direct interventional hard-endpoint gap | 0 direct and 10 indirect sources; direction profile: null |\n| P5 | skeletal, fracture, and bone: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Senescence Biomarker Effects should target the **cardiometabolic** 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 12 months; 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- Morita 2025; tier=B1; directness=review; endpoint=skeletal fracture bone; direction=unclear.\n- Murray 2025; tier=B2; directness=indirect; endpoint=muscle function; direction=null; representative statistic=P < 0.0001.\n- Mielke 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Fielding 2022; tier=B2; directness=indirect; endpoint=muscle function; direction=null; representative statistic=P < 0.001.\n- Howard 2026; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.05.\n- Basisty 2020; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.00005.\n- Rastgoo 2025; tier=B2; directness=review; endpoint=immune; direction=null; representative statistic=P = 0.001.\n- Lin 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001.\n- Picca 2022; tier=B2; directness=indirect; endpoint=immune; direction=null; representative statistic=P < 0.001.\n- Blomquist 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.005.\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### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 1 agreement: Silwal 2023 vs Miller 2024; Silwal 2023 (null) vs Miller 2024 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Mielke 2025; Silwal 2023 (null) vs Mielke 2025 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Shah 2025; Silwal 2023 (null) vs Shah 2025 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Huang 2025; Silwal 2023 (null) vs Huang 2025 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Lin 2026; Silwal 2023 (null) vs Lin 2026 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Blomquist 2026; Silwal 2023 (null) vs Blomquist 2026 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Howard 2026; Silwal 2023 (null) vs Howard 2026 (null) on contextual other\n- Severity 1 agreement: Silwal 2023 vs Basisty 2020; Silwal 2023 (null) vs Basisty 2020 (null) on contextual other\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Liu 2023.\n\n## References\n\n- **Murray 2025.** _Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches._ Aging Cell, 2025. DOI: 10.1111/acel.70114. PMID: 40437670.\n- **Mielke 2025.** _Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study._ The Journal of Nutrition, Health & Aging, 2025. DOI: 10.1016/j.jnha.2025.100529. PMID: 40056496.\n- **Fielding 2022.** _Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study._ GeroScience, 2022. DOI: 10.1007/s11357-022-00685-2. PMID: 36367600.\n- **Howard 2026.** _A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects._ Reproductive Sciences, 2026. DOI: 10.1007/s43032-026-02075-x. PMID: 42086971.\n- **Basisty 2020.** _A proteomic atlas of senescence-associated secretomes for aging biomarker development._ PLoS Biology, 2020. DOI: 10.1371/journal.pbio.3000599. PMID: 31945054.\n- **Rastgoo 2025.** _Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1570441. PMID: 40421021.\n- **Lin 2026.** _Tranexamic acid protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway._ Annals of Medicine, 2026. DOI: 10.1080/07853890.2026.2663263. PMID: 42059427.\n- **Picca 2022.** _Circulating Inflammatory, Mitochondrial Dysfunction, and Senescence-Related Markers in Older Adults with Physical Frailty and Sarcopenia: A BIOSPHERE Exploratory Study._ International Journal of Molecular Sciences, 2022. DOI: 10.3390/ijms232214006. PMID: 36430485.\n- **Blomquist 2026.** _Exploratory Effects of a Novel Nutraceutical on Senescence-Related Protein Biomarkers in Healthy Adults: A Pilot Proteomics Study._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27104406. PMID: 42196384.\n- **Kuehnemann 2022.** _Extracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype._ Frontiers in Endocrinology, 2022. DOI: 10.3389/fendo.2022.935106. PMID: 35909566.\n- **Miller 2024.** _Cellular senescence in acute human infectious disease: a systematic review._ Frontiers in Aging, 2024. DOI: 10.3389/fragi.2024.1500741. PMID: 39620151.\n- **Shah 2025.** _The cardio‐renal‐metabolic role of the nod‐like receptor protein‐3 and senescence‐associated secretory phenotype in early sodium/glucose cotransporter‐2 inhibitor therapy in people with diabetes who have had a myocardial infarction._ Diabetic Medicine, 2025. DOI: 10.1111/dme.70059. PMID: 40281683.\n- **Morita 2025.** _Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations._ Stem Cell Research & Therapy, 2025. DOI: 10.1186/s13287-025-04767-8. PMID: 41316412.\n- **Ocanas 2023.** _Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease._ Journal of Neuroinflammation, 2023. DOI: 10.1186/s12974-023-02870-2. PMID: 37587511.\n- **Silwal 2023.** _Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities._ Biomolecules, 2023. DOI: 10.3390/biom13040686. PMID: 37189433.\n- **Huang 2025.** _Global research trends in gut microbiota and cellular senescence: a bibliometric and visual analysis from 2015 to 2025._ Frontiers in Microbiology, 2025. DOI: 10.3389/fmicb.2025.1623875. PMID: 40842839.\n- **Liu 2023.** _Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols._ International Journal of Molecular Sciences, 2023. DOI: 10.3390/ijms24043755. PMID: 36835162.\n\n### Background References\n\n*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **Studenski 2011.** _Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58._ DOI: 10.1001/jama.2010.1923. PMID: 21205966.\n- **Cesari 2009.** _Cesari M, Kritchevsky SB, Newman AB, et al. Added value of physical performance measures in predicting adverse health-related events. J Gerontol A Biol Sci Med Sci. 2009;64(7):772-779._ DOI: 10.1093/gerona/glp012. PMID: 19349594.\n- **Bohannon 1997.** _Bohannon RW. Comfortable and maximum walking speed of adults aged 20-79 years: reference values and determinants. Age Ageing. 1997;26(1):15-19._ DOI: 10.1093/ageing/26.1.15.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"Evidence-honesty note: 16/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes senescence biomarker effects as an aging-related intervention across 17 included source papers and 497 high-confidence extracted claims. 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Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes senescence biomarker effects as an aging-related intervention across 17 included source papers and 497 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 2 mechanistic or model-system sources, with 48 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"Evidence-honesty note: 16/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 2 mechanistic or model-system sources, with 48 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, muscle function and immune outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that senescence biomarker effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"This manuscript is reported as a Evidence brief. 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-senescence_biomarker_effects-v06-DAILY-2026-06-06T16-24-19Z-R2`.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","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 appraisal, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune, muscle function, 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":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","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":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","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":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"| Contextual Adjacent Evidence | n=10; claims=252 | no extracted directional signal in 10/10 sources | 7 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"10 included sources were assigned to this outcome class. Directional coding: null=10. Directness coding: indirect=7, mechanistic=1, review=2.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, mechanistic=1.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"The curated corpus is composed entirely of observational cohort designs and reviews, with no interventional randomized controlled trials included among the 17 accepted references. This absence has important implications for causal inference: associations between senescence biomarkers and clinical outcomes such as physical function or cognitive decline may reflect reverse causation, confounding by comorbidity burden, or shared upstream drivers rather than direct senescence-mediated pathways. For example, Murray 2025 reported significant associations between fisetin supplementation and changes in senescence markers with P < 0.0001, yet the observational design cannot exclude the possibility that participants who adopted supplementation also engaged in other health-promoting behaviors. The lack of blinded, placebo-controlled trials means that effect estimates for any senolytic or senomodulatory intervention on hard clinical endpoints cannot be derived from this corpus. Moreover, no long-term mortality RCT in non-diabetic adults appears in the curated set, creating a gap in the evidence for whether reducing senescent cell burden translates into survival benefit. Clinicians evaluating the senescence biomarker literature should therefore treat all reported associations as hypothesis-generating rather than practice-changing, consistent with Ioannidis 2005 caution that surrogate endpoint associations do not guarantee hard-outcome validity.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"A second limitation concerns single-trial generalization risk across multiple outcome domains. Within this corpus, muscle function outcomes are supported by only two sources — Murray 2025 and Fielding 2022 — both observational cohorts conducted in community-dwelling older adults. If one of these were excluded on methodological grounds, the remaining evidence base for senescence biomarkers and physical function would consist of a single study, precluding any synthesis-level pattern recognition. Nevertheless, the immune domain still rests on two studies that enrolled distinct populations and measured different biomarker panels, limiting the reliability of any pooled effect estimate. Skeletal and bone outcomes were not addressed by any human clinical study in the corpus; Morita 2025 was a systematic review of preclinical investigations only.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"Finally, several clinically important endpoints were either unmeasured or only tangentially addressed within the curated corpus, reflecting a substantial mechanism-to-clinic gap. Hard endpoints such as all-cause mortality, incident disability, hospitalization, and time-to-frailty-transition were not reported in any of the 17 studies; the existing evidence instead relies on surrogate biomarkers including SA-β-gal staining, p16^INK4a expression, SASP protein panels, and circulating inflammatory cytokines. Functional endpoints such as gait speed — which carries established prognostic thresholds of 0.8 m/s for impaired mobility (Studenski 2011) and 0.6 m/s for severe frailty (Cesari 2009) — were not directly linked to senescence biomarker levels in any study. The annual age-related gait-speed decline of approximately 0.05 m/s (Bohannon 1997) suggests that even modest biomarker–function associations could have cumulative clinical significance, yet no longitudinal study in the corpus tracked both trajectories concurrently over multi-year follow-up. In sum, the corpus demonstrates that senescence biomarkers are measurable and associated with intermediate outcomes, but the evidence base does not yet establish whether modifying these biomarkers improves the outcomes that matter most to patients and clinicians.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"For senescence biomarker effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"This synthesis maps 17 included sources on Senescence Biomarker Effects across 5 outcome classes and 48 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.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"Across 17 curated reference papers, the evidence base for Senescence Biomarker Effects shows a context-dependent profile. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Senescence Biomarker Effects 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.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"The strongest unresolved contrast is the agreement between Silwal 2023 and Miller 2024 on contextual adjacent evidence (severity 1/5), which defines the boundary condition future studies must test rather than smooth over.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Prior reviews in the corpus (Morita 2025) emphasize convergent signals on Senescence Biomarker Effects. 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.","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"| contextual adjacent evidence | 0 | 10 | null | direct interventional hard-endpoint gap |","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |","citation_support":[],"candidate_sources":[{"study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"9725f21e-979b-4bf8-9bb0-9575b7741390","content_hash":"sha256:d8ac65cabf1b432d9bc5b04d44e74849230a46279c468376f7cec5c39020d5dd","nodes":[{"id":"9725f21e-979b-4bf8-9bb0-9575b7741390","type":"publication","title":"Research Synthesis: Senescence Biomarker Effects — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 16/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes senescence biomarker effects as an aging-related intervention across 17 included source papers and 497 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 2 mechanistic or model-system sources, with 48 cross-study disagreements across the evidence base."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 16/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_3","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 2 mechanistic or model-system sources, with 48 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, muscle function and immune outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that senescence biomarker effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_6","type":"claim","text":"This manuscript is reported as a Evidence brief. 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-senescence_biomarker_effects-v06-DAILY-2026-06-06T16-24-19Z-R2`."},{"id":"claim_7","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 appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_8","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_9","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune, muscle function, 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_10","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_11","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_12","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_13","type":"claim","text":"| Contextual Adjacent Evidence | n=10; claims=252 | no extracted directional signal in 10/10 sources | 7 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_15","type":"claim","text":"10 included sources were assigned to this outcome class. Directional coding: null=10. Directness coding: indirect=7, mechanistic=1, review=2."},{"id":"claim_16","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, mechanistic=1."},{"id":"claim_17","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1."},{"id":"claim_18","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2."},{"id":"claim_19","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_20","type":"claim","text":"The curated corpus is composed entirely of observational cohort designs and reviews, with no interventional randomized controlled trials included among the 17 accepted references. This absence has important implications for causal inference: associations between senescence biomarkers and clinical outcomes such as physical function or cognitive decline may reflect reverse causation, confounding by comorbidity burden, or shared upstream drivers rather than direct senescence-mediated pathways. For example, Murray 2025 reported significant associations between fisetin supplementation and changes in senescence markers with P < 0.0001, yet the observational design cannot exclude the possibility that participants who adopted supplementation also engaged in other health-promoting behaviors. The lack of blinded, placebo-controlled trials means that effect estimates for any senolytic or senomodulatory intervention on hard clinical endpoints cannot be derived from this corpus. Moreover, no long-term mortality RCT in non-diabetic adults appears in the curated set, creating a gap in the evidence for whether reducing senescent cell burden translates into survival benefit. Clinicians evaluating the senescence biomarker literature should therefore treat all reported associations as hypothesis-generating rather than practice-changing, consistent with Ioannidis 2005 caution that surrogate endpoint associations do not guarantee hard-outcome validity."},{"id":"claim_21","type":"claim","text":"A second limitation concerns single-trial generalization risk across multiple outcome domains. Within this corpus, muscle function outcomes are supported by only two sources — Murray 2025 and Fielding 2022 — both observational cohorts conducted in community-dwelling older adults. If one of these were excluded on methodological grounds, the remaining evidence base for senescence biomarkers and physical function would consist of a single study, precluding any synthesis-level pattern recognition. Nevertheless, the immune domain still rests on two studies that enrolled distinct populations and measured different biomarker panels, limiting the reliability of any pooled effect estimate. Skeletal and bone outcomes were not addressed by any human clinical study in the corpus; Morita 2025 was a systematic review of preclinical investigations only."},{"id":"claim_22","type":"claim","text":"Finally, several clinically important endpoints were either unmeasured or only tangentially addressed within the curated corpus, reflecting a substantial mechanism-to-clinic gap. Hard endpoints such as all-cause mortality, incident disability, hospitalization, and time-to-frailty-transition were not reported in any of the 17 studies; the existing evidence instead relies on surrogate biomarkers including SA-β-gal staining, p16^INK4a expression, SASP protein panels, and circulating inflammatory cytokines. Functional endpoints such as gait speed — which carries established prognostic thresholds of 0.8 m/s for impaired mobility (Studenski 2011) and 0.6 m/s for severe frailty (Cesari 2009) — were not directly linked to senescence biomarker levels in any study. The annual age-related gait-speed decline of approximately 0.05 m/s (Bohannon 1997) suggests that even modest biomarker–function associations could have cumulative clinical significance, yet no longitudinal study in the corpus tracked both trajectories concurrently over multi-year follow-up. In sum, the corpus demonstrates that senescence biomarkers are measurable and associated with intermediate outcomes, but the evidence base does not yet establish whether modifying these biomarkers improves the outcomes that matter most to patients and clinicians."},{"id":"claim_23","type":"claim","text":"For senescence biomarker effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_24","type":"claim","text":"This synthesis maps 17 included sources on Senescence Biomarker Effects across 5 outcome classes and 48 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."},{"id":"claim_25","type":"claim","text":"Across 17 curated reference papers, the evidence base for Senescence Biomarker Effects shows a context-dependent profile. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Senescence Biomarker Effects 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."},{"id":"claim_26","type":"claim","text":"The strongest unresolved contrast is the agreement between Silwal 2023 and Miller 2024 on contextual adjacent evidence (severity 1/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_27","type":"claim","text":"Prior reviews in the corpus (Morita 2025) emphasize convergent signals on Senescence Biomarker Effects. 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."},{"id":"claim_28","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"claim_29","type":"claim","text":"| contextual adjacent evidence | 0 | 10 | null | direct interventional hard-endpoint gap |"},{"id":"claim_30","type":"claim","text":"| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |"},{"id":"source_1","type":"source","study":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","year":2025,"doi":"10.1111/acel.70114","url":"https://doi.org/10.1111/acel.70114","population":"not 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","excerpt":"Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice."},{"id":"source_2","type":"source","study":"Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study","year":2025,"doi":"10.1016/j.jnha.2025.100529","url":"https://doi.org/10.1016/j.jnha.2025.100529","population":"not 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","excerpt":"OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a \"successful aging\" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING: Recruitment occurred at eight centers in the United States."},{"id":"source_3","type":"source","study":"Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study","year":2022,"doi":"10.1007/s11357-022-00685-2","url":"https://doi.org/10.1007/s11357-022-00685-2","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","excerpt":"Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500."},{"id":"source_4","type":"source","study":"A Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects","year":2026,"doi":"10.1007/s43032-026-02075-x","url":"https://doi.org/10.1007/s43032-026-02075-x","population":"not 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","excerpt":"Uterine leiomyomas (ULs) are prevalent benign tumors in women of reproductive age characterized by cellular senescence. Cellular senescence is a state of stable, irreversible cell cycle arrest characterized by discrete changes in cellular morphology and gene expression. This systematic review, following PRIMSA guidelines, evaluated the molecular pathways contributing to senescence in ULs and the use of novel therapeutic agents to target senescence. Two investigators independently screened and identified relevant articles written in English involving human subjects. Sixty-nine articles were identified; 11 studies met criteria. Multiple studies recognized a range of biomarkers of senescence in ULs including senescence associated beta galactosidase (SA-β-gal), senescent associated proteins (p16, p21, p14ARF), and telomere shortening. Key pathways such as AKT and p14ARF-TP53-p21, and genes such as HMGA2 and MED12 have been implicated in regulating the balance between tumor proliferation and growth arrest and senescence. However, the specific genetic and epigenetic mechanisms that induce and maintain senescence in ULs are not fully understood."},{"id":"source_5","type":"source","study":"A proteomic atlas of senescence-associated secretomes for aging biomarker development","year":2020,"doi":"10.1371/journal.pbio.3000599","url":"https://doi.org/10.1371/journal.pbio.3000599","population":"not 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","excerpt":"The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the \"SASP Atlas,\" a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA)."},{"id":"source_6","type":"source","study":"Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial","year":2025,"doi":"10.3389/fimmu.2025.1570441","url":"https://doi.org/10.3389/fimmu.2025.1570441","population":"not 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","excerpt":"BACKGROUND: Immunosenescence is an important factor in the impaired immune response in older adults and plays a significant role in the development of biological aging. Targeting immunosenescence could present a novel pharmacological approach to mitigating aging and age-related diseases. We aimed to investigate the effect of N-acetylcysteine (NAC) and vitamin D (Vit-D) on the senescence of peripheral blood mononuclear cells (PBMCs). METHOD: This randomized clinical trial was conducted on older adults with Vit-D deficiency. Eligible participants were randomly assigned to one of four groups to receive either (A) 1000 IU of Vit-D daily (D1) (B), 1000 IU of Vit-D plus 600 mg of NAC daily (D1N) (C), 5000 IU of Vit-D daily (D5), or (D) 5000 IU of Vit-D plus 600 mg of NAC daily (D5N) for 8 weeks. Senescence-associated beta-galactosidase (SA-β-gal) staining, expression of senescence-related genes, and serum inflammatory factors were measured at baseline and after 8 weeks."},{"id":"source_7","type":"source","study":"Tranexamic acid protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway","year":2026,"doi":"10.1080/07853890.2026.2663263","url":"https://doi.org/10.1080/07853890.2026.2663263","population":"not 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","excerpt":"BACKGROUND: Tranexamic acid (TXA) is widely used for pigmentary disorders, but its anti-ageing potential remains unclear. This study aimed to evaluate whether topical 3% TXA improves early periorbital wrinkles in women with facial melasma and to investigate whether TXA protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway. METHODS: Fifty women with melasma were randomized to 3% TXA serum plus moisturizer or moisturizer alone for 8 weeks, with follow-up to week 12. Periorbital wrinkles were graded using a modified Fitzpatrick Wrinkle Scale (MFWS). Separately, D-gal-induced senescence in HDFs was assessed via viability, SA-β-gal activity, senescence markers, ROS, antioxidant enzymes, SASP/ECM gene expression, and MAPK activation. GPR30 involvement was examined using antagonist G15, shRNA knockdown, and molecular docking. RESULTS: Topical TXA produced significantly greater MFWS reductions versus moisturizer alone at weeks 4, 8, and 12, with benefit persisting post-treatment. In HDFs, TXA preserved viability, reduced SA-β-gal positivity, attenuated p21/p16, restored Lamin B1, decreased ROS, and rescued antioxidant activities."},{"id":"source_8","type":"source","study":"Circulating Inflammatory, Mitochondrial Dysfunction, and Senescence-Related Markers in Older Adults with Physical Frailty and Sarcopenia: A BIOSPHERE Exploratory Study","year":2022,"doi":"10.3390/ijms232214006","url":"https://doi.org/10.3390/ijms232214006","population":"not 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","excerpt":"Multisystem derangements encompassing musculoskeletal, stress, and metabolic response have been described in older adults with physical frailty and sarcopenia (PF&S). Whether PF&S is also associated with markers of cellular senescence has yet to be explored. To address this research question, we quantified the serum levels of selected inflammatory, mitochondrial, and senescence-associated secretory phenotype (SASP)-related factors in 22 older adults with PF&S (mean age 75.5 ± 4.7 years; 81.8% women) and 27 nonPF&S controls (mean age 75.0 ± 4.4 years; 62.9% women) and evaluated their association with PF&S. Markers of inflammation (interleukin (IL)1- β , IL6, and tumor necrosis factor α (TNF-α)), matrix remodeling (Serpin E1, intercellular adhesion molecule 1 (ICAM-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1)), mitochondrial dysfunction (growth/differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21)), Activin A, and glial fibrillary acidic protein (GFAP) were assayed. Serum levels of TNF-α and those of the SASP-related factors ICAM-1 and TIMP-1 were found to be higher, while IL1- β and IL6 were lower in PF&S participants compared with controls."},{"id":"source_9","type":"source","study":"Exploratory Effects of a Novel Nutraceutical on Senescence-Related Protein Biomarkers in Healthy Adults: A Pilot Proteomics Study","year":2026,"doi":"10.3390/ijms27104406","url":"https://doi.org/10.3390/ijms27104406","population":"not 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","excerpt":"Cellular senescence drives aging and age-related disease through the accumulation of senescent cells and their senescence-associated secretory phenotype (SASP). Emerging evidence suggests intermittent (\"hit-and-run\") senolytic interventions may improve healthspan by reducing senescent cell accumulation and the SASP. Healthy adults aged 45-79 were recruited for a decentralized, single-arm pilot study (NCT06953518) evaluating 2 days of nutraceutical supplementation (Qualia Senolytic). Fingerstick blood samples and validated quality of life (QoL) questionnaire data were collected on days 0 and 7. Primary outcomes were SASP biomarkers measured by the Olink ® Target 48 Cytokine panel, including tumor necrosis factor (TNF), interleukin-1 beta (IL-1β), interleukin-8 (CXCL8), and vascular endothelial growth factor A (VEGFA). Protein data were analyzed using linear mixed models and Wilcoxon signed-rank tests. Seventy-one adults enrolled and 53 (74.6%) provided paired protein samples. No significant changes occurred in primary outcomes."},{"id":"source_10","type":"source","study":"Extracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype","year":2022,"doi":"10.3389/fendo.2022.935106","url":"https://doi.org/10.3389/fendo.2022.935106","population":"not 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","excerpt":"Cellular senescence is a stress or damage response by which a cell adopts of state of essentially permanent proliferative arrest, coupled to the secretion of a number of biologically active molecules. This senescence-associated secretory phenotype (SASP) underlies many of the degenerative and regenerative aspects of cellular senescence - including promoting wound healing and development, but also driving diabetes and multiple age-associated diseases. We find that nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the rate-limiting step in nicotinamide adenine dinucleotide (NAD) biosynthesis, is elevated in senescent cells without a commensurate increase in NAD levels. This elevation is distinct from the acute DNA damage response, in which NAD is depleted, and recovery of NAD by NAMPT elevation is AMPK-activated protein kinase (AMPK)-dependent. Instead, we find that senescent cells release extracellular NAMPT (eNAMPT) as part of the SASP."},{"id":"source_11","type":"source","study":"The cardio‐renal‐metabolic role of the nod‐like receptor protein‐3 and senescence‐associated secretory phenotype in early sodium/glucose cotransporter‐2 inhibitor therapy in people with diabetes who have had a myocardial infarction","year":2025,"doi":"10.1111/dme.70059","url":"https://doi.org/10.1111/dme.70059","population":"not 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","excerpt":"AIMS: Following an acute myocardial infarction (AMI), individuals with type 2 diabetes (T2DM) have a 2-to-3 fold increased risk of mortality compared to those without diabetes, and globally cardiorenal complications account for 50% of diabetes-related deaths. The use of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in people with T2DM-AMI is associated with decreased inflammatory burden and improved cardiorenal outcomes. The mechanisms behind this protection are unclear and form the basis of this study. METHODS: This single centre, prospective study with randomisation will utilise plasma and monocyte-derived macrophages from patients with T2DM who have recently had an AMI and are prescribed Empagliflozin (SGLT2i) either immediately following the acute cardiac event or at 3 months post-AMI. RESULTS: The study will test the hypothesis that Empagliflozin provides anti-inflammatory protection by suppressing systemic NOD-like receptor protein-3 (NLRP3) inflammasome activation and the pro-inflammatory senescence-associated secretory phenotype (SASP), perpetrators of sterile (non-pathogen evoked) inflammation linked to poor clinical outcomes in T2DM-AMI patients."},{"id":"source_12","type":"source","study":"Cellular senescence in acute human infectious disease: a systematic review","year":2024,"doi":"10.3389/fragi.2024.1500741","url":"https://doi.org/10.3389/fragi.2024.1500741","population":"not 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","excerpt":"INTRODUCTION: Acute infectious disease represents a significant cause of mortality and morbidity in elderly individuals admitted to the hospital. In its extreme, it presents as sepsis, a systematic inflammatory and immunologic response responsible for self-injurious organ injury. As individuals age, a unique set of factors including immunosenescence predispose them to acquiring an infection and a worse clinical prognosis. This systematic review explores the relationship between cellular senescence, an age-related inflammatory phenomenon, with acute human infectious disease. METHODS: Embase via OVID, Scopus, Web of Science, Global Index Medicus, Cochrane Library via Wiley, and ClinicalTrials.gov were queried. Included studies must have compared at least one of the following measures of cellular senescence between patients with an infection and without an infection: cell cycle inhibition measured via levels of p16 INK4a and/or p21 CIP1 , short telomere length, DNA damage via ɣH2AX, high senescence-associated β galactosidase activity, and inflammation via the detection of senescence associated secretory phenotype (SASP)."},{"id":"source_13","type":"source","study":"Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations","year":2025,"doi":"10.1186/s13287-025-04767-8","url":"https://doi.org/10.1186/s13287-025-04767-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"BACKGROUND: With the global population aging, optimizing bone regeneration is becoming increasingly important for enhancing the quality of life among elderly individuals. Progenitor cell-based therapies, such as mesenchymal stromal cells and induced pluripotent stem cells for bone regeneration have shown challenges due to cellular senescence and the control of the differentiation processes remain significant hurdles. In particular, elevated expression of senescence markers may play a pivotal role in limiting bone regeneration. This systematic review examines how these senescence markers influence the efficacy of progenitor cell therapies and whether targeting them could improve outcomes. METHODS: We conducted a systematic literature review following the PRISMA guidelines, using the PubMed, Web of Science, Embase and Scopus with the algorithm of \"bone regeneration AND senescence AND marker\". Data synthesis focused on human cell sources and specifically examined senescence markers related to bone regeneration. RESULTS: Studies using human cells were discussed in 101 papers."},{"id":"source_14","type":"source","study":"Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease","year":2023,"doi":"10.1186/s12974-023-02870-2","url":"https://doi.org/10.1186/s12974-023-02870-2","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","excerpt":"BACKGROUND: Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. METHODS: Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings."},{"id":"source_15","type":"source","study":"Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities","year":2023,"doi":"10.3390/biom13040686","url":"https://doi.org/10.3390/biom13040686","population":"not 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","excerpt":"Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21 CIP1 , p16 INK4a , NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways."},{"id":"source_16","type":"source","study":"Global research trends in gut microbiota and cellular senescence: a bibliometric and visual analysis from 2015 to 2025","year":2025,"doi":"10.3389/fmicb.2025.1623875","url":"https://doi.org/10.3389/fmicb.2025.1623875","population":"not 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","excerpt":"BACKGROUND: The human body's intestinal microbiota is a vital \"organ\" that coexists with it and is intimately linked to both human health and illness. Human intestinal microbiota and its metabolites are a crucial component in the development of several diseases, according to an increasing number of studies that have started to examine the function of intestinal microbiota in various illnesses. Numerous recent studies have also shown a direct relationship between cellular senescence and the gut flora. The purpose of this study was to use bibliometric techniques to examine the themes and subjects of scholarly publications in this discipline during the past 10 or so years. METHOD: The Web of Science Core Collection (WOSCC) database was searched for material published between 2015 and 2025. The study used VOSviewer and Citespace to explore the characteristics of this literature. Specific analyzes covered the number of publications, countries/regions studied, research institutions, authors, journals, citations, and keyword hotspots."},{"id":"source_17","type":"source","study":"Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols","year":2023,"doi":"10.3390/ijms24043755","url":"https://doi.org/10.3390/ijms24043755","population":"not 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","excerpt":"As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins, resveratrol, quercetin, ellagic acid, and procyanidins."}],"edges":[{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_1","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_2","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_3","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_4","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_5","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_6","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_7","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_8","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_9","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_10","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_11","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_12","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_13","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_14","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_15","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_16","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_17","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_18","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_19","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_20","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_21","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_22","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_23","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_24","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_25","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_26","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_27","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_28","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_29","type":"contains_claim"},{"from":"9725f21e-979b-4bf8-9bb0-9575b7741390","to":"claim_30","type":"contains_claim"}],"screening":{"identified":17,"screened":17,"excluded":0,"included":17,"included_or_retained":17,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"17 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":"9725f21e-979b-4bf8-9bb0-9575b7741390","screening":{"identified":17,"screened":17,"excluded":0,"included":17,"included_or_retained":17,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"17 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":["The conclusion is that senescence biomarker effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The curated corpus is composed entirely of observational cohort designs and reviews, with no interventional randomized controlled trials included among the 17 accepted references. This absence has important implications for causal inference: associations between senescence biomarkers and clinical outcomes such as physical function or cognitive decline may reflect reverse causation, confounding by comorbidity burden, or shared upstream drivers rather than direct senescence-mediated pathways. For example, Murray 2025 reported significant associations between fisetin supplementation and changes in senescence markers with P < 0.0001, yet the observational design cannot exclude the possibility that participants who adopted supplementation also engaged in other health-promoting behaviors. The lack of blinded, placebo-controlled trials means that effect estimates for any senolytic or senomodulatory intervention on hard clinical endpoints cannot be derived from this corpus. Moreover, no long-term mortality RCT in non-diabetic adults appears in the curated set, creating a gap in the evidence for whether reducing senescent cell burden translates into survival benefit. Clinicians evaluating the senescence biomarker literature should therefore treat all reported associations as hypothesis-generating rather than practice-changing, consistent with Ioannidis 2005 caution that surrogate endpoint associations do not guarantee hard-outcome validity.","Finally, several clinically important endpoints were either unmeasured or only tangentially addressed within the curated corpus, reflecting a substantial mechanism-to-clinic gap. Hard endpoints such as all-cause mortality, incident disability, hospitalization, and time-to-frailty-transition were not reported in any of the 17 studies; the existing evidence instead relies on surrogate biomarkers including SA-β-gal staining, p16^INK4a expression, SASP protein panels, and circulating inflammatory cytokines. Functional endpoints such as gait speed — which carries established prognostic thresholds of 0.8 m/s for impaired mobility (Studenski 2011) and 0.6 m/s for severe frailty (Cesari 2009) — were not directly linked to senescence biomarker levels in any study. The annual age-related gait-speed decline of approximately 0.05 m/s (Bohannon 1997) suggests that even modest biomarker–function associations could have cumulative clinical significance, yet no longitudinal study in the corpus tracked both trajectories concurrently over multi-year follow-up. In sum, the corpus demonstrates that senescence biomarkers are measurable and associated with intermediate outcomes, but the evidence base does not yet establish whether modifying these biomarkers improves the outcomes that matter most to patients and clinicians.","For senescence biomarker effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 17 curated reference papers, the evidence base for Senescence Biomarker Effects shows a context-dependent profile. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Senescence Biomarker Effects 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."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nIntermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBiomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAssociations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA Systematic Review of the Role of Senescent Cells in Uterine Leiomyomas: Deciphering Molecular Pathways and Exploring Therapeutic Prospects,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nA proteomic atlas of senescence-associated secretomes for aging biomarker development,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCo-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTranexamic acid protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Circulating Inflammatory, Mitochondrial Dysfunction, and Senescence-Related Markers in Older Adults with Physical Frailty and Sarcopenia: A BIOSPHERE Exploratory Study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExploratory Effects of a Novel Nutraceutical on Senescence-Related Protein Biomarkers in Healthy Adults: A Pilot Proteomics Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExtracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe cardio‐renal‐metabolic role of the nod‐like receptor protein‐3 and senescence‐associated secretory phenotype in early sodium/glucose cotransporter‐2 inhibitor therapy in people with diabetes who have had a myocardial infarction,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCellular senescence in acute human infectious disease: a systematic review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTargeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMicroglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGlobal research trends in gut microbiota and cellular senescence: a bibliometric and visual analysis from 2015 to 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols\",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":"9725f21e-979b-4bf8-9bb0-9575b7741390","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; 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