{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"825b123b-8868-470c-9e7e-9196adde37c5","name":"Hypothesis-Generating Brief: ABT-263 — full paper","doi":"10.17605/OSF.IO/5DFEG","doi_status":"minted","osf_url":"https://osf.io/5dfeg/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_d98ac5bce0ae4d91/chain","content_hash":"sha256:361af0f178a616d030624ca7fc8fd2bb47f9c638155b0edecd128406742ab0a3","provenance_passport":{"publication_id":"825b123b-8868-470c-9e7e-9196adde37c5","submission_id":"ea11f591-877d-4c3b-a36d-280dd5de2f5b","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:361af0f178a616d030624ca7fc8fd2bb47f9c638155b0edecd128406742ab0a3","persistent_identifiers":{"doi":"10.17605/OSF.IO/5DFEG","osf_url":"https://osf.io/5dfeg/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"provenance":{"dw_artifact_id":"claim_d98ac5bce0ae4d91","dw_chain_url":"https://provenance.researka.org/artifacts/claim_d98ac5bce0ae4d91/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"825b123b-8868-470c-9e7e-9196adde37c5","object_type":"publication","parent_object_id":"ea11f591-877d-4c3b-a36d-280dd5de2f5b","title":"Hypothesis-Generating Brief: ABT-263 — full paper","body_markdown":"# Hypothesis-Generating Brief: ABT-263 — full paper\n\n## Abstract\n\nThis paper synthesizes evidence on ABT-263 across 33 accepted source papers and 1290 high-confidence extracted claims.\n\nThe evidence profile contains 1 direct clinical source, 26 adjacent clinical sources, and 6 mechanistic or model-system sources, with 46 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the immune and inflammation, longevity, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, mechanism, immune and inflammation outcome classes, and negative signals 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 ABT-263 remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Thin-corpus 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-senolytics-v06-DAILY-2026-06-25T00-24-59Z`.\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: 2026-06-25.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `senolytic AND aging AND human`\n- `(dasatinib AND quercetin) AND aging`\n- `fisetin AND senescence AND aging`\n- `navitoclax AND senescent AND clinical`\n- `senolytic AND clinical trial AND randomized`\n- `(senolytic OR senescence) AND (longevity OR healthspan)`\n- `(p16 OR SASP OR senescent cell) AND human AND clinical`\n- `senotherapeutic AND older adults AND trial`\n- `(senescent cell OR SASP) AND frailty AND human`\n- `(dasatinib OR quercetin OR fisetin) AND safety AND tolerability`\n- (... 5 additional queries; see `methods_pack.json` for the full list)\n\n### Eligibility criteria\n- Sources whose primary content addresses senolytics.\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 646 records in the receipt-candidate union, 614 were classified as source candidates and 33 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 | 646 |\n| Classified source candidates | 614 |\n| No extractable claims | 26 |\n| None-only claim binding | 1 |\n| Mixed partial-or-none claim-binding candidates | 25 |\n| Partial-only claim-binding candidates | 9 |\n| Strict high-confidence sources | 4 |\n| Admitted final sources | 33 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nRisk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, longevity, mechanism, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n\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=14; claims=822 | no extracted directional signal in 11/14 sources | 10 indirect; 1 protocol; 3 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=7; claims=138 | no extracted directional signal in 4/7 sources | 1 indirect; 2 mechanistic; 1 protocol; 3 review | limited corpus depth in this outcome class |\n| Mechanism | n=4; claims=47 | no extracted directional signal in 4/4 sources | 4 mechanistic | limited corpus depth in this outcome class |\n| Cardiometabolic | n=3; claims=112 | no extracted directional signal in 3/3 sources | 3 indirect | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=3; claims=118 | no extracted directional signal in 2/3 sources | 1 direct; 2 indirect | limited corpus depth in this outcome class |\n| Deficiency Prevalence | n=1; claims=39 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Longevity | n=1; claims=14 | positive signal in 1/1 sources | 1 indirect | 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\n14 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=2. Directness coding: indirect=10, protocol=1, review=3.\n\n### Immune Inflammation Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.\n\nEvidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.\n\n### Mechanism Outcomes\n\n4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: mechanistic=4.\n\n### Cardiometabolic Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.\n\n### Skeletal Fracture Bone Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=2. Directness coding: direct=1, indirect=2.\n\n### Deficiency Prevalence Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Longevity Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: positive=1. Directness coding: indirect=1.\n\n## Limitations\n\nSingle-source outcome classes (Deficiency Prevalence, Longevity) are treated as hypothesis-generating and receive proportional narrative depth rather than standalone evidentiary weight.\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 heavily skewed toward preclinical and indirect interventional hard-endpoint evidence, and the headline conclusions cannot be re-anchored to long-term, hard-outcome human RCTs. Several trials frequently invoked in the senolytic literature, including extension studies of dasatinib+quercetin in diabetic kidney disease, the SToMP-AD cerebrospinal-fluid penetration study, and the SToMP-AD phase 1 feasibility work, are represented only as protocols or as reports in which the field-relevant clinical endpoints are not powered to confirm or refute efficacy. Consequently, any synthesis-level claim of clinical benefit is built on a thin spine of direct human evidence and a thick base of mechanistic or surrogate work, and the gap between mechanistic plausibility and clinic-ready demonstration cannot be closed from this corpus alone.\n\nSeveral outcome classes rest on a single source, and that single-source status is itself a within-corpus generalization risk that should be foregrounded. The directness asymmetry is also informative: Farr 2024 is the only source coded direct, while the surrounding directness=indirect and directness=mechanistic sources share no common endpoint definition, so a corroborating indirect signal cannot substitute for a missing direct one.\n\nThe populations enrolled in the direct and indirect human evidence are narrow, and the external-validity envelope is correspondingly tight. Shimizu 2025 randomized middle-aged humans to an Agrimonia pilosa extract. Outside these specific disease phenotypes, ages, and sex strata, the corpus offers no direct human signal: healthy community-dwelling older men, younger adults, and pediatric or non-European populations are absent. A substantial fraction of the supporting evidence is animal-only, including Falahatgaroshibi 2026 (male young Wistar rats, 10 and 30 mg/kg). Translational relevance to humans remains uncertain.\n\nEndpoint scope is another hard boundary of this corpus. With the exception of Farr 2024, no source reports a hard clinical endpoint such as incident fracture, myocardial infarction, stroke, sepsis-related mortality, or hospitalization; the field is dominated by surrogate and feasibility endpoints (feasibility, tolerability, biomarker change, single-cell transcriptomics, senescence-associated β-galactosidase activity, senescence-associated secretory phenotype factors, and pharmacokinetic parameters).\n\nFinally, the mechanism-to-clinic gap is itself a corpus-level limitation that no individual RoB column can encode. The result is a corpus in which a coherent mechanistic story is told, but the clinically relevant dose, schedule, target population, and hard outcome remain undefined, and any cross-domain inference from mechanistic or surrogate sources onto a clinical recommendation must be treated as hypothesis-generating rather than evidence-supported.\n\n## Conclusion\n\nFor ABT-263, the final interpretation is deliberately tiered: the retained clinical and mechanistic 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 33 included sources on Senolytics across 8 outcome classes and 46 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 33 curated reference papers, the evidence base for senolytics shows a context-dependent profile. Positive signals appear in: immune inflammation, longevity. Null findings dominate: contextual other, mechanism. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The senolytics 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\nAdditional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the null vs positive between Mahoney 2025 and Schweiger 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 1 | positive | direct interventional hard-endpoint gap |\n| cardiometabolic | 0 | 3 | null | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 5 | null, positive, unclear | conflict-resolution gap |\n| mechanism | 0 | 4 | null | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 14 | null, positive, unclear | conflict-resolution gap |\n| skeletal, fracture, and bone | 1 | 2 | mixed, null | replication gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: positive |\n| P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |\n| P3 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P4 | mechanism: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null |\n| P5 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 14 indirect sources; direction profile: null, positive, unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Senolytics should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Tensions and Gaps\n\nAdditional corpus sources included animal/preclinical evidence; evidence-gap priority: The tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. The manuscript reports 46 claim-level cross-study disagreements from the manifest; that number is a claim-level count, not an independently pooled source-pair count. Actually surfaced tensions include:\n- Fan 2026 vs Farr 2024: surfaced tension/disagreement in Skeletal, Fracture, and Bone because directions are null versus mixed.\n- Falahatgaroshibi 2026 vs Furuuchi 2026: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are unclear versus null.\n- Islam 2023 vs Jean 2024: surfaced tension/disagreement in Immune and Inflammation because directions are positive versus null.\n\n## Evidence Snapshot\n\nSource directness breakdown: 1/33 retained sources directly address the stated topic and aging-relevant hard endpoints; 32/33 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.\n\n### Source Classification Map\n\n- Additional corpus sources included animal/preclinical evidence; Nambiar 2023: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Falahatgaroshibi 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.\n- Sengun 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.\n- Justice 2019: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Mahoney 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Islam 2023: outcome=Immune and Inflammation; direction=positive; directness=indirect; tier=B2.\n- Zhang 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Wakita 2026: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n- Fan 2026: outcome=Skeletal, Fracture, and Bone; direction=null; directness=indirect; tier=B2.\n- Kawamoto 2026: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n- Chen 2020: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n- Lim 2026: outcome=Skeletal, Fracture, and Bone; direction=null; directness=indirect; tier=B2.\n- Novais 2026: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n- Peng 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Su 2026: outcome=Deficiency Prevalence; direction=null; directness=indirect; tier=B2.\n- Tripathi 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Shimizu 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Cadar 2025: outcome=Immune and Inflammation; direction=unclear; directness=mechanistic; tier=C1.\n- Farr 2024: outcome=Skeletal, Fracture, and Bone; direction=mixed; directness=direct; tier=A1.\n- Silva 2024: outcome=Immune and Inflammation; direction=null; directness=protocol; tier=D1.\n- Ichim 2026: outcome=Longevity; direction=positive; directness=indirect; tier=B2.\n- Furuuchi 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n- Gonzales 2022: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n- Effect of Natural Senolytic 2024: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n- Delval 2026: outcome=Immune and Inflammation; direction=positive; directness=mechanistic; tier=C1.\n- Schweiger 2025: outcome=Contextual Adjacent Evidence; direction=positive; directness=protocol; tier=D1.\n- Jean 2024: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n- Fang 2023: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n- Mahoney 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n- Gonzales 2023: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n- Tripathi 2025b: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n- Avila 2024: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n- Miller 2023: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n\nEvidence type metadata note: evidence-type labels are resolved against source excerpts; review, RCT/trial, and excerpt evidence are reclassified under the source classification map before claims are interpreted.\n\nIn animal/preclinical evidence, topic-fit rationale: Sources are retained only when they operationalize senolytics directly or provide adjacent/contextual boundary evidence for the same construct. 1/33 retained sources are classified as direct; adjacent, contextual, review-level, or mechanistic sources are reclassified as boundary evidence rather than used for broad efficacy claims. Representative source-fit checks: Nambiar 2023 (indirect; Contextual Adjacent Evidence), Falahatgaroshibi 2026 (indirect; Contextual Adjacent Evidence), Sengun 2026 (indirect; Contextual Adjacent Evidence), Justice 2019 (indirect; Contextual Adjacent Evidence), Mahoney 2026 (indirect; Contextual Adjacent Evidence).\n\nDirectional coding note: Null or no extracted directional signal means no coded positive, negative, or mixed effect was extracted for that specific outcome class; it is not an absence-of-support finding. Positive, negative, mixed, unclear, and null are outcome-specific codes, so a bounded rationale can be supported by adjacent or different outcome evidence while another outcome remains null or unclear. Contextual claims contain bibliographic background, mechanism, methods, exposure definitions, or population context rather than effect-direction evidence. When an outcome-class summary uses no extracted directional signal, it should state the source proportion, such as X/Y sources, to avoid ambiguity.\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Additional corpus sources included animal/preclinical evidence; Farr 2024; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=mixed; representative statistic=P = 0.004.\n- Nambiar 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Falahatgaroshibi 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.01.\n- Sengun 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001.\n- Justice 2019; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=p ≤.05.\n- Mahoney 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.465.\n- Islam 2023; tier=B2; directness=indirect; endpoint=immune inflammation; direction=positive; representative statistic=p ≤ 0.0001.\n- Zhang 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Wakita 2026; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.\n- Fan 2026; tier=B2; directness=indirect; endpoint=skeletal fracture bone; direction=null.\n\n### Source Outcome-Class Map\n\nTension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies, so these contrasts are treated as unresolved evidence gaps.\n\n- Nambiar 2023: Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Falahatgaroshibi 2026: The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Sengun 2026: Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.\n\n- Justice 2019: Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Mahoney 2026: Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- Islam 2023: Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age: outcome=Immune and Inflammation; direction=positive; directness=indirect; tier=B2.\n\n- Zhang 2025: Senolytic-loaded asymmetric wound dressing for targeted senescent cell clearance in diabetic wound healing: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Wakita 2026: Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n\n- Fan 2026: Supramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing: outcome=Skeletal, Fracture, and Bone; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Kawamoto 2026: Reevaluating the senolytic activity of a GLS1 inhibitor and an anti-PD-1 antibody: toward greater reproducibility and methodological rigor: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n\n- Chen 2020: Is exercise a senolytic medicine? A systematic review: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n\n- In animal/preclinical evidence, Lim 2026: DEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss: outcome=Skeletal, Fracture, and Bone; direction=null; directness=indirect; tier=B2.\n\n- Novais 2026: Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n\n- Peng 2026: Synergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Su 2026: Senolytics alleviate cyclophosphamide-induced premature ovarian insufficiency by eliminating senescent cells: outcome=Deficiency Prevalence; direction=null; directness=indirect; tier=B2.\n\n- Tripathi 2025: Senolytic‐Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- Shimizu 2025: Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- Cadar 2025: Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza‐Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice: outcome=Immune and Inflammation; direction=unclear; directness=mechanistic; tier=C1.\n\n- Farr 2024: Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.: outcome=Skeletal, Fracture, and Bone; direction=mixed; directness=direct; tier=A1.\n\n- Silva 2024: Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial: outcome=Immune and Inflammation; direction=null; directness=protocol; tier=D1.\n\n- In animal/preclinical evidence, Ichim 2026: Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan: outcome=Longevity; direction=positive; directness=indirect; tier=B2.\n\n- Furuuchi 2026: Natural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.\n\n- In animal/preclinical evidence, Gonzales 2022: Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.\n\n- Effect of Natural Senolytic 2024: Effect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n\n- Delval 2026: Senolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza: outcome=Immune and Inflammation; direction=positive; directness=mechanistic; tier=C1.\n\n- Schweiger 2025: Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders: outcome=Contextual Adjacent Evidence; direction=positive; directness=protocol; tier=D1.\n\n- Jean 2024: Senolytic effects of exercise in human muscles require acute inflammation.: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n\n- Fang 2023: Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n\n- In animal/preclinical evidence, Mahoney 2025: Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.\n\n- Gonzales 2023: Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n\n- Tripathi 2025b: Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2.\n\n- Avila 2024: Effect of senolytic drugs in young female mice chemically induced to estropause: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n\n- In animal/preclinical evidence, Miller 2023: Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Additional corpus sources included animal/preclinical evidence; severity 4 null vs positive: Mahoney 2025 vs Schweiger 2025; Schweiger 2025 (positive on contextual other) vs Mahoney 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Effect of Natural Senolytic 2024 vs Schweiger 2025; Schweiger 2025 (positive on contextual other) vs Effect of Natural Senolytic 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Nambiar 2023 vs Schweiger 2025; Schweiger 2025 (positive on contextual other) vs Nambiar 2023 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Silva 2024 vs Islam 2023; Islam 2023 (positive on immune inflammation) vs Silva 2024 (null on immune inflammation) — partial conflict\n- Severity 4 null vs positive: Shimizu 2025 vs Schweiger 2025; Schweiger 2025 (positive on contextual other) vs Shimizu 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Schweiger 2025 vs Tripathi 2025; Schweiger 2025 (positive on contextual other) vs Tripathi 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Schweiger 2025 vs Zhang 2025; Schweiger 2025 (positive on contextual other) vs Zhang 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Schweiger 2025 vs Peng 2026; Schweiger 2025 (positive on contextual other) vs Peng 2026 (null on contextual other) — partial conflict\n\n## References\n\n- **Nambiar 2023.** _Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability._ eBioMedicine, 2023. DOI: 10.1016/j.ebiom.2023.104481. PMID: 36857968.\n- **Falahatgaroshibi 2026.** _The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke._ Pharmaceuticals, 2026. DOI: 10.3390/ph19030431. PMID: 41901278.\n- **Sengun 2026.** _Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits._ Heart rhythm, 2026. DOI: 10.1016/j.hrthm.2026.01.007. PMID: 41513056.\n- **Justice 2019.** _Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study._ EBioMedicine, 2019. DOI: 10.1016/j.ebiom.2018.12.052. PMID: 30616998.\n- **Mahoney 2026.** _Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12._ Aging Cell, 2026. DOI: 10.1111/acel.70500. PMID: 42021544.\n- **Islam 2023.** _Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age._ Aging Cell, 2023. DOI: 10.1111/acel.13767. PMID: 36637079.\n- **Zhang 2025.** _Senolytic-loaded asymmetric wound dressing for targeted senescent cell clearance in diabetic wound healing._ Materials Today Bio, 2025. DOI: 10.1016/j.mtbio.2025.102741. PMID: 41560809.\n- **Wakita 2026.** _Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance._ Nature Aging, 2026. DOI: 10.1038/s43587-025-01057-z. PMID: 41611832.\n- **Fan 2026.** _Supramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing._ Journal of Nanobiotechnology, 2026. DOI: 10.1186/s12951-026-04138-2. PMID: 41709294.\n- **Kawamoto 2026.** _Reevaluating the senolytic activity of a GLS1 inhibitor and an anti-PD-1 antibody: toward greater reproducibility and methodological rigor._ EMBO Reports, 2026. DOI: 10.1038/s44319-026-00740-5. PMID: 41933117.\n- **Chen 2020.** _Is exercise a senolytic medicine? A systematic review._ Aging Cell, 2020. DOI: 10.1111/acel.13294. PMID: 33378138.\n- **Lim 2026.** _DEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss._ Advanced Science, 2026. DOI: 10.1002/advs.202509263. PMID: 41556369.\n- **Novais 2026.** _Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice._ Bone Research, 2026. DOI: 10.1038/s41413-026-00526-4. PMID: 41974671.\n- **Peng 2026.** _Synergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis._ Bioactive Materials, 2026. DOI: 10.1016/j.bioactmat.2025.11.047. PMID: 41625497.\n- **Su 2026.** _Senolytics alleviate cyclophosphamide-induced premature ovarian insufficiency by eliminating senescent cells._ European Journal of Histochemistry: EJH, 2026. DOI: 10.4081/ejh.2026.4537. PMID: 42011821.\n- **Tripathi 2025.** _Senolytic‐Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers._ Aging Cell, 2025. DOI: 10.1111/acel.70358. PMID: 41462575.\n- **Shimizu 2025.** _Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study._ Nutrients, 2025. DOI: 10.3390/nu17040667. PMID: 40004995.\n- **Cadar 2025.** _Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza‐Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice._ Aging Cell, 2025. DOI: 10.1111/acel.70345. PMID: 41462563.\n- **Farr 2024.** _Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial._ Nat Med, 2024. DOI: 10.1038/s41591-024-03096-2. PMID: 38956196.\n- **Silva 2024.** _Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial._ Trials, 2024. DOI: 10.1186/s13063-024-08474-2. PMID: 39434114.\n- **Ichim 2026.** _Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan._ Journal of Translational Medicine, 2026. DOI: 10.1186/s12967-026-08221-y. PMID: 42260530.\n- **Furuuchi 2026.** _Natural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis._ iScience, 2026. DOI: 10.1016/j.isci.2026.115607. PMID: 42028013.\n- **Gonzales 2022.** _Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial._ The Journal of Prevention of Alzheimer's Disease, 2022. DOI: 10.14283/jpad.2021.62. PMID: 35098970.\n- **Effect of Natural Senolytic 2024.** _Effect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis._ 2024. Identifier unavailable; no DOI or PMID in source metadata.\n- **Delval 2026.** _Senolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza._ Aging Cell, 2026. DOI: 10.1111/acel.70480. PMID: 41952036.\n- **Schweiger 2025.** _Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders._ F1000Research, 2025. DOI: 10.12688/f1000research.151963.2. PMID: 40443429.\n- **Jean 2024.** _Senolytic effects of exercise in human muscles require acute inflammation._ Aging (Albany NY), 2024. DOI: 10.18632/aging.205827. PMID: 38752873.\n- **Fang 2023.** _Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice._ bioRxiv preprint, 2023. DOI: 10.1101/2023.12.12.571277.\n- **Mahoney 2025.** _Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12._ bioRxiv preprint, 2025. DOI: 10.1101/2025.08.13.670216.\n- **Gonzales 2023.** _Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial._ Nat Med, 2023. DOI: 10.1038/s41591-023-02543-w. PMID: 37679434.\n- **Tripathi 2025b.** _Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers._ bioRxiv preprint, 2025. DOI: 10.1101/2025.08.27.672709.\n- **Avila 2024.** _Effect of senolytic drugs in young female mice chemically induced to estropause._ bioRxiv preprint, 2024. DOI: 10.1101/2024.05.22.595355.\n- **Miller 2023.** _Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease._ Frontiers in Neurology, 2023. DOI: 10.3389/fneur.2023.1271941. PMID: 37840914.\n\n### Background References\n\n*Canonical reference values and methodological references cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n","metadata":{"abstract":"This paper synthesizes evidence on ABT-263 across 33 accepted source papers and 1290 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 26 adjacent clinical sources, and 6 mechanistic or model-system sources, with 46 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation, longevity, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, mechanism, immune and inflammation outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. 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paper synthesizes evidence on ABT-263 across 33 accepted source papers and 1290 high-confidence extracted claims.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor 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class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_4","claim":"The conclusion is that ABT-263 remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_5","claim":"This manuscript is reported as a Thin-corpus 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-senolytics-v06-DAILY-2026-06-25T00-24-59Z`.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_6","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_7","claim":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_8","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, longevity, mechanism, 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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_9","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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_10","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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_11","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_12","claim":"| Contextual Adjacent Evidence | n=14; claims=822 | no extracted directional signal in 11/14 sources | 10 indirect; 1 protocol; 3 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_13","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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_14","claim":"14 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=2. Directness coding: indirect=10, protocol=1, review=3.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_15","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_16","claim":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_17","claim":"4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: mechanistic=4.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_18","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_19","claim":"3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=2. Directness coding: direct=1, indirect=2.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_20","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_21","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_22","claim":"The curated corpus is heavily skewed toward preclinical and indirect interventional hard-endpoint evidence, and the headline conclusions cannot be re-anchored to long-term, hard-outcome human RCTs. Several trials frequently invoked in the senolytic literature, including extension studies of dasatinib+quercetin in diabetic kidney disease, the SToMP-AD cerebrospinal-fluid penetration study, and the SToMP-AD phase 1 feasibility work, are represented only as protocols or as reports in which the field-relevant clinical endpoints are not powered to confirm or refute efficacy. Consequently, any synthesis-level claim of clinical benefit is built on a thin spine of direct human evidence and a thick base of mechanistic or surrogate work, and the gap between mechanistic plausibility and clinic-ready demonstration cannot be closed from this corpus alone.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_23","claim":"Several outcome classes rest on a single source, and that single-source status is itself a within-corpus generalization risk that should be foregrounded. The directness asymmetry is also informative: Farr 2024 is the only source coded direct, while the surrounding directness=indirect and directness=mechanistic sources share no common endpoint definition, so a corroborating indirect signal cannot substitute for a missing direct one.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_24","claim":"The populations enrolled in the direct and indirect human evidence are narrow, and the external-validity envelope is correspondingly tight. Shimizu 2025 randomized middle-aged humans to an Agrimonia pilosa extract. Outside these specific disease phenotypes, ages, and sex strata, the corpus offers no direct human signal: healthy community-dwelling older men, younger adults, and pediatric or non-European populations are absent. A substantial fraction of the supporting evidence is animal-only, including Falahatgaroshibi 2026 (male young Wistar rats, 10 and 30 mg/kg). Translational relevance to humans remains uncertain.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_25","claim":"Finally, the mechanism-to-clinic gap is itself a corpus-level limitation that no individual RoB column can encode. The result is a corpus in which a coherent mechanistic story is told, but the clinically relevant dose, schedule, target population, and hard outcome remain undefined, and any cross-domain inference from mechanistic or surrogate sources onto a clinical recommendation must be treated as hypothesis-generating rather than evidence-supported.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_26","claim":"For ABT-263, the final interpretation is deliberately tiered: the retained clinical and mechanistic 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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_27","claim":"This synthesis maps 33 included sources on Senolytics across 8 outcome classes and 46 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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_28","claim":"Across 33 curated reference papers, the evidence base for senolytics shows a context-dependent profile. Positive signals appear in: immune inflammation, longevity. Null findings dominate: contextual other, mechanism. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The senolytics 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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_29","claim":"Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the null vs positive between Mahoney 2025 and Schweiger 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]},{"claim_id":"claim_30","claim":"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.","candidate_sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"825b123b-8868-470c-9e7e-9196adde37c5","content_hash":"sha256:361af0f178a616d030624ca7fc8fd2bb47f9c638155b0edecd128406742ab0a3","nodes":[{"id":"825b123b-8868-470c-9e7e-9196adde37c5","type":"publication","title":"Hypothesis-Generating Brief: ABT-263 — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on ABT-263 across 33 accepted source papers and 1290 high-confidence extracted claims."},{"id":"claim_2","type":"claim","text":"The evidence profile contains 1 direct clinical source, 26 adjacent clinical sources, and 6 mechanistic or model-system sources, with 46 cross-study disagreements across the evidence base."},{"id":"claim_3","type":"claim","text":"Positive study-level signals are summarized in the immune and inflammation, longevity, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, mechanism, immune and inflammation outcome classes, and negative signals 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_4","type":"claim","text":"The conclusion is that ABT-263 remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_5","type":"claim","text":"This manuscript is reported as a Thin-corpus 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-senolytics-v06-DAILY-2026-06-25T00-24-59Z`."},{"id":"claim_6","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_7","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_8","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, longevity, mechanism, 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_9","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_10","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_11","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_12","type":"claim","text":"| Contextual Adjacent Evidence | n=14; claims=822 | no extracted directional signal in 11/14 sources | 10 indirect; 1 protocol; 3 review | limited corpus depth in this outcome class |"},{"id":"claim_13","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_14","type":"claim","text":"14 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=2. Directness coding: indirect=10, protocol=1, review=3."},{"id":"claim_15","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2."},{"id":"claim_16","type":"claim","text":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim."},{"id":"claim_17","type":"claim","text":"4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: mechanistic=4."},{"id":"claim_18","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3."},{"id":"claim_19","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=2. Directness coding: direct=1, indirect=2."},{"id":"claim_20","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_21","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_22","type":"claim","text":"The curated corpus is heavily skewed toward preclinical and indirect interventional hard-endpoint evidence, and the headline conclusions cannot be re-anchored to long-term, hard-outcome human RCTs. Several trials frequently invoked in the senolytic literature, including extension studies of dasatinib+quercetin in diabetic kidney disease, the SToMP-AD cerebrospinal-fluid penetration study, and the SToMP-AD phase 1 feasibility work, are represented only as protocols or as reports in which the field-relevant clinical endpoints are not powered to confirm or refute efficacy. Consequently, any synthesis-level claim of clinical benefit is built on a thin spine of direct human evidence and a thick base of mechanistic or surrogate work, and the gap between mechanistic plausibility and clinic-ready demonstration cannot be closed from this corpus alone."},{"id":"claim_23","type":"claim","text":"Several outcome classes rest on a single source, and that single-source status is itself a within-corpus generalization risk that should be foregrounded. The directness asymmetry is also informative: Farr 2024 is the only source coded direct, while the surrounding directness=indirect and directness=mechanistic sources share no common endpoint definition, so a corroborating indirect signal cannot substitute for a missing direct one."},{"id":"claim_24","type":"claim","text":"The populations enrolled in the direct and indirect human evidence are narrow, and the external-validity envelope is correspondingly tight. Shimizu 2025 randomized middle-aged humans to an Agrimonia pilosa extract. Outside these specific disease phenotypes, ages, and sex strata, the corpus offers no direct human signal: healthy community-dwelling older men, younger adults, and pediatric or non-European populations are absent. A substantial fraction of the supporting evidence is animal-only, including Falahatgaroshibi 2026 (male young Wistar rats, 10 and 30 mg/kg). Translational relevance to humans remains uncertain."},{"id":"claim_25","type":"claim","text":"Finally, the mechanism-to-clinic gap is itself a corpus-level limitation that no individual RoB column can encode. The result is a corpus in which a coherent mechanistic story is told, but the clinically relevant dose, schedule, target population, and hard outcome remain undefined, and any cross-domain inference from mechanistic or surrogate sources onto a clinical recommendation must be treated as hypothesis-generating rather than evidence-supported."},{"id":"claim_26","type":"claim","text":"For ABT-263, the final interpretation is deliberately tiered: the retained clinical and mechanistic 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_27","type":"claim","text":"This synthesis maps 33 included sources on Senolytics across 8 outcome classes and 46 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_28","type":"claim","text":"Across 33 curated reference papers, the evidence base for senolytics shows a context-dependent profile. Positive signals appear in: immune inflammation, longevity. Null findings dominate: contextual other, mechanism. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The senolytics 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_29","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the null vs positive between Mahoney 2025 and Schweiger 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_30","type":"claim","text":"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":"source_1","type":"source","study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","year":2023,"doi":"10.1016/j.ebiom.2023.104481","url":"https://doi.org/10.1016/j.ebiom.2023.104481","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_2","type":"source","study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","year":2026,"doi":"10.3390/ph19030431","url":"https://doi.org/10.3390/ph19030431","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_3","type":"source","study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","year":2026,"doi":"10.1016/j.hrthm.2026.01.007","url":"https://doi.org/10.1016/j.hrthm.2026.01.007","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_4","type":"source","study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","year":2026,"doi":"10.1111/acel.70500","url":"https://doi.org/10.1111/acel.70500","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_5","type":"source","study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","year":2023,"doi":"10.1111/acel.13767","url":"https://doi.org/10.1111/acel.13767","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_6","type":"source","study":"Senolytic-loaded asymmetric wound dressing for targeted senescent cell clearance in diabetic wound healing","year":2025,"doi":"10.1016/j.mtbio.2025.102741","url":"https://doi.org/10.1016/j.mtbio.2025.102741","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_7","type":"source","study":"Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance","year":2026,"doi":"10.1038/s43587-025-01057-z","url":"https://doi.org/10.1038/s43587-025-01057-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_8","type":"source","study":"Supramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing","year":2026,"doi":"10.1186/s12951-026-04138-2","url":"https://doi.org/10.1186/s12951-026-04138-2","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"},{"id":"source_9","type":"source","study":"Reevaluating the senolytic activity of a GLS1 inhibitor and an anti-PD-1 antibody: toward greater reproducibility and methodological rigor","year":2026,"doi":"10.1038/s44319-026-00740-5","url":"https://doi.org/10.1038/s44319-026-00740-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_10","type":"source","study":"Is exercise a senolytic medicine? A systematic review","year":2020,"doi":"10.1111/acel.13294","url":"https://doi.org/10.1111/acel.13294","population":"not 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"},{"id":"source_11","type":"source","study":"DEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss","year":2026,"doi":"10.1002/advs.202509263","url":"https://doi.org/10.1002/advs.202509263","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_12","type":"source","study":"Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice","year":2026,"doi":"10.1038/s41413-026-00526-4","url":"https://doi.org/10.1038/s41413-026-00526-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"Synergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis","year":2026,"doi":"10.1016/j.bioactmat.2025.11.047","url":"https://doi.org/10.1016/j.bioactmat.2025.11.047","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_14","type":"source","study":"Senolytics alleviate cyclophosphamide-induced premature ovarian insufficiency by eliminating senescent cells","year":2026,"doi":"10.4081/ejh.2026.4537","url":"https://doi.org/10.4081/ejh.2026.4537","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_15","type":"source","study":"Senolytic‐Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers","year":2025,"doi":"10.1111/acel.70358","url":"https://doi.org/10.1111/acel.70358","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_16","type":"source","study":"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. 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sidecar","directness":"primary"},{"id":"source_18","type":"source","study":"Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.","year":2024,"doi":"10.1038/s41591-024-03096-2","url":"https://doi.org/10.1038/s41591-024-03096-2","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"},{"id":"source_19","type":"source","study":"Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial","year":2024,"doi":"10.1186/s13063-024-08474-2","url":"https://doi.org/10.1186/s13063-024-08474-2","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"},{"id":"source_20","type":"source","study":"Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan","year":2026,"doi":"10.1186/s12967-026-08221-y","url":"https://doi.org/10.1186/s12967-026-08221-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_21","type":"source","study":"Natural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis","year":2026,"doi":"10.1016/j.isci.2026.115607","url":"https://doi.org/10.1016/j.isci.2026.115607","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_22","type":"source","study":"Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial","year":2022,"doi":"10.14283/jpad.2021.62","url":"https://doi.org/10.14283/jpad.2021.62","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_23","type":"source","study":"Effect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis","year":2024,"doi":null,"url":null,"population":"not 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"},{"id":"source_24","type":"source","study":"Senolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza","year":2026,"doi":"10.1111/acel.70480","url":"https://doi.org/10.1111/acel.70480","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_25","type":"source","study":"Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders","year":2025,"doi":"10.12688/f1000research.151963.2","url":"https://doi.org/10.12688/f1000research.151963.2","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"},{"id":"source_26","type":"source","study":"Senolytic effects of exercise in human muscles require acute inflammation.","year":2024,"doi":"10.18632/aging.205827","url":"https://doi.org/10.18632/aging.205827","population":"not 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"},{"id":"source_27","type":"source","study":"Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12","year":2025,"doi":"10.1101/2025.08.13.670216","url":"https://doi.org/10.1101/2025.08.13.670216","population":"not 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"},{"id":"source_28","type":"source","study":"Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F 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outcome slices.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_35","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_36","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_37","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_38","type":"source","study":"Effect of Natural Senolytic 2024","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"}],"edges":[{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_1","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_2","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_3","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_4","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_5","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_6","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_7","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_8","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_9","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_10","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_11","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_12","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_13","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_14","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_15","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_16","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_17","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_18","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_19","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_20","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_21","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_22","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_23","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_24","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_25","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_26","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_27","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_28","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_29","type":"contains_claim"},{"from":"825b123b-8868-470c-9e7e-9196adde37c5","to":"claim_30","type":"contains_claim"}],"screening":{"identified":33,"screened":33,"excluded":0,"included":33,"included_or_retained":33,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"33 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":"825b123b-8868-470c-9e7e-9196adde37c5","screening":{"identified":33,"screened":33,"excluded":0,"included":33,"included_or_retained":33,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"33 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 ABT-263 remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=2. Directness coding: direct=1, indirect=2.","Several outcome classes rest on a single source, and that single-source status is itself a within-corpus generalization risk that should be foregrounded. The directness asymmetry is also informative: Farr 2024 is the only source coded direct, while the surrounding directness=indirect and directness=mechanistic sources share no common endpoint definition, so a corroborating indirect signal cannot substitute for a missing direct one.","Finally, the mechanism-to-clinic gap is itself a corpus-level limitation that no individual RoB column can encode. The result is a corpus in which a coherent mechanistic story is told, but the clinically relevant dose, schedule, target population, and hard outcome remain undefined, and any cross-domain inference from mechanistic or surrogate sources onto a clinical recommendation must be treated as hypothesis-generating rather than evidence-supported.","For ABT-263, the final interpretation is deliberately tiered: the retained clinical and mechanistic 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 33 curated reference papers, the evidence base for senolytics shows a context-dependent profile. Positive signals appear in: immune inflammation, longevity. Null findings dominate: contextual other, mechanism. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The senolytics 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\n\"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic-loaded asymmetric wound dressing for targeted senescent cell clearance in diabetic wound healing,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nComparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSupramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nReevaluating the senolytic activity of a GLS1 inhibitor and an anti-PD-1 antibody: toward greater reproducibility and methodological rigor,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nIs exercise a senolytic medicine? A systematic review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSynergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytics alleviate cyclophosphamide-induced premature ovarian insufficiency by eliminating senescent cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic‐Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza‐Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSynergistic senolytic–regenerative therapy significantly extends healthspan and lifespan,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNatural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSenolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nProtocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic effects of exercise in human muscles require acute inflammation.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSenolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSenolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEffect of senolytic drugs in young female mice chemically induced to estropause,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSenolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nEffect of Natural Senolytic 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"825b123b-8868-470c-9e7e-9196adde37c5","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability","doi":"10.1016/j.ebiom.2023.104481","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke","doi":"10.3390/ph19030431","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits","doi":"10.1016/j.hrthm.2026.01.007","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic Treatment With Fisetin Reverses Age‐Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12","doi":"10.1111/acel.70500","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age","doi":"10.1111/acel.13767","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic-loaded asymmetric wound dressing for targeted senescent cell clearance in diabetic wound healing","doi":"10.1016/j.mtbio.2025.102741","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance","doi":"10.1038/s43587-025-01057-z","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Supramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing","doi":"10.1186/s12951-026-04138-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Reevaluating the senolytic activity of a GLS1 inhibitor and an anti-PD-1 antibody: toward greater reproducibility and methodological rigor","doi":"10.1038/s44319-026-00740-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Is exercise a senolytic medicine? A systematic review","doi":"10.1111/acel.13294","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"DEL‐1 is an Endogenous Senolytic Protein that Inhibits Senescence‐Associated Bone Loss","doi":"10.1002/advs.202509263","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice","doi":"10.1038/s41413-026-00526-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Synergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis","doi":"10.1016/j.bioactmat.2025.11.047","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytics alleviate cyclophosphamide-induced premature ovarian insufficiency by eliminating senescent cells","doi":"10.4081/ejh.2026.4537","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic‐Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers","doi":"10.1111/acel.70358","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study","doi":"10.3390/nu17040667","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza‐Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice","doi":"10.1111/acel.70345","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.","doi":"10.1038/s41591-024-03096-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial","doi":"10.1186/s13063-024-08474-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan","doi":"10.1186/s12967-026-08221-y","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Natural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis","doi":"10.1016/j.isci.2026.115607","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial","doi":"10.14283/jpad.2021.62","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Senolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza","doi":"10.1111/acel.70480","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders","doi":"10.12688/f1000research.151963.2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic effects of exercise in human muscles require acute inflammation.","doi":"10.18632/aging.205827","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12","doi":"10.1101/2025.08.13.670216","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice","doi":"10.1101/2023.12.12.571277","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.","doi":"10.1038/s41591-023-02543-w","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers","doi":"10.1101/2025.08.27.672709","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Effect of senolytic drugs in young female mice chemically induced to estropause","doi":"10.1101/2024.05.22.595355","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease","doi":"10.3389/fneur.2023.1271941","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study","doi":"10.1016/j.ebiom.2018.12.052","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"Effect of Natural Senolytic 2024","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"}]}}]}