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# Hypothesis-Generating Brief: ABT-263 — full paper ## 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. 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. ## Methods ### Review type and protocol This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-senolytics-v06-DAILY-2026-06-24T23-06-41Z`. ### Information sources Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-24. ### Search strategy The following topic-anchored queries were executed against the information sources listed above: - `senolytic AND aging AND human` - `(dasatinib AND quercetin) AND aging` - `fisetin AND senescence AND aging` - `navitoclax AND senescent AND clinical` - `senolytic AND clinical trial AND randomized` - `(senolytic OR senescence) AND (longevity OR healthspan)` - `(p16 OR SASP OR senescent cell) AND human AND clinical` - `senotherapeutic AND older adults AND trial` - `(senescent cell OR SASP) AND frailty AND human` - `(dasatinib OR quercetin OR fisetin) AND safety AND tolerability` - (... 5 additional queries; see `methods_pack.json` for the full list) ### Eligibility criteria - Sources whose primary content addresses senolytics. - Sources with extractable quantitative or qualitative findings. - Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable. - Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle). ### Selection of sources of evidence The 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. ### source admission funnel | Admission bucket | n | |---|---:| | Receipt candidate union | 646 | | Classified source candidates | 614 | | No extractable claims | 26 | | None-only claim binding | 1 | | Mixed partial-or-none claim-binding candidates | 25 | | Partial-only claim-binding candidates | 9 | | Strict high-confidence sources | 4 | | Admitted final sources | 33 | ### Exclusion reasons - 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. ### Data items 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. ### Risk-of-bias appraisal 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. ### Synthesis approach 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. ### AI-use disclosure 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. ### Accountability Accountability 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. ## Results **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. | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | 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 | | 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 | | Mechanism | n=4; claims=47 | no extracted directional signal in 4/4 sources | 4 mechanistic | limited corpus depth in this outcome class | | Cardiometabolic | n=3; claims=112 | no extracted directional signal in 3/3 sources | 3 indirect | limited corpus depth in this outcome class | | 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 | | Deficiency Prevalence | n=1; claims=39 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | Longevity | n=1; claims=14 | positive signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 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. ### Immune Inflammation Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2. 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. ### Mechanism Outcomes 4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: mechanistic=4. ### Cardiometabolic Outcomes 3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3. ### Skeletal Fracture Bone Outcomes 3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=2. Directness coding: direct=1, indirect=2. ### Deficiency Prevalence Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Longevity Outcomes 1 included source were assigned to this outcome class. Directional coding: positive=1. Directness coding: indirect=1. ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. The curated corpus contains no long-term mortality or hard cardiovascular endpoint trial in non-diabetic, community-dwelling older adults, and no adequately powered phase 3 RCT of any senolytic combination. Accordingly, headline statements about lifespan extension cannot be grounded in human trial data within this corpus and rely on preclinical survival curves (e. For example, Ichim 2026) where only mechanistic plausibility has been demonstrated. In animal/preclinical evidence, several outcome classes are supported by only a single source, which means within-corpus replication is impossible. The longevity signal rests on Ichim 2026 alone, the deficiency prevalence outcome class on Su 2026 alone, and the cardiometabolic outcome class on Wakita 2026 and Kawamoto 2026 with conflicting null-versus-null but mechanistically incompatible designs. (mild Alzheimer's disease, n = 5 with CSF IL-6 increasing at t(4) = 3.913, P = 0.008) likewise sits as the only human senolytic CSF-penetration readout in this set. Conclusions drawn from these single-source outcome classes should therefore be treated as exploratory rather than confirmatory, and the broader cross-study disagreement map records multiple null vs positive conflicts (severity 4) that the corpus itself cannot adjudicate. The enrolled populations are narrow in age, sex, and comorbidity profile, which restricts external validity. Where human participants are present, they are predominantly older adults with a specific disease: idiopathic pulmonary fibrosis (Justice 2019, Nambiar 2023), postmenopausal osteoporosis (Farr 2024), mild Alzheimer's disease (Gonzales 2023), and middle-aged subjects in the Agrimonia pilosa trial (Shimizu 2025). Preclinical work skews heavily toward aged C57BL/6 mice (e. For example, young 6 months vs old 27 months in Mahoney 2026, 21-month-old influenza model in Delval 2026, 80-week-old mice in Kawamoto 2026), male Wistar rats in the navitoclax stroke model (Falahatgaroshibi 2026), and SM/J mice for disc degeneration (Novais 2026). Translational relevance to humans remains uncertain. Healthy mid-life adults, women across the full age range, and ethnically diverse cohorts are essentially absent; effect sizes therefore cannot be transported to a general geriatric population or to younger at-risk groups. Endpoint scope is heavily skewed toward biomarkers, mechanism, and tolerability rather than functional or hard outcomes. The direct clinical RCT (Farr 2024) reports bone-turnover markers with mixed effects (P = 0.020, P = 0.024, P = 0.035, P = 0.004 alongside non-significant P = 0.611 and P = 0.149) but not fracture incidence, mobility, or quality of life; Justice 2019 and Nambiar 2023 were feasibility/tolerability pilots; Gonzales 2023 measured CSF penetration and SASP markers, not cognition. The Ioannidis 2005 caution that surrogate endpoints do not guarantee hard-outcome validity therefore applies with full force: the mechanistic anti-senescence signal does not yet translate into validated functional or survival endpoints within this corpus. Several clinically actionable claims rest on mechanistic or preclinical evidence only, creating a documented mechanism-to-clinic gap. Translation-relevant surrogate associations, in the sense flagged by Ioannidis 2005, have not been confirmed in adequately powered human trials within this corpus. The senolytic-resistant senescent-cell population described by Tripathi 2025b further suggests that even if mechanistic clearance is real, its clinical ceiling may be substantially lower than headline efficacy estimates imply — a ceiling the present corpus cannot quantify. ## Conclusion 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. ## What This Synthesis Adds 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. 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. 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. 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. ### Boundary-Condition Matrix | Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary | |---|---:|---:|---|---| | longevity | 0 | 1 | positive | direct interventional hard-endpoint gap | | cardiometabolic | 0 | 3 | null | direct interventional hard-endpoint gap | | immune and inflammation | 0 | 5 | null, positive, unclear | conflict-resolution gap | | mechanism | 0 | 4 | null | direct interventional hard-endpoint gap | | contextual adjacent evidence | 0 | 14 | null, positive, unclear | conflict-resolution gap | | skeletal, fracture, and bone | 1 | 2 | mixed, null | replication gap | ### Evidence-Gap Priority | Priority | Gap | Rationale | |---|---|---| | P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: positive | | P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null | | P3 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null | | P4 | mechanism: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null | | P5 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 14 indirect sources; direction profile: null, positive, unclear | ### Next-Study Design Recommendation The 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. ## Evidence Snapshot The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement. ### Load-Bearing Included Studies - Additional corpus sources included animal/preclinical evidence; Farr 2024; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=mixed; representative statistic=P = 0.004. - Nambiar 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null. - Falahatgaroshibi 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.01. - Sengun 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001. - Justice 2019; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=p ≤.05. - Mahoney 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.465. - Islam 2023; tier=B2; directness=indirect; endpoint=immune inflammation; direction=positive; representative statistic=p ≤ 0.0001. - Zhang 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null. - Wakita 2026; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null. - Fan 2026; tier=B2; directness=indirect; endpoint=skeletal fracture bone; direction=null. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - Additional corpus sources included animal/preclinical evidence; Farr 2024: outcome=skeletal fracture bone; directness=direct; tier=A1; direction=mixed; claims=22. - Nambiar 2023: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=169. - Falahatgaroshibi 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=106. - Sengun 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=104. - Justice 2019: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=98. - Mahoney 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=95. - Islam 2023: outcome=immune inflammation; directness=indirect; tier=B2; direction=positive; claims=78. - Zhang 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=76. - Wakita 2026: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=54. - Fan 2026: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=52. - Kawamoto 2026: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=47. - Chen 2020: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=46. - Lim 2026: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=44. - Peng 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=39. - Su 2026: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=39. - Tripathi 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=32. - Shimizu 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=27. - Ichim 2026: outcome=longevity; directness=indirect; tier=B2; direction=positive; claims=14. - Furuuchi 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13. - Gonzales 2022: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=11. - Effect of Natural Senolytic 2024: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=9. - Jean 2024: outcome=immune inflammation; directness=review; tier=B2; direction=null; claims=5. - Gonzales 2023: outcome=immune; directness=review; tier=B2; direction=null; claims=3. - Mahoney 2025: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=3. - Tripathi 2025b: outcome=immune; directness=review; tier=B2; direction=null; claims=2. - Novais 2026: outcome=mechanism; directness=mechanistic; tier=C1; direction=null; claims=42. - Cadar 2025: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=unclear; claims=27. - Delval 2026: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=positive; claims=6. - Fang 2023: outcome=mechanism; directness=mechanistic; tier=C1; direction=null; claims=3. - Avila 2024: outcome=mechanism; directness=mechanistic; tier=C1; direction=null; claims=1. - Miller 2023: outcome=mechanism; directness=mechanistic; tier=C1; direction=null; claims=1. - Silva 2024: outcome=immune inflammation; directness=protocol; tier=D1; direction=null; claims=17. - Schweiger 2025: outcome=contextual adjacent evidence; directness=protocol; tier=D1; direction=positive; claims=5. ### Classification Criteria - **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices. - **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. - **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. - **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. ### Load-Bearing Tensions - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 ## References - **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. - **Falahatgaroshibi 2026.** _The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke._ Pharmaceuticals, 2026. DOI: 10.3390/ph19030431. PMID: 41901278. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **Chen 2020.** _Is exercise a senolytic medicine? A systematic review._ Aging Cell, 2020. DOI: 10.1111/acel.13294. PMID: 33378138. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **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. - **Effect of Natural Senolytic 2024.** _Effect of Natural Senolytic Agents & NLRP3 Inhibitors on Osteoarthritis._ 2024. Identifier unavailable; no DOI or PMID in source metadata. - **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. - **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. - **Jean 2024.** _Senolytic effects of exercise in human muscles require acute inflammation._ Aging (Albany NY), 2024. DOI: 10.18632/aging.205827. PMID: 38752873. - **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. - **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. - **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. - **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. - **Avila 2024.** _Effect of senolytic drugs in young female mice chemically induced to estropause._ bioRxiv preprint, 2024. DOI: 10.1101/2024.05.22.595355. - **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. ### Background References *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).* - **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.
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"domain_slug": "longevity",
"researka_object_type": "submission",
"researka_submission_id": "d340c6cf-3bf1-47b8-b39d-2213a9712c97",
"title": "Hypothesis-Generating Brief: ABT-263 \u2014 full paper"
}