Adjacent Evidence Brief: SASP secretome

Adjacent Evidence Brief: SASP secretome

Abstract

Evidence-honesty note: 11/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This paper synthesizes evidence on SASP secretome across 17 accepted source papers and 193 high-confidence extracted claims.

The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 1 mechanistic or model-system source, with 3 cross-study disagreements across the evidence base.

Positive study-level signals are summarized in the longevity outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation outcome class. The paper therefore reports a source-directness and outcome-class map rather than a pooled effect.

The conclusion is narrower: the retained evidence maps associations, mechanisms, and candidate endpoints for follow-up; it does not establish clinical benefit, therapeutic actionability, or anti-aging efficacy.

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-sasp_secretome-v06-DAILY-2026-06-26T20-06-36Z.

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: 2026-06-26.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• SASP secretome AND aging AND human
• SASP secretome AND older adults
• SASP secretome AND randomized controlled trial
• senescence-associated secretory phenotype AND aging AND human
• senescence-associated secretory phenotype AND older adults
• senescence-associated secretory phenotype AND randomized controlled trial
• SASP AND aging AND human
• SASP AND older adults
• SASP AND randomized controlled trial
• senescent-cell secretome AND aging AND human

Eligibility criteria

• Sources whose primary content addresses sasp secretome.
• 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 124 records in the receipt-candidate union, 40 were classified as source candidates and 17 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
source candidate union	124
Classified source candidates	40
No extractable claims	32
None-only claim binding	9
Mixed partial-or-none claim-binding candidates	31
Partial-only claim-binding candidates	10
Strict high-confidence sources	2
Admitted final sources	17

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 (contextual adjacent evidence, immune and inflammation, longevity); 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

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
SASP secretome / Contextual Adjacent Evidence	n=10; claims=92	significant source statistic in 5/10 sources; receipt-level direction coded null	9 indirect; 1 review	limited corpus depth in this outcome class
SASP secretome / Immune and Inflammation	n=5; claims=86	significant source statistic in 3/5 sources; receipt-level direction coded null	3 indirect; 1 mechanistic; 1 review	limited corpus depth in this outcome class
SASP secretome / Longevity	n=2; claims=15	positive signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class

Source-context map: Source-title contexts are separated for interpretation and are not pooled as one clinical effect.

• Aging and geroscience context: 4 sources; significant source statistic in 1/4 sources; receipt-level direction coded null.
• Oncology and cancer context: 4 sources; significant source statistic in 3/4 sources; receipt-level direction coded null.
• Skeletal and muscle context: 1 sources; negative signal in 1/1 sources.

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.

Contextual Adjacent Evidence Outcomes

Additional corpus sources included animal/preclinical evidence; contextual Adjacent Evidence remains a separate Results slice for SASP secretome (n=10; claims=92; significant source statistic in 5/10 sources; receipt-level direction coded null; 9 indirect; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Zhang 2019 (Folic Acid Supplementation Suppresses Sleep Deprivation-Induced Telomere Dysfunction and Senescence-Associated; representative statistic P < 0.05; source-level statistic reported; direction=null; directness=indirect; tier=B2).
• Coppe 2008 (Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor; representative statistic p > 0.05; source-level statistic reported; direction=null; directness=indirect; tier=B2).
• Niklander 2020 (ROCK inhibition modulates the senescence‐associated secretory phenotype (SASP) in oral keratinocytes; representative statistic P > 0.05; source-level statistic reported; direction=null; directness=indirect; tier=B2).
• Nicoloro-Santabarbara 2025 (A Senescence Associated Secretory Phenotype (SASP) in Indolent Systemic Mastocytosis Compared to Healthy Controls; representative statistic p < 0.001; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).

Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.

Immune and Inflammation Outcomes

Immune and Inflammation remains a separate Results slice for SASP secretome (n=5; claims=86; significant source statistic in 3/5 sources; receipt-level direction coded null; 3 indirect; 1 mechanistic; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Zuccolo 2020 (The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells; representative statistic p = 0.0132; source-level statistic reported; direction=negative; directness=indirect; tier=B2).
• ADT 2024 (Abstract 2954: Androgen deprivation therapy (ADT) and senescence-associated secretory phenotype (SASP) in vitro; representative statistic p=0.001; source-level statistic reported; direction=negative; directness=mechanistic; tier=C1).
• Ostrowska 2024 (Senescence in head and neck squamous cell carcinoma: relationship between senescence-associated secretory phenotype; representative statistic p < 0.0001; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).
• Sanchez-Romero 2026 (Evidence gaps in the effects of exercise on SASP-Related biomarkers in older adults: a systematic review and; 30 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=review; tier=B2).

Longevity Outcomes

Additional corpus sources included animal/preclinical evidence; longevity remains a separate Results slice for SASP secretome (n=2; claims=15; positive signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Ichim 2026 (Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan; representative statistic p < 0.05; source-level statistic reported; direction=positive; directness=indirect; tier=B2).
• Alam 2025 (The Impact of Senescence-Associated Secretory Phenotype (SASP) on Head and Neck Cancers: From Biology to Therapy; 1 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).

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 principal limitation is evidence-role imbalance. The retained corpus contains no sources classified primarily as direct interventional hard-endpoint evidence, 16 adjacent clinical sources, and 1 mechanistic or model-system source, which means causal interpretation depends on how much weight is assigned to each evidence tier.

A second limitation is endpoint heterogeneity. Study-level signals span the longevity outcome class, the contextual adjacent evidence, immune and inflammation, longevity outcome classes, the immune and inflammation outcome class, and no dominant outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design.

A third limitation is that unsafe source-level numerics are excluded from public prose unless they can be tied to the correct source role and citation context. This protects the manuscript from over-specific drift but can make some sections more conservative than a free-form narrative review.

Conclusion

The conclusion is narrower: the retained evidence maps associations, mechanisms, and candidate endpoints for follow-up; it does not establish clinical benefit, therapeutic actionability, or anti-aging efficacy. 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 17 included sources on Sasp Secretome across 4 outcome classes and 3 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 17 curated reference papers, the evidence base for SASP shows a context-dependent profile. Positive signals appear in: longevity. Negative signals appear in: immune. Null findings dominate: contextual other, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The SASP 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 Alam 2025 and Ichim 2026 on longevity (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	2	null, positive	conflict-resolution gap
immune and inflammation	0	4	negative, null, unclear	conflict-resolution gap
contextual adjacent evidence	0	10	null, unclear	direct interventional hard-endpoint gap
immune and inflammation	0	1	null	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 2 indirect sources; direction profile: null, positive
P2	immune and inflammation: conflict-resolution gap	0 direct and 4 indirect sources; direction profile: negative, null, unclear
P3	contextual adjacent evidence: direct interventional hard-endpoint gap	0 direct and 10 indirect sources; direction profile: null, unclear
P4	immune and inflammation: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null

Next-Study Design Recommendation

The next high-yield study for Sasp Secretome should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.

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; Zhang 2019; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.
• Sanchez-Romero 2026; tier=B2; directness=review; endpoint=immune; direction=null.
• Zuccolo 2020; tier=B2; directness=indirect; endpoint=immune; direction=negative; representative statistic=P < 0.0001.
• Terlecki-Zaniewicz 2018; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.
• Ichim 2026; tier=B2; directness=indirect; endpoint=longevity; direction=positive; representative statistic=P < 0.05.
• Coppe 2008; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.
• Shah 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.
• Yue 2022; tier=B2; directness=indirect; endpoint=immune inflammation; direction=null.
• Ostrowska 2024; tier=B2; directness=indirect; endpoint=immune; direction=unclear; representative statistic=P < 0.0001.
• Niklander 2020; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.

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 negative: Sanchez-Romero 2026 vs Zuccolo 2020; Zuccolo 2020 (negative on immune) vs Sanchez-Romero 2026 (null on immune) — partial conflict
• Severity 4 null vs positive: Alam 2025 vs Ichim 2026; Ichim 2026 (positive on longevity) vs Alam 2025 (null on longevity) — partial conflict
• Severity 2 agreement: ADT 2024 vs Zuccolo 2020; ADT 2024 and Zuccolo 2020 both report negative effect on immune

Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Evans 2023, Nicoloro-Santabarbara 2025, Franco 2025, Giuliani 2023, Filipek 2026.

References

• Zhang 2019. Folic Acid Supplementation Suppresses Sleep Deprivation-Induced Telomere Dysfunction and Senescence-Associated Secretory Phenotype (SASP). Oxidative Medicine and Cellular Longevity, 2019. DOI: 10.1155/2019/4569614. PMID: 31949878.
• Sanchez-Romero 2026. Evidence gaps in the effects of exercise on SASP-Related biomarkers in older adults: a systematic review and meta-analysis of randomized controlled trials. BMC Geriatrics, 2026. DOI: 10.1186/s12877-026-07025-5. PMID: 41652340.
• Zuccolo 2020. The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification. International Journal of Molecular Sciences, 2020. DOI: 10.3390/ijms21124454. PMID: 32585876.
• ADT 2024. Abstract 2954: Androgen deprivation therapy (ADT) and senescence-associated secretory phenotype (SASP) in vitro: Correlation with SASP in tumor specimens as well as in the serum of patients after ADT. Cancer Research, 2024. DOI: 10.1158/1538-7445.am2024-2954.
• Terlecki-Zaniewicz 2018. Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype. Aging (Albany NY), 2018. DOI: 10.18632/aging.101452. PMID: 29779019.
• 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.
• Shah 2025. The cardio‐renal‐metabolic role of the nod‐like receptor protein‐3 and senescence‐associated secretory phenotype in early sodium/glucose cotransporter‐2 inhibitor therapy in people with diabetes who have had a myocardial infarction. Diabetic Medicine, 2025. DOI: 10.1111/dme.70059. PMID: 40281683.
• Coppe 2008. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biology, 2008. DOI: 10.1371/journal.pbio.0060301. PMID: 19053174.
• Yue 2022. Senescence-associated secretory phenotype and its impact on oral immune homeostasis. Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.1019313. PMID: 36275775.
• Ostrowska 2024. Senescence in head and neck squamous cell carcinoma: relationship between senescence-associated secretory phenotype (SASP) mRNA expression level and clinicopathological features. Clinical & Translational Oncology, 2024. DOI: 10.1007/s12094-023-03364-6. PMID: 38175424.
• Niklander 2020. ROCK inhibition modulates the senescence‐associated secretory phenotype (SASP) in oral keratinocytes. FEBS Open Bio, 2020. DOI: 10.1002/2211-5463.13012. PMID: 33095981.
• Evans 2023. Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2023. DOI: 10.1093/gerona/glad265. PMID: 37982669.
• Nicoloro-Santabarbara 2025. A Senescence Associated Secretory Phenotype (SASP) in Indolent Systemic Mastocytosis Compared to Healthy Controls. Innovation in Aging, 2025. DOI: 10.1093/geroni/igaf122.3519.
• Franco 2025. Senescence‐associated secretory phenotype (SASP) index in individuals across the Alzheimer’s disease continuum. Alzheimer's & Dementia, 2025. DOI: 10.1002/alz.092727.
• Giuliani 2023. Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation. Antioxidants, 2023. DOI: 10.3390/antiox12111956. PMID: 38001810.
• Alam 2025. The Impact of Senescence-Associated Secretory Phenotype (SASP) on Head and Neck Cancers: From Biology to Therapy. Cancers, 2025. DOI: 10.3390/cancers17244024. PMID: 41463272.
• Filipek 2026. Inflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies. Psoriasis: Targets and Therapy, 2026. DOI: 10.2147/PTT.S598115. PMID: 42232205.

Background References

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).