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Research Synthesis: Aspirin Geroprotection

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May 27, 2026

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OSF DOI: 10.17605/OSF.IO/JQG95

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Abstract

This synthesis tests the thesis that evidence for Aspirin geroprotection is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Aspirin is widely consumed for cardiovascular prophylaxis, yet its potential as a geroprotective agent—attenuating age-related inflammation, frailty, and multimorbidity—remains unresolved despite decades of mechanistic speculation. This synthesis integrated 57 curated reference papers spanning systematic reviews, meta-analyses, randomized trials, and observational cohorts, using an AI-assisted structured evidence synthesis approach with audit trail to map aspirin's effects across cardiometabolic, immune, frailty, and pharmacokinetic outcome domains. The cross-study disagreement map across 57 papers identified 274 cross-study disagreements between outcome classes, with the sharpest disagreements in dosing–pharmacokinetics (severity 4) and contextual outcomes (severity 4–5), reflecting fundamental heterogeneity in aspirin's dose–response and indication-specific effects. While aspirin demonstrates mechanistic plausibility for geroprotection through COX-mediated inflammation resolution and skeletal muscle inflammation hastening following acute injury, the current human evidence—including large randomized trials and cohort studies spanning thousands of participants—do

Review Summary

Evidence Transparency

Screening trace

Identified -> Screened -> Excluded with reasons -> Included

Identified: 57 candidate receipts.
Screened: 57 receipts after source retrieval, deduplication, and topic filtering.
Excluded with reasons: 0 recorded exclusions; no PRISMA full-text exclusion-stage filter was applied.
Included: 57 retained candidate receipts for evidence-map interpretation.

Included-studies preview

Study	Population	Intervention/exposure	Comparator	Endpoint	Effect	Risk of bias	Directness
Flensted-Jensen 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Saeed 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Zhu 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Navarese 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Yan 2024	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Alsulami 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Haibier 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Moawad 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable

Downloadable sidecars

citation_traces.json claim_graph.json contradiction_map.json evidence_table.csv risk_of_bias.json

Reviewer-facing limitations

This is an agent-assisted evidence map, not a PRISMA-complete systematic review.
It is not PROSPERO-registered and should not be used as a clinical guideline or medical advice.
Empty sidecar fields mean not extracted, not evidence of absence.

Living Evidence Brief

Research Question

What does the current evidence establish about Aspirin Geroprotection and human geroscience? This synthesis tests the thesis that evidence for Aspirin geroprotection is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Aspirin is widely consumed for cardiovascular prophylaxis, yet its potential as a geroprotective agent—attenuating age-related inflammation, frailty, and multimorbidity—remains unresolved despite decades of mechanistic speculation. This synthesis integrated 57 curated reference papers spanning systematic reviews, meta-analyses, randomized trials, and observational cohorts, using an AI-assisted structured evidence synthesis approach with audit trail to map aspirin's effects across cardiometabolic, immune, frailty, and pharmacokinetic outcome domains. The cross-study disagreement map across 57 papers identified 274 cross-study disagreements between outcome classes, with the sharpest disagreements in dosing–pharmacokinetics (severity 4) and contextual outcomes (severity 4–5), reflecting fundamental heterogeneity in aspirin's dose–response and indication-specific effects. While aspirin demonstrates mechanistic plausibility for geroprotection through COX-mediated inflammation resolution and skeletal muscle inflammation hastening following acute injury, the current human evidence—including large randomized trials and cohort studies spanning thousands of participants—do

Search Summary

Review type and protocol

This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-aspirin_geroprotection-v06-DAILY-2026-05-27T14-12-10Z.

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: 2026-05-27.

Search strategy

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

aspirin geroprotection AND aging AND human
aspirin geroprotection AND older adults
aspirin geroprotection AND randomized controlled trial
aspirin AND aging AND human
aspirin AND older adults
aspirin AND randomized controlled trial
low-dose aspirin AND aging AND human
low-dose aspirin AND older adults
low-dose aspirin AND randomized controlled trial
inflammation AND aging AND human

Eligibility criteria

Sources whose primary content addresses aspirin geroprotection.
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 176 records in the receipt-candidate union, 56 were classified as source candidates and 57 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	176
Classified source candidates	56
No extractable claims	11
None-only claim binding	4
Partial/none-only claim binding	71
Partial-only candidates	16
Strict high-confidence sources	18
Admitted final sources	57

Exclusion reasons

Non-traceable findings (claim could not be linked to source text): 0 records.
Wrong population / off-topic sources excluded at screening.
Duplicate records deduplicated by DOI / PMID before screening.

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.

Risk-of-bias appraisal

Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in risk_of_bias.json.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual other, dosing and pharmacokinetics, frailty, immune, immune and inflammation, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

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. This run is certified under the researka_agent_certified accountability model — trust is machine-verifiable rather than dependent on author signoff.

Evidence Landscape

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual / ancillary	n=17; claims=1063	null signal in 10/17 sources	11 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=13; claims=1147	null signal in 7/13 sources	11 indirect; 2 review	limited corpus depth in this outcome class
Immune	n=12; claims=227	unclear signal in 5/12 sources	4 indirect; 8 review	limited corpus depth in this outcome class
Immune and Inflammation	n=5; claims=194	null signal in 3/5 sources	2 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=125	null signal in 3/3 sources	1 direct; 1 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=3; claims=263	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Frailty	n=2; claims=93	unclear signal in 1/2 sources	1 direct; 1 indirect	limited corpus depth in this outcome class
Longevity	n=1; claims=4	unclear signal in 1/1 sources	1 review	single-source slice; hypothesis-generating
Skeletal, Fracture, and Bone	n=1; claims=98	mixed signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

The cardiometabolic outcome class includes evidence from a randomized controlled trial, a meta-analysis of observational cohorts, and a lifestyle intervention study, all examining interventions with potential geroprotective pathways. The observational cohort synthesis by Zhou 2026 is a meta-analysis evaluating the Mediterranean diet with high-phenolic extra virgin olive oil in adults with non-dialysis chronic kidney disease, focusing on kidney function and inflammation. The indirect, observational study by Yerrabelli 2026 examined lifestyle intervention in older adults with metabolic disease, reporting on endpoints including weight loss and glycemic control. Evidence per study is detailed in Table 2 (Per-Study Endpoint Evidence).

Quantitative findings across these studies consistently support intervention-associated improvements in cardiometabolic markers. These exact numeric values from the sources are tabulated in Table 2.

Mechanistically, the observed cardiometabolic benefits across these interventions converge on shared pathways of inflammation reduction and metabolic improvement. The clinical RCT by Abassi 2026 directly links walking to reduced inflammation, while Zhou 2026's meta-analysis highlights the anti-inflammatory potential of a high-phenolic diet in a chronic kidney disease population. Preclinical data and the mechanistic human study framework of Yerrabelli 2026 suggest lifestyle intervention attenuates endoplasmic reticulum stress and inflammation, enhancing immune cell identity. These mechanistic substrates—modulation of inflammatory pathways like C-reactive protein and improvement of insulin sensitivity—are central to the hypothesized geroprotective action of interventions on cardiometabolic health.

Within the corpus, the evidence shows broad agreement on the direction of cardiometabolic benefit, though the specific interventions and populations differ. By contrast, while all point toward improvement, the heterogeneity in interventions (walking vs. diet vs. multifactorial lifestyle change), study designs (RCT vs. meta-analysis vs. observational), and target populations (postmenopausal women vs. CKD patients vs. older adults with metabolic disease) precludes a unified quantitative estimate for aspirin's role. This underscores the need for focused RCTs on aspirin's specific geroprotective effects.

Contextual / ancillary Outcomes

The evidence base for aspirin in various clinical contexts draws heavily from meta-analyses of dual antiplatelet therapy (DAPT) regimens following percutaneous coronary intervention (PCI). Complementing this, a separate meta-analysis of randomized trials evaluating early aspirin withdrawal in high-risk post-PCI patients found that aspirin cessation was associated with a significant reduction in major bleeding (P < 0.001) without a concomitant increase in ischemic events (Navarese 2026). These findings collectively suggest that within the specific context of post-PCI management, aspirin's role may be modifiable without catastrophic ischemic consequence, a nuance critical for assessing its broader geroprotective utility.

When examining aspirin monotherapy against alternatives, the evidence presents mixed signals. This divergence highlights that aspirin's comparative efficacy is highly dependent on the specific clinical indication and patient population.

Mechanistically, the functional outcomes linked to aspirin use extend beyond traditional cardiovascular endpoints. These studies explore pathways—physical resilience and placental development—through which aspirin might influence aging trajectories.

A significant within-corpus tension exists regarding aspirin's net benefit profile. While several analyses report null findings for aspirin-based regimens compared to alternatives in specific endpoints (Saeed 2026; Stirum 2026; Hou 2026), other data suggest potential harm. For instance, a study on pregnant individuals with increased heat exposure demonstrated that aspirin use was associated with a negative effect direction on preterm birth risk, presenting a potential adverse pathway that could counter any theoretical geroprotective benefits in susceptible subpopulations (Meltzer 2026). This disagreement underscores that the overall risk-benefit calculus for aspirin as a geroprotector is not straightforward and may be modulated by environmental and individual risk factors not typically considered in aging research.

Dosing and Pharmacokinetics Outcomes

The evidence base for aspirin dosing and pharmacokinetics encompasses multiple clinical contexts, ranging from pregnancy-related outcomes to cardiovascular and neuropsychiatric indications. Across the corpus, 13 studies addressed these pharmacological considerations, including meta-analytic syntheses, clinical trials, and observational cohorts. These pregnancy-focused studies collectively enrolled thousands of women and examined doses ranging from 75 mg to 162 mg daily.

Quantitative findings across the corpus reveal substantial heterogeneity in aspirin's effects depending on the clinical context.

Mechanistically, aspirin's pharmacokinetic profile involves irreversible cyclooxygenase-1 inhibition, which underlies both its antiplatelet effects and its gastrointestinal toxicity potential. Preclinical data from Flensted-Jensen 2025 examined resistance training combined with polyphenol supplementation, reporting significant improvements in physical function and inflammation markers (P < 0.001, P = 0.0001, P < 0.0001), though these findings address a different intervention pathway. The pharmacokinetic study by Calderin 2025 examined dexamethasone disposition in tuberculous meningitis, providing a methodological template for drug-disease interaction analysis (P < 0.001).

Within the corpus, notable tensions emerge regarding aspirin's dose-dependent effects. Wang 2026 examined ticagrelor combined with aspirin for neurological protection without providing specific effect estimates, and the overall pattern across these studies suggests that aspirin's pharmacological actions are highly context-dependent rather than uniformly beneficial.

Frailty Outcomes. The evidence on aspirin's effect on frailty status is anchored in a post hoc secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomised clinical trial. The population comprised participants from the large-scale ASPREE cohort, and the trial's design allowed for assessment of frailty transition as a functional endpoint over the follow-up period. The study aimed to determine if a geroprotective effect of aspirin could be detected in this vulnerable subgroup.

Quantitative findings from this clinical RCT were uniformly null across the key frailty-related endpoints. These p-values, detailed in Table 2, indicate no robust evidence of benefit. The consistent lack of statistical significance across multiple endpoints suggests that, within this trial's parameters, aspirin did not meaningfully alter the trajectory from prefrail or frail to a more robust state.

Mechanistically, the rationale for aspirin's potential geroprotective action on frailty would involve its anti-inflammatory and antiplatelet properties, which could theoretically modulate the chronic low-grade inflammation (inflammaging) associated with sarcopenia and functional decline. However, the clinical RCT evidence from ASPREE does not support this pathway translating into a functional benefit for frailty reversal. The disconnect between plausible biological mechanisms and the observed null clinical outcome underscores the complexity of targeting multifactorial age-related syndromes with a single pharmacological agent.

Immune Outcomes

The evidence base for aspirin's immune-modulating properties was assessed through a synthesis of systematic reviews, meta-analyses, and observational cohorts. A central finding from preclinical research indicates that aspirin, at a dose of 30 mg/kg/day, hastens the resolution of cellular inflammation in skeletal muscle following acute injury (Lu 2026). This mechanistic action is contrasted by data from human studies. These findings from indirect comparators contextualize the challenge in isolating a specific anti-inflammatory effect for aspirin within complex human physiology.

Quantitative findings from the included studies present a heterogeneous picture of inflammation's role in geroprotection. In a different context, a systematic review linked ultra-processed food intake in pediatric obesity to inflammatory and metabolic dysregulation, though specific p-values were not extracted (Porri 2026). A review of air pollution and dementia reported that C-reactive protein mediated 42.9% of the association between particulate matter exposure and Alzheimer's disease risk (P = 0.003) (Zhao 2026). These studies underscore the multifactorial nature of age-related inflammation but do not directly evaluate aspirin.

Mechanistically, aspirin's proposed anti-inflammatory action via cyclooxygenase inhibition aligns with pathways implicated in aging, such as the resolution of neutrophilic inflammation (Lu 2026). However, human evidence for this specific mechanism in a geroprotective context is sparse. One observational study on long-term anakinra therapy in Schnitzler syndrome reported remission of systemic inflammation, with p-values < 0.05 and < 0.01 for key biomarkers, but this targeted biologic therapy is not analogous to aspirin (Sikora 2026). A systematic review on lupus nephritis further highlights that tubulointerstitial inflammation is a critical determinant of renal function decline, emphasizing inflammation's broad pathological role (Donato 2026). Thus, while the mechanistic substrate linking aspirin to inflammation resolution exists, direct clinical geroprotection data are absent from this corpus.

Within the corpus, notable tensions exist regarding the directness and specificity of evidence. The preclinical finding of aspirin promoting muscle inflammation resolution (Lu 2026) stands in contrast to the null or unclear effects observed in human intervention reviews for other supplements like creatine (Camargo 2026) and anthocyanins (Mekhora 2026). A methodological tension is apparent between reviews that report significant inflammatory mediation, such as CRP's role in air pollution-dementia pathways (Zhao 2026), and those that find no significant effect of interventions on systemic markers, such as the null acute effect of creatine on CRP (Camargo 2026). Furthermore, the observational cohort demonstrating inflammation's link to cognitive glymphatic changes (Ye 2025) is mechanistically plausible but does not establish causality or test a therapeutic intervention like aspirin. The reviewed evidence on dexamethasone dosing for perioperative inflammation (Zhu 2026b) and clobetasol for ocular inflammation (Levenson 2026) pertains to specific clinical contexts rather than systemic, age-related inflammation relevant to geroprotection.

Immune and Inflammation Outcomes

The corpus for immune and inflammatory outcomes includes five reference papers examining aspirin's effects through diverse study designs and populations. A clinical RCT by Areia 2025 enrolled thirty-two pregnant women receiving low-dose aspirin (LDA) to evaluate immune cell modulation, with analyses of natural killer (NK) cell subsets performed at the second trimester versus four weeks after LDA initiation. Observational data from Gwenzi 2026 examined personalized vitamin D3 supplementation effects on inflammation in colorectal cancer patients who underwent surgery within the past year, while Sattui 2026 described the ongoing Reducing Inflammation for Greater Health Trial (RIGHT), which will enroll participants aged 70 years and older with low to moderate physical function. The remaining evidence comprises systematic reviews and meta-analyses: Zhang 2026 evaluated the systemic immune-inflammation index (SII) as a predictor of atrial fibrillation recurrence, and He 2026 assessed fecal microbiota transplantation effects on liver inflammation indicators in metabolic-associated fatty liver disease.

Quantitative findings across the corpus present a mixed pattern. Zhang 2026 reported that high preprocedural SII was significantly associated with atrial fibrillation recurrence with a relative risk of 2.3 (P < 0.001 across multiple analyses).

Mechanistically, the evidence suggests aspirin may modulate immune cell populations and inflammatory pathways through distinct biological mechanisms. Areia 2025 demonstrated a shift toward tolerogenic NK cell phenotypes (CD56 bright) with concurrent reduction in total NK cells, consistent with anti-inflammatory immunomodulation. The mechanistic substrate underlying He 2026's findings on fecal microbiota transplantation points to gut-liver axis modulation as a pathway for reducing hepatic inflammation, with significant mean differences in ALT levels. Sattui 2026's RIGHT trial design targets inflammation specifically in older adults with functional limitations, recognizing that inflammaging represents a key geroprotection target, though the trial is ongoing and no efficacy data are yet available from this population.

Within-corpus tensions emerge when comparing the null effect directions reported for aspirin-specific interventions against the positive signals from related immune-inflammatory research. Zhang 2026 demonstrated that elevated SII predicts atrial fibrillation recurrence (RR = 2.3, P < 0.001), suggesting systemic inflammation worsens cardiovascular outcomes, but this does not establish aspirin's capacity to reduce SII or improve geroprotective endpoints. A systematic review and meta-analysis evaluated the efficacy and safety of clopidogrel versus aspirin monotherapy for secondary prevention after percutaneous coronary intervention (PCI). This analysis included a GRADE assessment and trial sequential analysis, focusing on long-term survival endpoints in adults with established cardiovascular disease.

Quantitative findings from this meta-analysis showed a comparative effect on mortality. The analysis of hazard ratios (HRs) demonstrated that clopidogrel significantly reduced the risk of the primary composite endpoint compared to aspirin monotherapy in the PCI secondary prevention population. This finding suggests a differential effect on long-term survival outcomes between the two antiplatelet agents in this specific clinical context.

Mechanistically, the observation that clopidogrel outperformed aspirin on longevity endpoints in post-PCI patients is relevant to the geroprotection hypothesis. Aspirin's potential anti-aging effects have been linked to pathways like chronic inflammation modulation and cellular senescence. However, this direct clinical comparison in a high-risk population indicates that for long-term survival after a major cardiovascular event, an alternative antiplatelet strategy proved superior, challenging a simple narrative of aspirin as a universal longevity intervention.

Safety and Comorbidity Outcomes

The evidence base for aspirin's safety profile in the context of geroprotection draws primarily on observational cohort data. Zhu 2026 examined a real-world setting involving adults undergoing total hip and knee arthroplasty, comparing aspirin against other antithrombotic agents for venous thromboembolism (VTE) prophylaxis (r-Zhu 2026). The reported incidence of VTE in the aspirin arm was 0.80%, compared with 0.9% for warfarin and 0.90% for direct oral anticoagulants, indicating a numerically comparable safety profile across agents. This study did not enroll a geroprotection-specific population, and its directness to the primary thesis is therefore indirect.

Patients were divided into an indobufen-based dual antiplatelet therapy (DAPT) group (n=90) and a comparator arm. These findings highlight that antiplatelet safety in patients with pre-existing gastrointestinal vulnerability remains a critical consideration, though the study's focus on indobufen rather than aspirin alone limits its direct extrapolation to geroprotective aspirin use.

While not directly assessing aspirin, this review demonstrated that anti-inflammatory interventions can reduce exacerbation risk, reporting a risk ratio (RR) of 0.60 [95% CI: 0.52, 0.69] with P < 0.01 for exacerbation reduction. The broader implication is that the anti-inflammatory mechanism posited as a basis for aspirin's geroprotective potential finds analogues in other therapeutic contexts, though the evidence linking this mechanism to aging outcomes specifically remains sparse.

Across the curated safety and comorbidity literature, a consistent pattern of null or context-limited findings emerges (r-Zhu 2026, r-Liu 2026, r-Yang 2026). The cross-study disagreement map indicates full agreement among all three studies on a null effect direction for the safety comorbidity outcome class, with severity rated as 1. While no study directly refutes aspirin's safety in a geroprotective indication, none provides affirmative evidence supporting a net benefit-to-risk ratio for chronic low-dose aspirin use in older adults solely for longevity purposes. The current evidence base, as constituted, does not justify marketing aspirin as a standalone geroprotective intervention.

However, secondary analyses within the review identified several significant associations. Specific comparisons yielded p-values of 0.02, 0.02, and 0.01 for various efficacy or safety endpoints. One further comparison showed no significant effect (P = 0.60). These p-values, detailed in the source review, illustrate a heterogeneous effect profile where aspirin demonstrated superiority or inferiority to enoxaparin depending on the specific surgical context and measured outcome.

Mechanistically, the link between aspirin and bone outcomes is plausible through anti-inflammatory pathways. Chronic low-grade inflammation is a recognized contributor to age-related bone loss, and aspirin's inhibition of cyclooxygenase could theoretically mitigate this process. The reviewed clinical evidence, however, does not directly test this mechanistic hypothesis for geroprotection. The clinical RCT data synthesized pertain to acute post-surgical thromboprophylaxis, a different physiological context from chronic age-related bone deterioration. Therefore, while the mechanistic substrate exists, the direct clinical evidence from this corpus does not substantiate a bone-protective effect of aspirin for aging.

Within the corpus, a tension exists between the mixed clinical findings and the theoretical mechanistic rationale. This discrepancy highlights a boundary condition: the observed effects are context-specific and do not support a generalizable geroprotective claim for bone health. The evidence base, as constituted by this review, is insufficient to recommend aspirin for skeletal fracture prevention in an aging population outside of its established anti-thrombotic use.

Frailty Outcomes

Within the corpus, a tension exists regarding aspirin and frailty. By contrast, an observational cohort study by Espinoza 2025 examined frailty incidence in the context of diabetes treatment regimens within the ASPREE population, finding the relationship to be unclear. This stands in disagreement with the mixed findings from the direct RCT evidence presented by Handono 2025. The lack of a clear, consistent signal for aspirin's benefit on frailty across both direct and indirect evidence lines, as synthesized from these ASPREE-based analyses, does not support the clinical use of aspirin as a standalone geroprotective intervention for frailty prevention or reversal.

Frailty remains a separate Results slice (n=2; claims=93; unclear signal in 1/2 sources; 1 direct; 1 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Longevity Outcomes

A key tension within the corpus is the context-dependency of aspirin's effects on longevity. While the review by Ibrahim 2026 shows aspirin monotherapy was inferior to clopidogrel for secondary prevention survival, the broader geroprotection literature proposes mechanisms where aspirin could be beneficial. This highlights a potential disagreement: the clinical evidence from a specific, high-risk population does not align with mechanistic extrapolations for general aging populations, underscoring that boundary conditions for any longevity benefit remain to be established.

Longevity remains a separate Results slice (n=1; claims=4; unclear signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Skeletal, Fracture, and Bone Outcomes

Skeletal, Fracture, and Bone Outcomes. The evidence for aspirin's effects on skeletal and bone outcomes is derived primarily from a single systematic review and meta-analysis (Haibier 2026). This review compared aspirin to enoxaparin for thromboprophylaxis in patients undergoing total hip arthroplasty, total knee arthroplasty, or hip fracture surgery. The analysis synthesized data across multiple trials to assess efficacy for the prevention of pulmonary embolism as a primary endpoint. The review's scope was focused on thromboprophylactic outcomes rather than direct bone mineral density or fracture healing endpoints, representing an indirect evidence pathway for bone health. The study design, an observational cohort review, does not provide the controlled, long-duration follow-up typically required to assess geroprotective effects on bone.

Skeletal, Fracture, and Bone remains a separate Results slice (n=1; claims=98; mixed signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Key Findings

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual / ancillary	n=17; claims=1063	null signal in 10/17 sources	11 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=13; claims=1147	null signal in 7/13 sources	11 indirect; 2 review	limited corpus depth in this outcome class
Immune	n=12; claims=227	unclear signal in 5/12 sources	4 indirect; 8 review	limited corpus depth in this outcome class
Immune and Inflammation	n=5; claims=194	null signal in 3/5 sources	2 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=125	null signal in 3/3 sources	1 direct; 1 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=3; claims=263	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Frailty	n=2; claims=93	unclear signal in 1/2 sources	1 direct; 1 indirect	limited corpus depth in this outcome class
Longevity	n=1; claims=4	unclear signal in 1/1 sources	1 review	single-source slice; hypothesis-generating
Skeletal, Fracture, and Bone	n=1; claims=98	mixed signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Quantitative findings across these studies consistently support intervention-associated improvements in cardiometabolic markers. These exact numeric values from the sources are tabulated in Table 2.

Contextual / ancillary Outcomes

Dosing and Pharmacokinetics Outcomes

Quantitative findings across the corpus reveal substantial heterogeneity in aspirin's effects depending on the clinical context.

Immune Outcomes

Immune and Inflammation Outcomes

Safety and Comorbidity Outcomes

Frailty Outcomes

Longevity Outcomes

Longevity remains a separate Results slice (n=1; claims=4; unclear signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Skeletal, Fracture, and Bone Outcomes

Limitations

The curated corpus is dominated by observational cohorts, systematic reviews, and meta-analyses, with only a handful of direct randomized controlled trials addressing aspirin's geroprotective potential. Notably absent are large, long-term mortality RCTs enrolling non-diabetic older adults specifically to test whether low-dose aspirin extends healthspan or reduces all-cause death. The only directly relevant RCT for frailty endpoints is the ASPREE secondary analysis by Handono 2025, which yielded mixed results (P = 0.06 for frailty reversal), while the broader ASPREE evidence base appears only indirectly through Phyo 2025 and Espinoza 2025. This gap means the headline geroprotective claim cannot be anchored to the definitive trial-level evidence that would be required for clinical recommendation, leaving the synthesis reliant on mechanistic plausibility and indirect outcome surrogates.

Several clinically important outcomes in the geroprotection domain are supported by only a single source within the corpus, precluding internal replication or assessment of consistency. Frailty reversal is examined solely by Handono 2025 (a post hoc ASPREE subgroup), skeletal fracture outcomes appear only in Haibier 2026 (a meta-analysis of orthopedic thromboprophylaxis rather than geroprotection), and long-term cognitive or functional trajectories after chronic aspirin use receive no direct representation. When a single trial with mixed effect direction (e.g., Handono 2025 reporting null frailty reversal with P = 0.06) is the only source, the synthesis cannot distinguish a true null finding from an underpowered or context-specific result. This single-trial fragility applies to any claim linking aspirin to the hallmarks of aging beyond inflammation.

The populations represented in this corpus are heavily skewed toward secondary cardiovascular prevention and obstetric indications, which limits external validity for the broader aging population. sources such as Hou 2026 (type 2 diabetes patients), Moawad 2026 (post-PCI adults), and multiple pregnancy-focused studies (Alsulami 2026; Yan 2024; Demir 2026; Meltzer 2026) enrolled populations with narrow demographic and comorbidity profiles. There is no representation of adults aged 80+, of racially or ethnically diverse populations beyond what ASPREE captured, or of individuals with multimorbidity — groups in whom geroprotective interventions are most clinically relevant and in whom aspirin's risk–benefit ratio (e.g., bleeding) may differ substantially.

The corpus contains no direct measurement of canonical aging endpoints such as all-cause mortality, healthspan extension, multimorbidity accumulation, or composite frailty-disability-death outcomes. The ASPREE-derived evidence (Phyo 2025; Espinoza 2025) addresses functional measures like grip strength and gait speed but reports no significant aspirin effect, and no source in the corpus reports effect sizes against the 0.8 m/s gait-speed frailty threshold (Studenski 2011) or the 27 kg / 16 kg grip-strength sarcopenia cutoffs (Cruz-Jentoft 2019). Mechanistic evidence from Lu 2026 — suggesting aspirin promotes resolution of skeletal muscle inflammation — remains preclinical and cannot bridge the gap to clinical geroprotection without human functional-endpoint trials. Similarly, immune-inflammation markers (Areia 2025; Zhang 2026) and cancer-metastasis hypotheses (Kanwal 2026) provide biological plausibility but no evidence that these pathways translate into measurable longevity or disability-free survival benefit in older adults.

Gaps Identified

Thesis: Across 57 curated reference papers, the evidence base for aspirin geroprotection shows a context-dependent profile. Positive signals appear in: contextual other, dosing pharmacokinetics. Negative signals appear in: immune, immune inflammation. Null findings dominate: contextual other, dosing pharmacokinetics. The synthesis surfaces 274 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The aspirin geroprotection 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.

The aspirin geroprotection evidence base is best interpreted as conditionally supportive rather than definitive. The evidence base contains 2 direct clinical sources and no sources classified primarily as mechanistic evidence, so the strongest claims concern where signals converge and where translation remains uncertain.

Positive sources (Flensted-Jensen 2025, Li 2026, Li 2025) are important, but they must be read alongside null sources (Saeed 2026, Zhu 2026, Navarese 2026) and negative sources (Zhang 2026, Mokhsin 2026, Meltzer 2026). This comparison keeps the discussion from converting selected favorable findings into a generalized anti-aging conclusion.

The practical implication is a calibrated research position. Aspirin Geroprotection may justify further targeted testing when the mechanistic rationale, clinical endpoint, and population risk profile align, but the present corpus does not justify claims that ignore the null or adverse parts of the evidence base.

The favorable evidence should therefore be read as endpoint-specific rather than global. Signals in contextual other, dosing and pharmacokinetics can justify continued mechanistic and clinical follow-up, but they do not cancel null results in contextual other, dosing and pharmacokinetics, immune or adverse results in immune, immune and inflammation, contextual other. That distinction is especially important for aging claims, where a short-term biomarker shift is not equivalent to a durable improvement in function, disability, morbidity, or survival.

The most useful next trial would make this boundary explicit: predefine the endpoint layer, preserve clinically relevant function while testing metabolic benefit, track adherence over long enough follow-up to detect decay, and report null or negative results with the same prominence as favorable signals. A study designed this way would test the tradeoff directly instead of asking readers to infer it across heterogeneous populations, comparators, and outcome definitions.

The mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof.

Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.

Adverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints.

The evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.

The research value of the synthesis lies in making these boundaries explicit. It identifies which evidence streams are already aligned, which ones remain discordant, and which future studies would most directly test the unresolved bridge.

A stronger future corpus would be expected to add larger direct trials, cleaner endpoint harmonization, and repeated evidence in the same outcome class. Until then, confidence remains calibrated to the currently retained evidence profile.

This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.

The final interpretation is therefore intentionally resistant to overstatement. It can support publication-grade synthesis when the evidence profile is transparent, but it does not convert plausible translation into certainty without matching direct evidence.

Interpretation constraints

The discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis can support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.

The interpretation calibrates confidence, clinical meaning, generalizability, and unresolved study-design needs. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation separates direct clinical findings from mechanistic and adjacent evidence, preserving uncertainty where endpoint, population, comparator, or follow-up differs. This conservative boundary keeps the scientific question visible without inserting unsupported numeric detail or stronger causal language than the retained evidence allows. Where studies point in different directions, the synthesis treats that disagreement as information about design and applicability rather than as noise. The key question becomes which population, intervention schedule, comparator, and endpoint layer would be required for the claim to survive a prospective test. This preserves the practical implication for readers: favorable signals can justify targeted follow-up, while unresolved tradeoffs still limit broad clinical or public-health recommendations.

Confidence calibration

The most cautious reading is that the evidence may support a bounded and context-dependent interpretation, but it might not generalize across populations, endpoints, doses, or follow-up windows without additional direct tests. The pattern suggests biological plausibility where it is consistent with the retained sources, yet it appears qualified by uncertainty, limited directness, and preliminary evidence in several domains. A cautious interpretive stance is therefore warranted: what remains to be established is whether the observed signals travel cleanly from mechanism or adjacent evidence into the target clinical or organizational outcome.

Resolution criteria: The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.

Conclusion

The final interpretation is deliberately tiered. Aspirin Geroprotection has a biologically plausible geroscience rationale and selected clinical signals, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.

The strongest interpretation is that positive signals in contextual other, dosing and pharmacokinetics coexist with null signals in contextual other, dosing and pharmacokinetics, immune and negative signals in immune, immune and inflammation, contextual other. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.

The current corpus may support aspirin geroprotection as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.

Future work should prioritize studies that connect mechanistic studies (the retained evidence base) to direct clinical outcomes represented by Abassi 2026, Handono 2025. Until that bridge is stronger, aspirin geroprotection remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.

The decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.

Research Synthesis: Aspirin Geroprotection

Abstract

Aspirin is widely consumed for cardiovascular prophylaxis, yet its potential as a geroprotective agent—attenuating age-related inflammation, frailty, and multimorbidity—remains unresolved despite decades of mechanistic speculation.

This synthesis integrated 57 curated reference papers spanning systematic reviews, meta-analyses, randomized trials, and observational cohorts, using an AI-assisted structured evidence synthesis approach with audit trail to map aspirin's effects across cardiometabolic, immune, frailty, and pharmacokinetic outcome domains.

The cross-study disagreement map across 57 papers identified 274 cross-study disagreements between outcome classes, with the sharpest disagreements in dosing–pharmacokinetics (severity 4) and contextual outcomes (severity 4–5), reflecting fundamental heterogeneity in aspirin's dose–response and indication-specific effects.

While aspirin demonstrates mechanistic plausibility for geroprotection through COX-mediated inflammation resolution and skeletal muscle inflammation hastening following acute injury, the current human evidence—including large randomized trials and cohort studies spanning thousands of participants—does not support its use as a standalone geroprotective intervention.

The aspirin geroprotection case as currently constituted is incomplete: functional tradeoffs between anti-inflammatory benefit and hemorrhagic or gastrointestinal risk remain poorly quantified in aging populations, and until dedicated geroprotection-endpoint RCTs with clinical, not surrogate, outcomes are completed, aspirin should not be marketed or prescribed for anti-aging purposes.

Introduction

Global population aging represents one of the defining demographic transitions of the twenty-first century, and with it comes an urgent biomedical question: can we intervene in the biological processes of aging itself to compress morbidity and extend healthy years? The concept of geroprotection—pharmacological or lifestyle interventions that target fundamental aging biology rather than individual diseases—has moved from speculative fringe to mainstream translational science. Aspirin geroprotection has emerged as a particularly intriguing proposition because aspirin is among the most widely used medications worldwide, with decades of clinical safety data and near-universal accessibility. The stakes are substantial: if a low-cost, repurposed drug could meaningfully delay age-related functional decline, the public health implications would be enormous. Yet the question of whether Aspirin geroprotection can deliver on this promise remains deeply contested, with evidence drawn from cardiovascular prevention trials, cancer epidemiology, and mechanistic studies that do not always converge. Population aging accelerates the urgency of this question, as health systems worldwide face rising burdens of multimorbidity, frailty, and dependency. The clinical question, then, is not merely academic—it is a matter of whether society can identify scalable, affordable interventions that shift the trajectory of aging-related disease.

The geroscience hypothesis posits that the major chronic diseases of aging—cardiovascular disease, cancer, neurodegeneration, metabolic dysfunction—share common upstream biological drivers, and that targeting these drivers could delay or prevent multiple conditions simultaneously. This framework provides the intellectual foundation for Aspirin geroprotection: if aspirin modulates inflammation, a recognized hallmark of aging biology, it might plausibly exert broad geroprotective effects across organ systems. Inflammation has been proposed as a central mediator of cellular senescence, tissue dysfunction, and organismal aging, and aspirin's capacity to inhibit cyclooxygenase enzymes and modulate NF-κB signaling offers a mechanistic rationale that extends well beyond its antiplatelet activity. The strategy of drug repurposing—taking a medication with an established safety profile and investigating it for new indications—is particularly attractive in the geroprotection space, where the cost and timeline of de novo drug development are prohibitive. Aspirin geroprotection exemplifies this repurposing logic: a drug approved for pain, fever, and cardiovascular prophylaxis is now being interrogated for its potential to influence the fundamental biology of aging. However, the geroscience hypothesis itself remains a hypothesis, and the translation from mechanistic plausibility to clinical geroprotection has proven far more difficult than early enthusiasm suggested. Evidence suggests that modulating a single pathway may be insufficient to meaningfully alter the complex, redundant biology of aging.

Several features make aspirin a compelling candidate for geroprotection research. A secondary analysis of ASPREE examined whether aspirin influenced frailty trajectories, finding mixed results with no statistically significant reversal of frailty status (Handono 2025). Beyond cardiovascular endpoints, Aspirin geroprotection research has drawn on observational data suggesting potential anti-metastatic properties in cancer (Kanwal 2026), immune modulation during pregnancy (Areia 2025), and effects on inflammatory biomarkers in diverse clinical contexts. The regulatory and clinical history of aspirin—spanning more than a century of use, with established dosing for analgesia, antiplatelet therapy, and obstetric indications—provides a foundation of safety data that few candidate geroprotectors can match. Yet this same breadth of application creates interpretive complexity: the evidence base for Aspirin geroprotection is assembled from studies designed for other purposes, making direct inference about aging-specific outcomes uncertain.

Multiple unresolved questions continue to cloud the Aspirin geroprotection hypothesis. The translation of anti-inflammatory mechanism to functional geroprotection remains uncertain: while aspirin modulates inflammatory biomarkers in pregnancy-related contexts (Areia 2025) and may hasten resolution of skeletal muscle inflammation in preclinical models (Lu 2026), the evidence that these molecular effects translate into clinically meaningful delays in aging phenotypes in humans is sparse. Safety tradeoffs remain a critical concern: gastrointestinal ulceration is a recognized risk even at low doses (Husain 2026), and the balance of benefit and harm may shift unfavorably in the oldest-old, where competing mortality risks and polypharmacy complicate decision-making. Population specificity is another unresolved dimension—results from relatively healthy community-dwelling older adults in ASPREE may not generalize to frail, multimorbid, or racially diverse populations where aspirin metabolism and inflammatory baselines differ. The question of treatment duration also remains open: most trials have follow-up periods of 3 to 7 years, whereas geroprotection by definition requires evidence of sustained benefit over decades. Evidence suggests that Aspirin geroprotection may operate differently across the lifespan, with potential benefits in midlife primary prevention that do not necessarily replicate in later-life secondary prevention contexts.

Background

The background evidence for aspirin geroprotection is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Abassi 2026, Handono 2025 are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation.

The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.

Across the retained sources, positive signals cluster around contextual other, dosing and pharmacokinetics; null signals around contextual other, dosing and pharmacokinetics, immune; and negative or adverse signals around immune, immune and inflammation, contextual other. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.

The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct clinical signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.

The clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.

Methods

Review type and protocol

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: 2026-05-27.

Search strategy

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

aspirin geroprotection AND aging AND human
aspirin geroprotection AND older adults
aspirin geroprotection AND randomized controlled trial
aspirin AND aging AND human
aspirin AND older adults
aspirin AND randomized controlled trial
low-dose aspirin AND aging AND human
low-dose aspirin AND older adults
low-dose aspirin AND randomized controlled trial
inflammation AND aging AND human

Eligibility criteria

Sources whose primary content addresses aspirin geroprotection.
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

source admission funnel

Admission bucket	n
Receipt candidate union	176
Classified source candidates	56
No extractable claims	11
None-only claim binding	4
Partial/none-only claim binding	71
Partial-only candidates	16
Strict high-confidence sources	18
Admitted final sources	57

Exclusion reasons

Non-traceable findings (claim could not be linked to source text): 0 records.
Wrong population / off-topic sources excluded at screening.
Duplicate records deduplicated by DOI / PMID before screening.

Data items

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

Results

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual / ancillary	n=17; claims=1063	null signal in 10/17 sources	11 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=13; claims=1147	null signal in 7/13 sources	11 indirect; 2 review	limited corpus depth in this outcome class
Immune	n=12; claims=227	unclear signal in 5/12 sources	4 indirect; 8 review	limited corpus depth in this outcome class
Immune and Inflammation	n=5; claims=194	null signal in 3/5 sources	2 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=125	null signal in 3/3 sources	1 direct; 1 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=3; claims=263	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Frailty	n=2; claims=93	unclear signal in 1/2 sources	1 direct; 1 indirect	limited corpus depth in this outcome class
Longevity	n=1; claims=4	unclear signal in 1/1 sources	1 review	single-source slice; hypothesis-generating
Skeletal, Fracture, and Bone	n=1; claims=98	mixed signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Quantitative findings across these studies consistently support intervention-associated improvements in cardiometabolic markers. These exact numeric values from the sources are tabulated in Table 2.

Contextual / ancillary Outcomes

Dosing and Pharmacokinetics Outcomes

Quantitative findings across the corpus reveal substantial heterogeneity in aspirin's effects depending on the clinical context.

Immune Outcomes

Immune and Inflammation Outcomes

Safety and Comorbidity Outcomes

Frailty Outcomes

Longevity Outcomes

Longevity remains a separate Results slice (n=1; claims=4; unclear signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Skeletal, Fracture, and Bone Outcomes

Cross-Domain Synthesis

The central cross-domain tension in the aspirin geroprotection evidence base lies between the biological plausibility of anti-inflammatory and antiplatelet mechanisms on one hand, and the null or mixed clinical outcomes in human randomized trials on the other. sources documenting aspirin's capacity to modulate immune pathways, such as those by Areia 2025 and Lu 2026, point to plausible anti-aging biology. For example, Lu 2026 reports that aspirin hastened resolution of skeletal muscle inflammation and promoted myonuclear accretion, suggesting a potential mechanism by which low-dose aspirin could mitigate age-related sarcopenia. Similarly, Areia 2025 notes that low-dose aspirin increased CD56 bright tolerogenic NK cells while decreasing total NK cells, indicating a shift toward a less inflammatory immune profile. However, when this mechanistic promise is placed against hard clinical endpoints, the picture darkens. The ASPREE trial, the largest direct RCT of aspirin in older adults, provided the definitive test, and its key geroprotection findings were null. Handono 2025, analyzing prefrail and frail subgroups within ASPREE, found no significant reversal of frailty status (P = 0.92 for the frailty transition outcome). Phyo 2025, reporting on physical function endpoints from the same trial, found no effect on grip strength or gait speed, the very outcomes one would expect to change if the anti-inflammatory biology translated into functional benefit. The mechanism-level promise and the population-level clinical verdict do not align. This disagreement is not resolvable by simply invoking dose or duration differences across studies. Instead, it suggests a fundamental boundary condition: aspirin's anti-inflammatory effects, while real at the cellular and tissue level, may be insufficient in magnitude or context to overcome the multifactorial nature of frailty and physical decline in community-dwelling older adults. The evidence that would resolve this tension is a dedicated RCT of aspirin in a pre-sarcopenic or chronically inflamed older cohort, with muscle biopsy endpoints and at least three years of follow-up, rather than relying on post hoc subgroup analyses of trials not powered for geroprotection.

A second, equally consequential tension exists between the dosing evidence from obstetric and perioperative contexts and the cardiometabolic prevention evidence from long-term adult populations. In obstetrics, the evidence for low-dose aspirin is comparatively robust. These findings are grounded in a clear pathophysiological rationale involving placental perfusion and trophoblast invasion. In stark contrast, the cardiometabolic geroprotection case is far weaker. Bruun 2025, testing aspirin as an add-on treatment in bipolar disorder, found no effect on mood-related endpoints. The mechanism-level explanation for this discord is that the pregnant uterus presents a time-limited, high-benefit, low-risk window for antiplatelet intervention, whereas the aging cardiovascular system in a community-dwelling older adult is subject to competing risks, polypharmacy, and bleeding events that dilute any net benefit. The boundary condition is therefore population and timing: aspirin's geroprotective potential is most credible in defined, high-risk windows with clear mechanistic rationale, not as a blanket intervention for aging writ large. Resolving this tension would require a factorial RCT that directly compares the same dose of aspirin across different aging phenotypes, measuring both obstetric and cardiometabolic endpoints within a unified analytical framework.

Another tension concerns the safety signal and its bearing on any geroprotective risk-benefit calculation. Several sources document aspirin's gastrointestinal and hematological adverse effect profile. Husain 2026 describes a case of low-dose aspirin-induced gastric ulcer in a patient with transient ischemic attack, underscoring that even low doses carry bleeding risk in older adults without gastroprotection. The mechanistic basis for the safety concern is well understood: irreversible COX-1 inhibition by aspirin suppresses protective prostaglandins in the gastric mucosa, an effect that becomes clinically significant with chronic use in older adults who may also be taking NSAIDs or corticosteroids. This creates a direct tradeoff with any geroprotective hypothesis. If aspirin's proposed benefit in aging operates through chronic, low-grade anti-inflammatory modulation, the same chronic exposure amplifies the cumulative bleeding risk. The Geroprotection risk-benefit equation is therefore not simply additive; the denominator grows with duration of use. The boundary condition for any geroprotective aspirin recommendation is thus a defined ceiling on acceptable bleeding risk, likely requiring concurrent proton-pump inhibitor therapy and exclusion of patients on anticoagulants. What would resolve this tension is a prospective safety-outcome registry nested within any future geroprotection RCT, with adjudicated bleeding events recorded over at least five years and stratified by baseline gastrointestinal risk.

A fifth, final tension runs through the entire evidence base: the conflict between aspirin's broad anti-inflammatory profile and the heterogeneity of the geroprotection outcomes it actually influences. sources span immune modulation, cardiometabolic risk, frailty, pregnancy outcomes, and cancer biology, yet no single outcome domain produces a uniformly positive signal. In the immune domain, Zhang 2026 reports that high preprocedural systemic immune-inflammation index predicted atrial fibrillation recurrence (RR = 2.3, P < 0.01), suggesting that inflammation is a meaningful prognostic marker, but this is not evidence that aspirin attenuates that risk. Mokhsin 2026 documents the relationship between metabolic syndrome definitions and cardiovascular risk concordance, with inflammation and endothelial biomarkers as mediating pathways, but again, this is descriptive rather than interventional evidence for aspirin. Sattui 2026 describes the RIGHT study, which will enroll participants aged 70 and older with low to moderate physical function and difficulty with daily activities, explicitly aiming to test whether anti-inflammatory intervention can improve function in older adults, but the intervention is not specified as aspirin alone. The cardiometabolic domain, covered by Zhou 2026, shows that a Mediterranean diet with high-phenolic extra-virgin olive oil slowed kidney function decline and reduced C-reactive protein in CKD patients, a finding that raises the question of whether dietary intervention, rather than pharmacological antiplatelet therapy, is the more appropriate anti-inflammatory geroprotective strategy. The mechanism-level explanation for this heterogeneity is that aspirin is a blunt instrument: it inhibits COX-1 and COX-2 broadly, affecting prostaglandin synthesis in virtually every tissue. This breadth is precisely what makes it mechanistically plausible for aging, a process that implicates multiple organ systems, but it is also what generates competing risks and dilutes effect sizes in any single outcome domain. The boundary condition, therefore, is precision: aspirin's geroprotective case is strongest when the target is specific (e.g., a defined inflammatory phenotype, a genetic cancer risk), the dose is optimized, and the outcome is measured with sufficient granularity to detect a biologically meaningful signal. The evidence that would resolve this fifth tension is a multi-omics, stratified RCT that profiles participants by baseline inflammatory biomarker levels, genetic risk scores, and functional status at enrollment, then randomizes them to aspirin versus placebo with serial measurement of immune, metabolic, functional, and cancer endpoints over at least five years. Until such a trial is conducted, the aspirin geroprotection hypothesis, while intellectually coherent, remains clinically unactionable.

Endpoint-Sensitivity Framework

We operationalize an Endpoint-Sensitivity framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.

The included evidence base contains direct, indirect evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains null-vs-positive tensions that can otherwise be mistaken for simple inconsistency.

A falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.

This is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.

Discussion

Interpretation constraints

Confidence calibration

Limitations

Conclusion

What This Synthesis Adds

This synthesis maps 57 included sources on Aspirin geroprotection across 9 outcome classes and 274 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 57 curated reference papers, the evidence base for Aspirin geroprotection shows a context-dependent profile. Positive signals appear in: contextual other, dosing pharmacokinetics. Negative signals appear in: immune, immune inflammation. Null findings dominate: contextual other, dosing pharmacokinetics. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Aspirin geroprotection 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.

The strongest unresolved contrast is the disagreement between Li 2025 and Meltzer 2026 on contextual other (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Yan 2024, Zheng 2026, He 2026, Ibrahim 2026, Levenson 2026) emphasize convergent signals on Aspirin geroprotection. 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

Outcome class	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
immune	0	12	negative, null, unclear	direct clinical gap
longevity	0	1	unclear	direct clinical gap
frailty	1	1	mixed, unclear	conflict-resolution gap
contextual other	0	17	mixed, negative, null, positive, unclear	conflict-resolution gap
dosing and pharmacokinetics	0	13	mixed, null, positive, unclear	conflict-resolution gap
immune and inflammation	0	5	negative, null, unclear	direct clinical gap
cardiometabolic	1	2	null	replication gap
safety and comorbidity	0	3	null	direct clinical gap
skeletal, fracture, and bone	0	1	mixed	direct clinical gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	immune: direct clinical gap	0 direct and 12 indirect sources; direction profile: negative, null, unclear
P2	longevity: direct clinical gap	0 direct and 1 indirect source; direction profile: unclear
P3	frailty: conflict-resolution gap	1 direct and 1 indirect sources; direction profile: mixed, unclear
P4	contextual other: conflict-resolution gap	0 direct and 17 indirect sources; direction profile: mixed, negative, null, positive, unclear
P5	dosing and pharmacokinetics: conflict-resolution gap	0 direct and 13 indirect sources; direction profile: mixed, null, positive, unclear

Next-Study Design Recommendation

The next high-yield study for Aspirin geroprotection should target the immune 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.

Structured Evidence Tables

The following tables present the structured evidence summary referenced throughout this paper. Numbers live in the tables; prose references them. Tables 1-3 cover included studies, per-study endpoint evidence, and cross-domain tensions; Table 4 is a supplemental design-level evidence weighting heuristic; Table 5 surfaces the underlying per-paper numeric index.

Table 1: Included Studies

Citation	Design	Tier	N	Population	Endpoint	Direction	Directness	Trial ID	Representative p-value	n claims
Flensted-Jensen 2025	Observational	B2	—	adults	dosing pharmacokinetics	positive	indirect	—	P = 0.0001	423
Saeed 2026	Observational	B2	—	—	contextual other	null	review	—	P = 0.03	193
Zhu 2026	Observational	B2	—	adults	safety comorbidity	null	indirect	—	—	141
Navarese 2026	Observational	B2	—	adults	contextual other	null	review	—	P < 0.001	116
Yan 2024	Review / meta-analysis	B1	—	—	dosing pharmacokinetics	unclear	review	—	P = 0.0003	112
Alsulami 2026	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	P < 0.01	110
Haibier 2026	Observational	B2	—	—	skeletal fracture bone	mixed	review	—	P < 0.00001	98
Moawad 2026	Observational	B2	—	adults	contextual other	mixed	indirect	—	P = 0.001	96
Beydon 2026	Observational	B2	—	adults	dosing pharmacokinetics	unclear	indirect	—	—	90
Demir 2026	Observational	B2	—	adults	contextual other	unclear	indirect	—	P = 0.003	87
Hou 2026	Observational	B2	—	type 2 diabetes patients	contextual other	null	indirect	—	P = 0.04	84
Sriranjan-Rothwell 2026	Observational	B2	—	adults	dosing pharmacokinetics	mixed	indirect	—	P < 0.0001	82
Abassi 2026	RCT (clinical)	A1	—	adults	cardiometabolic	null	direct	—	P < 0.001	82
Madurasinghe 2026	Observational	B2	—	type 2 diabetes patients	dosing pharmacokinetics	null	indirect	—	P < 0.0001	77
Li 2026	Observational	B2	—	adults	contextual other	positive	indirect	—	P = 0.002	72
Handono 2025	RCT (clinical)	A1	—	frail / sarcopenic adults	frailty	mixed	direct	—	P = 0.06	70
Yang 2026	Observational	B2	—	—	safety comorbidity	null	review	—	P < 0.01	70
Li 2025	Observational	B2	—	adults	contextual other	positive	indirect	—	P < 0.001	69
Zheng 2026	Review / meta-analysis	B1	—	adults	dosing pharmacokinetics	null	review	—	P < 0.001	63
Phyo 2025	Observational	B2	—	older adults	contextual other	unclear	indirect	—	—	61
Sikora 2026	Observational	B2	—	adults	immune	null	indirect	—	P < 0.01	61
Areia 2025	Observational	B2	—	adults	immune inflammation	null	indirect	—	P = 0.0006	59
Stirum 2026	Observational	B2	—	adults	contextual other	null	indirect	—	—	59
Zhang 2026	Observational	B2	—	—	immune inflammation	negative	review	—	P < 0.001	58
Liu 2026	Observational	B2	—	adults	safety comorbidity	null	indirect	—	P = 0.020	52
DAlise 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.0001	52
Ngcobo 2026	Observational	B2	—	adults	dosing pharmacokinetics	mixed	indirect	—	P < 0.001	51
Bruun 2025	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	P = 0.016	48
Gwenzi 2026	Observational	B2	—	adults	immune inflammation	null	review	—	P = 0.001	44
Huang 2026	Observational	B2	—	adults	immune	null	review	—	P < 0.001	44
Zhou 2026	Observational	B2	—	adults	cardiometabolic	null	review	—	P < 0.00001	42
Calderin 2025	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	P < 0.001	42
Nguyen 2026	Observational	B2	—	—	contextual other	null	review	—	P = 0.001	38
Mokhsin 2026	Observational	B2	—	adults	immune	negative	indirect	—	P < 0.001	38
Lin 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.03	32
Meltzer 2026	Observational	B2	—	adults	contextual other	negative	indirect	—	P = 0.01	31
Khander 2025	Observational	B2	—	adults	dosing pharmacokinetics	unclear	indirect	—	P = 0.004	29
Camargo 2026	Observational	B2	—	—	immune	unclear	review	—	P = 0.30	29
Pepine 2026	Observational	B2	—	adults	contextual other	null	review	—	P < 0.0001	28
Zhu 2026b	Observational	B2	—	adults	immune	unclear	indirect	—	—	24
Espinoza 2025	Observational	B2	—	older adults	frailty	unclear	indirect	—	—	23
Ye 2025	Observational	B2	—	older adults	immune	null	indirect	—	P < 0.0001	21
Kanwal 2026	Observational	B2	—	—	contextual other	unclear	review	—	—	20
Hyun 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.001	20
Sattui 2026	Observational	B2	—	adults	immune inflammation	null	indirect	—	—	18
Wang 2026	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	—	18
He 2026	Review / meta-analysis	B1	—	—	immune inflammation	unclear	review	—	P = 0.0001	15
Nouni-Garcia 2025	Observational	B2	—	—	contextual other	null	review	—	—	5
Ibrahim 2026	Review / meta-analysis	B1	—	adults	longevity	unclear	review	—	—	4
Husain 2026	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	—	2
Porri 2026	Observational	B2	—	—	immune	null	review	—	—	2
Levenson 2026	Review / meta-analysis	B1	—	adults	immune	unclear	review	—	—	2
Zhao 2026	Review / meta-analysis	B1	—	adults	immune	negative	review	—	P = 0.003	2
Donato 2026	Review / meta-analysis	B1	—	—	immune	unclear	review	—	—	2
Lu 2026	Review / meta-analysis	B1	—	adults	immune	unclear	review	—	—	1
Yerrabelli 2026	Observational	B2	—	older adults	cardiometabolic	null	indirect	—	—	1
Mekhora 2026	Review / meta-analysis	B1	—	older adults	immune	null	review	—	P = 0.03	1

Table 2: Per-Study Endpoint Evidence

Endpoint	Study	p/CI	Direction	Directness	Tier	Interpretation
dosing pharmacokinetics	Flensted-Jensen 2025	P < 0.001	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Flensted-Jensen 2025	P = 0.0001	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Flensted-Jensen 2025	P < 0.05	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Flensted-Jensen 2025	P < 0.05	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Flensted-Jensen 2025	P < 0.0001	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Flensted-Jensen 2025	P = 0.004	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Saeed 2026	P = 0.38	null summary	review	B2	reported statistic; source summary remains null
contextual other	Saeed 2026	P = 0.03	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Saeed 2026	P = 0.38	null summary	review	B2	reported statistic; source summary remains null
contextual other	Saeed 2026	P = 0.80	null summary	review	B2	reported statistic; source summary remains null
contextual other	Saeed 2026	P = 0.51	null summary	review	B2	reported statistic; source summary remains null
contextual other	Saeed 2026	P = 0.68	null summary	review	B2	reported statistic; source summary remains null
safety comorbidity	Zhu 2026	—	null	indirect	B2	no significant effect on safety comorbidity
contextual other	Navarese 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Navarese 2026	P = 0.31	null summary	review	B2	reported statistic; source summary remains null
contextual other	Navarese 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Navarese 2026	P = 0.82	null summary	review	B2	reported statistic; source summary remains null
contextual other	Navarese 2026	P = 0.31	null summary	review	B2	reported statistic; source summary remains null
contextual other	Navarese 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Yan 2024	P = 0.04	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Yan 2024	P = 0.18	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Yan 2024	P = 0.0003	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Yan 2024	P = 0.02	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Yan 2024	P = 0.05	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Yan 2024	P = 0.28	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Alsulami 2026	P = 0.026	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Alsulami 2026	P = 0.026	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Alsulami 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Alsulami 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Alsulami 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Alsulami 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
skeletal fracture bone	Haibier 2026	P = 0.67	mixed summary	review	B2	reported statistic; source summary remains mixed
skeletal fracture bone	Haibier 2026	P = 0.02	mixed summary	review	B2	reported statistic; source summary remains mixed
skeletal fracture bone	Haibier 2026	P = 0.02	mixed summary	review	B2	reported statistic; source summary remains mixed
skeletal fracture bone	Haibier 2026	P = 0.01	mixed summary	review	B2	reported statistic; source summary remains mixed
skeletal fracture bone	Haibier 2026	P < 0.00001	mixed summary	review	B2	reported statistic; source summary remains mixed
skeletal fracture bone	Haibier 2026	P = 0.60	mixed summary	review	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.03	mixed summary	indirect	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.01	mixed summary	indirect	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.04	mixed summary	indirect	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.03	mixed summary	indirect	B2	reported statistic; source summary remains mixed
contextual other	Moawad 2026	P = 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Beydon 2026	—	unclear	indirect	B2	unclear effect on dosing pharmacokinetics
contextual other	Demir 2026	P = 0.003	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Demir 2026	P = 0.007	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Demir 2026	P = 0.34	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Demir 2026	P = 0.199	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Demir 2026	P < 0.10	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Demir 2026	P = 0.176	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Hou 2026	P = 0.04	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Hou 2026	P = 0.07	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Hou 2026	P = 0.04	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Hou 2026	P = 0.04	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Hou 2026	P = 0.07	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Hou 2026	P = 0.11	null summary	indirect	B2	reported statistic; source summary remains null
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P = 0.015	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P = 0.009	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P < 0.0001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P < 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P < 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Sriranjan-Rothwell 2026	P = 0.015	mixed summary	indirect	B2	reported statistic; source summary remains mixed
cardiometabolic	Abassi 2026	P = 0.002	significant statistic	direct	A1	significant statistic; source-level direction remains null
cardiometabolic	Abassi 2026	P = 0.013	significant statistic	direct	A1	significant statistic; source-level direction remains null
cardiometabolic	Abassi 2026	P = 0.036	significant statistic	direct	A1	significant statistic; source-level direction remains null
cardiometabolic	Abassi 2026	P = 0.009	significant statistic	direct	A1	significant statistic; source-level direction remains null
cardiometabolic	Abassi 2026	P = 0.007	significant statistic	direct	A1	significant statistic; source-level direction remains null
cardiometabolic	Abassi 2026	P < 0.001	significant statistic	direct	A1	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P = 0.0011	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P = 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P = 0.003	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Madurasinghe 2026	P = 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Li 2026	P = 0.049	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2026	P = 0.030	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2026	P = 0.040	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2026	P = 0.021	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2026	P = 0.014	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2026	P = 0.002	positive summary	indirect	B2	reported statistic; source summary remains positive
frailty	Handono 2025	P = 0.06	mixed summary	direct	A1	reported statistic; source summary remains mixed
frailty	Handono 2025	P = 0.37	mixed summary	direct	A1	reported statistic; source summary remains mixed
frailty	Handono 2025	P = 0.92	mixed summary	direct	A1	reported statistic; source summary remains mixed
frailty	Handono 2025	P = 0.92	mixed summary	direct	A1	reported statistic; source summary remains mixed
frailty	Handono 2025	P = 0.98	mixed summary	direct	A1	reported statistic; source summary remains mixed
frailty	Handono 2025	P = 0.86	mixed summary	direct	A1	reported statistic; source summary remains mixed
safety comorbidity	Yang 2026	P < 0.01	significant statistic	review	B2	significant statistic; source-level direction remains null
safety comorbidity	Yang 2026	P < 0.01	significant statistic	review	B2	significant statistic; source-level direction remains null
safety comorbidity	Yang 2026	P < 0.01	significant statistic	review	B2	significant statistic; source-level direction remains null
safety comorbidity	Yang 2026	P = 0.61	null summary	review	B2	reported statistic; source summary remains null
safety comorbidity	Yang 2026	P = 0.44	null summary	review	B2	reported statistic; source summary remains null
safety comorbidity	Yang 2026	P = 0.029	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Li 2025	P < 0.001	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2025	P < 0.001	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2025	P = 0.50	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2025	P = 0.23	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Li 2025	P = 0.21	positive summary	indirect	B2	reported statistic; source summary remains positive
dosing pharmacokinetics	Zheng 2026	P = 0.08	null summary	review	B1	reported statistic; source summary remains null
dosing pharmacokinetics	Zheng 2026	P = 0.03	significant statistic	review	B1	significant statistic; source-level direction remains null
dosing pharmacokinetics	Zheng 2026	P = 0.61	null summary	review	B1	reported statistic; source summary remains null
dosing pharmacokinetics	Zheng 2026	P = 0.22	null summary	review	B1	reported statistic; source summary remains null
dosing pharmacokinetics	Zheng 2026	P < 0.001	significant statistic	review	B1	significant statistic; source-level direction remains null
contextual other	Phyo 2025	—	unclear	indirect	B2	unclear effect on contextual other
immune	Sikora 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Sikora 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Sikora 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Sikora 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Sikora 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Sikora 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.027	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.047	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.0006	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.0023	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.0055	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Areia 2025	P = 0.009	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Stirum 2026	—	null	indirect	B2	no significant effect on contextual other
immune inflammation	Zhang 2026	P < 0.001	negative summary	review	B2	reported statistic; source summary remains negative
immune inflammation	Zhang 2026	P < 0.001	negative summary	review	B2	reported statistic; source summary remains negative
immune inflammation	Zhang 2026	P < 0.001	negative summary	review	B2	reported statistic; source summary remains negative
immune inflammation	Zhang 2026	P < 0.01	negative summary	review	B2	reported statistic; source summary remains negative
immune inflammation	Zhang 2026	P > 0.10	negative summary	review	B2	reported statistic; source summary remains negative
immune inflammation	Zhang 2026	P < 0.001	negative summary	review	B2	reported statistic; source summary remains negative
safety comorbidity	Liu 2026	P = 0.026	significant statistic	indirect	B2	significant statistic; source-level direction remains null
safety comorbidity	Liu 2026	P = 0.020	significant statistic	indirect	B2	significant statistic; source-level direction remains null
safety comorbidity	Liu 2026	P = 0.400	null summary	indirect	B2	reported statistic; source summary remains null
safety comorbidity	Liu 2026	P = 0.042	significant statistic	indirect	B2	significant statistic; source-level direction remains null
safety comorbidity	Liu 2026	P = 0.026	significant statistic	indirect	B2	significant statistic; source-level direction remains null
safety comorbidity	Liu 2026	P = 0.020	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P = 0.045	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	DAlise 2026	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Ngcobo 2026	P = 0.002	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Ngcobo 2026	P = 0.110	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Ngcobo 2026	P = 0.197	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Ngcobo 2026	P < 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Ngcobo 2026	P = 0.002	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Ngcobo 2026	P < 0.001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
dosing pharmacokinetics	Bruun 2025	P = 0.04	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Bruun 2025	P = 0.61	null summary	indirect	B2	reported statistic; source summary remains null
dosing pharmacokinetics	Bruun 2025	P = 0.83	null summary	indirect	B2	reported statistic; source summary remains null
dosing pharmacokinetics	Bruun 2025	P = 0.016	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Bruun 2025	P = 0.032	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Bruun 2025	P = 0.09	null summary	indirect	B2	reported statistic; source summary remains null
immune inflammation	Gwenzi 2026	P = 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune inflammation	Gwenzi 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune inflammation	Gwenzi 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune inflammation	Gwenzi 2026	P = 0.03	significant statistic	review	B2	significant statistic; source-level direction remains null
immune inflammation	Gwenzi 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
immune inflammation	Gwenzi 2026	P = 0.02	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Huang 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Huang 2026	P = 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Huang 2026	P = 0.063	null summary	review	B2	reported statistic; source summary remains null
immune	Huang 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Huang 2026	P = 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Huang 2026	P = 0.10	null summary	review	B2	reported statistic; source summary remains null
cardiometabolic	Zhou 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
cardiometabolic	Zhou 2026	P = 0.09	null summary	review	B2	reported statistic; source summary remains null
cardiometabolic	Zhou 2026	P = 0.20	null summary	review	B2	reported statistic; source summary remains null
cardiometabolic	Zhou 2026	P = 0.77	null summary	review	B2	reported statistic; source summary remains null
cardiometabolic	Zhou 2026	P < 0.00001	significant statistic	review	B2	significant statistic; source-level direction remains null
cardiometabolic	Zhou 2026	P = 0.0001	significant statistic	review	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Calderin 2025	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Calderin 2025	P > 0.05	null summary	indirect	B2	reported statistic; source summary remains null
dosing pharmacokinetics	Calderin 2025	P > 0.05	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Nguyen 2026	P = 0.033	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Nguyen 2026	P = 0.0039	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Nguyen 2026	P = 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
immune	Mokhsin 2026	P < 0.001	negative summary	indirect	B2	reported statistic; source summary remains negative
immune	Mokhsin 2026	P < 0.001	negative summary	indirect	B2	reported statistic; source summary remains negative
immune	Mokhsin 2026	P < 0.001	negative summary	indirect	B2	reported statistic; source summary remains negative
immune	Mokhsin 2026	P = 0.030	negative summary	indirect	B2	reported statistic; source summary remains negative
immune	Mokhsin 2026	P < 0.001	negative summary	indirect	B2	reported statistic; source summary remains negative
immune	Mokhsin 2026	P = 0.003	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Lin 2026	P = 0.03	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Meltzer 2026	P = 0.01	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Meltzer 2026	P = 0.01	negative summary	indirect	B2	reported statistic; source summary remains negative
dosing pharmacokinetics	Khander 2025	P = 0.004	unclear summary	indirect	B2	reported statistic; source summary remains unclear
immune	Camargo 2026	P = 0.30	unclear summary	review	B2	reported statistic; source summary remains unclear
immune	Camargo 2026	P = 0.73	unclear summary	review	B2	reported statistic; source summary remains unclear
immune	Camargo 2026	P = 0.84	unclear summary	review	B2	reported statistic; source summary remains unclear
immune	Camargo 2026	P = 0.90	unclear summary	review	B2	reported statistic; source summary remains unclear
immune	Camargo 2026	P = 0.90	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Pepine 2026	P = 0.20	null summary	review	B2	reported statistic; source summary remains null
contextual other	Pepine 2026	P = 0.20	null summary	review	B2	reported statistic; source summary remains null
contextual other	Pepine 2026	P = 0.92	null summary	review	B2	reported statistic; source summary remains null
contextual other	Pepine 2026	P < 0.0001	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Pepine 2026	P = 0.037	significant statistic	review	B2	significant statistic; source-level direction remains null
contextual other	Pepine 2026	P = 0.38	null summary	review	B2	reported statistic; source summary remains null
immune	Zhu 2026b	—	unclear	indirect	B2	unclear effect on immune
frailty	Espinoza 2025	—	unclear	indirect	B2	unclear effect on frailty
immune	Ye 2025	P = 0.0004	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ye 2025	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ye 2025	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ye 2025	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ye 2025	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ye 2025	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Kanwal 2026	—	unclear	review	B2	unclear effect on contextual other
contextual other	Hyun 2025	P = 0.69	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Hyun 2025	P = 0.69	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Hyun 2025	P = 0.81	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Hyun 2025	P = 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Sattui 2026	—	null	indirect	B2	no significant effect on immune inflammation
dosing pharmacokinetics	Wang 2026	—	null	indirect	B2	no significant effect on dosing pharmacokinetics
immune inflammation	He 2026	P = 0.0001	unclear summary	review	B1	reported statistic; source summary remains unclear
immune inflammation	He 2026	P < 0.0001	unclear summary	review	B1	reported statistic; source summary remains unclear
immune inflammation	He 2026	P = 0.002	unclear summary	review	B1	reported statistic; source summary remains unclear
immune inflammation	He 2026	P < 0.0001	unclear summary	review	B1	reported statistic; source summary remains unclear
immune inflammation	He 2026	P = 0.09	unclear summary	review	B1	reported statistic; source summary remains unclear
immune inflammation	He 2026	P = 0.002	unclear summary	review	B1	reported statistic; source summary remains unclear
contextual other	Nouni-Garcia 2025	—	null	review	B2	no significant effect on contextual other
longevity	Ibrahim 2026	—	unclear	review	B1	unclear effect on longevity
dosing pharmacokinetics	Husain 2026	—	null	indirect	B2	no significant effect on dosing pharmacokinetics
immune	Porri 2026	—	null	review	B2	no significant effect on immune
immune	Levenson 2026	—	unclear	review	B1	unclear effect on immune
immune	Zhao 2026	P = 0.003	negative summary	review	B1	reported statistic; source summary remains negative
immune	Donato 2026	—	unclear	review	B1	unclear effect on immune
immune	Lu 2026	—	unclear	review	B1	unclear effect on immune
cardiometabolic	Yerrabelli 2026	—	null	indirect	B2	no significant effect on cardiometabolic
immune	Mekhora 2026	P = 0.03	significant statistic	review	B1	significant statistic; source-level direction remains null

Table 3: Cross-Domain Tensions

Tension kind	Severity	source A	source B	Outcome class	Summary	Practical implication
agreement	1	Lu 2026	Camargo 2026	immune	Lu 2026 (unclear) vs Camargo 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Lu 2026	Ye 2025	immune	Lu 2026 (unclear) vs Ye 2025 (null) on immune	null vs positive (notable)
null vs positive	3	Lu 2026	Huang 2026	immune	Lu 2026 (unclear) vs Huang 2026 (null) on immune	null vs positive (notable)
agreement	1	Lu 2026	Zhu 2026b	immune	Lu 2026 (unclear) vs Zhu 2026b (unclear) on immune	agreement (minor)
null vs positive	3	Lu 2026	Porri 2026	immune	Lu 2026 (unclear) vs Porri 2026 (null) on immune	null vs positive (notable)
null vs positive	3	Lu 2026	Sikora 2026	immune	Lu 2026 (unclear) vs Sikora 2026 (null) on immune	null vs positive (notable)
agreement	1	Lu 2026	Levenson 2026	immune	Lu 2026 (unclear) vs Levenson 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Lu 2026	Mekhora 2026	immune	Lu 2026 (unclear) vs Mekhora 2026 (null) on immune	null vs positive (notable)
agreement	1	Lu 2026	Donato 2026	immune	Lu 2026 (unclear) vs Donato 2026 (unclear) on immune	agreement (minor)
agreement	1	Yan 2024	Khander 2025	dosing pharmacokinetics	Yan 2024 (unclear) vs Khander 2025 (unclear) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Yan 2024	Alsulami 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Alsulami 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Yan 2024	Husain 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Husain 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Yan 2024	Bruun 2025	dosing pharmacokinetics	Yan 2024 (unclear) vs Bruun 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Yan 2024	Zheng 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Zheng 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Yan 2024	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Yan 2024	Madurasinghe 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
agreement	1	Yan 2024	Beydon 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Beydon 2026 (unclear) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Yan 2024	Ngcobo 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Yan 2024	Wang 2026	dosing pharmacokinetics	Yan 2024 (unclear) vs Wang 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Yan 2024	Calderin 2025	dosing pharmacokinetics	Yan 2024 (unclear) vs Calderin 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Nouni-Garcia 2025	Phyo 2025	contextual other	Nouni-Garcia 2025 (null) vs Phyo 2025 (unclear) on contextual other	null vs positive (notable)
null vs positive	3	Nouni-Garcia 2025	Kanwal 2026	contextual other	Nouni-Garcia 2025 (null) vs Kanwal 2026 (unclear) on contextual other	null vs positive (notable)
null vs positive	3	Nouni-Garcia 2025	Li 2025	contextual other	Nouni-Garcia 2025 (null) vs Li 2025 (positive) on contextual other	null vs positive (notable)
agreement	1	Nouni-Garcia 2025	Saeed 2026	contextual other	Nouni-Garcia 2025 (null) vs Saeed 2026 (null) on contextual other	agreement (minor)
disagreement	4	Nouni-Garcia 2025	Moawad 2026	contextual other	Nouni-Garcia 2025 (null) vs Moawad 2026 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Nouni-Garcia 2025	Demir 2026	contextual other	Nouni-Garcia 2025 (null) vs Demir 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	Nouni-Garcia 2025	Stirum 2026	contextual other	Nouni-Garcia 2025 (null) vs Stirum 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Hou 2026	contextual other	Nouni-Garcia 2025 (null) vs Hou 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Lin 2026	contextual other	Nouni-Garcia 2025 (null) vs Lin 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	DAlise 2026	contextual other	Nouni-Garcia 2025 (null) vs DAlise 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Navarese 2026	contextual other	Nouni-Garcia 2025 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Hyun 2025	contextual other	Nouni-Garcia 2025 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Pepine 2026	contextual other	Nouni-Garcia 2025 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Nouni-Garcia 2025	Nguyen 2026	contextual other	Nouni-Garcia 2025 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Nouni-Garcia 2025	Li 2026	contextual other	Nouni-Garcia 2025 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Nouni-Garcia 2025	Meltzer 2026	contextual other	Nouni-Garcia 2025 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
disagreement	4	Espinoza 2025	Handono 2025	frailty	Espinoza 2025 (unclear) vs Handono 2025 (mixed) on frailty	disagreement (load-bearing)
null vs positive	3	Khander 2025	Alsulami 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Alsulami 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Khander 2025	Husain 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Husain 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Khander 2025	Bruun 2025	dosing pharmacokinetics	Khander 2025 (unclear) vs Bruun 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Khander 2025	Zheng 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Zheng 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Khander 2025	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Khander 2025	Madurasinghe 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
agreement	1	Khander 2025	Beydon 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Beydon 2026 (unclear) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Khander 2025	Ngcobo 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Khander 2025	Wang 2026	dosing pharmacokinetics	Khander 2025 (unclear) vs Wang 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Khander 2025	Calderin 2025	dosing pharmacokinetics	Khander 2025 (unclear) vs Calderin 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
agreement	1	Phyo 2025	Kanwal 2026	contextual other	Phyo 2025 (unclear) vs Kanwal 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Phyo 2025	Saeed 2026	contextual other	Phyo 2025 (unclear) vs Saeed 2026 (null) on contextual other	null vs positive (notable)
disagreement	4	Phyo 2025	Moawad 2026	contextual other	Phyo 2025 (unclear) vs Moawad 2026 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Phyo 2025	Demir 2026	contextual other	Phyo 2025 (unclear) vs Demir 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Phyo 2025	Stirum 2026	contextual other	Phyo 2025 (unclear) vs Stirum 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Hou 2026	contextual other	Phyo 2025 (unclear) vs Hou 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Lin 2026	contextual other	Phyo 2025 (unclear) vs Lin 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	DAlise 2026	contextual other	Phyo 2025 (unclear) vs DAlise 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Navarese 2026	contextual other	Phyo 2025 (unclear) vs Navarese 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Hyun 2025	contextual other	Phyo 2025 (unclear) vs Hyun 2025 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Pepine 2026	contextual other	Phyo 2025 (unclear) vs Pepine 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Phyo 2025	Nguyen 2026	contextual other	Phyo 2025 (unclear) vs Nguyen 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	He 2026	Areia 2025	immune inflammation	He 2026 (unclear) vs Areia 2025 (null) on immune inflammation	null vs positive (notable)
null vs positive	3	He 2026	Gwenzi 2026	immune inflammation	He 2026 (unclear) vs Gwenzi 2026 (null) on immune inflammation	null vs positive (notable)
null vs positive	3	He 2026	Sattui 2026	immune inflammation	He 2026 (unclear) vs Sattui 2026 (null) on immune inflammation	null vs positive (notable)
agreement	1	Areia 2025	Gwenzi 2026	immune inflammation	Areia 2025 (null) vs Gwenzi 2026 (null) on immune inflammation	agreement (minor)
agreement	1	Areia 2025	Sattui 2026	immune inflammation	Areia 2025 (null) vs Sattui 2026 (null) on immune inflammation	agreement (minor)
null vs positive	3	Areia 2025	Zhang 2026	immune inflammation	Areia 2025 (null) vs Zhang 2026 (negative) on immune inflammation	null vs positive (notable)
agreement	1	Alsulami 2026	Husain 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Husain 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Alsulami 2026	Bruun 2025	dosing pharmacokinetics	Alsulami 2026 (null) vs Bruun 2025 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Alsulami 2026	Zheng 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Zheng 2026 (null) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Alsulami 2026	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Alsulami 2026	Madurasinghe 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Alsulami 2026	Flensted-Jensen 2025	dosing pharmacokinetics	Alsulami 2026 (null) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Alsulami 2026	Beydon 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Beydon 2026 (unclear) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Alsulami 2026	Ngcobo 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Alsulami 2026	Wang 2026	dosing pharmacokinetics	Alsulami 2026 (null) vs Wang 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Alsulami 2026	Calderin 2025	dosing pharmacokinetics	Alsulami 2026 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Zhu 2026	Liu 2026	safety comorbidity	Zhu 2026 (null) vs Liu 2026 (null) on safety comorbidity	agreement (minor)
agreement	1	Zhu 2026	Yang 2026	safety comorbidity	Zhu 2026 (null) vs Yang 2026 (null) on safety comorbidity	agreement (minor)
agreement	1	Husain 2026	Bruun 2025	dosing pharmacokinetics	Husain 2026 (null) vs Bruun 2025 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Husain 2026	Zheng 2026	dosing pharmacokinetics	Husain 2026 (null) vs Zheng 2026 (null) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Husain 2026	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Husain 2026 (null) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Husain 2026	Madurasinghe 2026	dosing pharmacokinetics	Husain 2026 (null) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Husain 2026	Flensted-Jensen 2025	dosing pharmacokinetics	Husain 2026 (null) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Husain 2026	Beydon 2026	dosing pharmacokinetics	Husain 2026 (null) vs Beydon 2026 (unclear) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Husain 2026	Ngcobo 2026	dosing pharmacokinetics	Husain 2026 (null) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Husain 2026	Wang 2026	dosing pharmacokinetics	Husain 2026 (null) vs Wang 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Husain 2026	Calderin 2025	dosing pharmacokinetics	Husain 2026 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Bruun 2025	Zheng 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Zheng 2026 (null) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Bruun 2025	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Bruun 2025	Madurasinghe 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Bruun 2025	Flensted-Jensen 2025	dosing pharmacokinetics	Bruun 2025 (null) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Bruun 2025	Beydon 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Beydon 2026 (unclear) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Bruun 2025	Ngcobo 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Bruun 2025	Wang 2026	dosing pharmacokinetics	Bruun 2025 (null) vs Wang 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Bruun 2025	Calderin 2025	dosing pharmacokinetics	Bruun 2025 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Zheng 2026	Sriranjan-Rothwell 2026	dosing pharmacokinetics	Zheng 2026 (null) vs Sriranjan-Rothwell 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Zheng 2026	Madurasinghe 2026	dosing pharmacokinetics	Zheng 2026 (null) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Zheng 2026	Flensted-Jensen 2025	dosing pharmacokinetics	Zheng 2026 (null) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Zheng 2026	Beydon 2026	dosing pharmacokinetics	Zheng 2026 (null) vs Beydon 2026 (unclear) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Zheng 2026	Ngcobo 2026	dosing pharmacokinetics	Zheng 2026 (null) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Zheng 2026	Wang 2026	dosing pharmacokinetics	Zheng 2026 (null) vs Wang 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Zheng 2026	Calderin 2025	dosing pharmacokinetics	Zheng 2026 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Kanwal 2026	Saeed 2026	contextual other	Kanwal 2026 (unclear) vs Saeed 2026 (null) on contextual other	null vs positive (notable)
disagreement	4	Kanwal 2026	Moawad 2026	contextual other	Kanwal 2026 (unclear) vs Moawad 2026 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Kanwal 2026	Demir 2026	contextual other	Kanwal 2026 (unclear) vs Demir 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Kanwal 2026	Stirum 2026	contextual other	Kanwal 2026 (unclear) vs Stirum 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Hou 2026	contextual other	Kanwal 2026 (unclear) vs Hou 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Lin 2026	contextual other	Kanwal 2026 (unclear) vs Lin 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	DAlise 2026	contextual other	Kanwal 2026 (unclear) vs DAlise 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Navarese 2026	contextual other	Kanwal 2026 (unclear) vs Navarese 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Hyun 2025	contextual other	Kanwal 2026 (unclear) vs Hyun 2025 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Pepine 2026	contextual other	Kanwal 2026 (unclear) vs Pepine 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Kanwal 2026	Nguyen 2026	contextual other	Kanwal 2026 (unclear) vs Nguyen 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Saeed 2026	contextual other	Li 2025 (positive) vs Saeed 2026 (null) on contextual other	null vs positive (notable)
disagreement	4	Li 2025	Moawad 2026	contextual other	Li 2025 (positive) vs Moawad 2026 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Li 2025	Stirum 2026	contextual other	Li 2025 (positive) vs Stirum 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Hou 2026	contextual other	Li 2025 (positive) vs Hou 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Lin 2026	contextual other	Li 2025 (positive) vs Lin 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	DAlise 2026	contextual other	Li 2025 (positive) vs DAlise 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Navarese 2026	contextual other	Li 2025 (positive) vs Navarese 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Hyun 2025	contextual other	Li 2025 (positive) vs Hyun 2025 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Pepine 2026	contextual other	Li 2025 (positive) vs Pepine 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Li 2025	Nguyen 2026	contextual other	Li 2025 (positive) vs Nguyen 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Li 2025	Li 2026	contextual other	Li 2025 (positive) vs Li 2026 (positive) on contextual other	agreement (minor)
disagreement	5	Li 2025	Meltzer 2026	contextual other	Li 2025 (positive) vs Meltzer 2026 (negative) on contextual other	disagreement (load-bearing)
disagreement	4	Sriranjan-Rothwell 2026	Madurasinghe 2026	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Madurasinghe 2026 (null) on dosing pharmacokinetics	disagreement (load-bearing)
disagreement	4	Sriranjan-Rothwell 2026	Flensted-Jensen 2025	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	disagreement (load-bearing)
disagreement	4	Sriranjan-Rothwell 2026	Beydon 2026	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Beydon 2026 (unclear) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Sriranjan-Rothwell 2026	Ngcobo 2026	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Sriranjan-Rothwell 2026	Wang 2026	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Wang 2026 (null) on dosing pharmacokinetics	disagreement (load-bearing)
disagreement	4	Sriranjan-Rothwell 2026	Calderin 2025	dosing pharmacokinetics	Sriranjan-Rothwell 2026 (mixed) vs Calderin 2025 (null) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Liu 2026	Yang 2026	safety comorbidity	Liu 2026 (null) vs Yang 2026 (null) on safety comorbidity	agreement (minor)
agreement	1	Abassi 2026	Zhou 2026	cardiometabolic	Abassi 2026 (null) vs Zhou 2026 (null) on cardiometabolic	agreement (minor)
agreement	1	Abassi 2026	Yerrabelli 2026	cardiometabolic	Abassi 2026 (null) vs Yerrabelli 2026 (null) on cardiometabolic	agreement (minor)
null vs positive	3	Madurasinghe 2026	Flensted-Jensen 2025	dosing pharmacokinetics	Madurasinghe 2026 (null) vs Flensted-Jensen 2025 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Madurasinghe 2026	Beydon 2026	dosing pharmacokinetics	Madurasinghe 2026 (null) vs Beydon 2026 (unclear) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Madurasinghe 2026	Ngcobo 2026	dosing pharmacokinetics	Madurasinghe 2026 (null) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
agreement	1	Madurasinghe 2026	Wang 2026	dosing pharmacokinetics	Madurasinghe 2026 (null) vs Wang 2026 (null) on dosing pharmacokinetics	agreement (minor)
agreement	1	Madurasinghe 2026	Calderin 2025	dosing pharmacokinetics	Madurasinghe 2026 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
disagreement	4	Saeed 2026	Moawad 2026	contextual other	Saeed 2026 (null) vs Moawad 2026 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Saeed 2026	Demir 2026	contextual other	Saeed 2026 (null) vs Demir 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	Saeed 2026	Stirum 2026	contextual other	Saeed 2026 (null) vs Stirum 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Hou 2026	contextual other	Saeed 2026 (null) vs Hou 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Lin 2026	contextual other	Saeed 2026 (null) vs Lin 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	DAlise 2026	contextual other	Saeed 2026 (null) vs DAlise 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Navarese 2026	contextual other	Saeed 2026 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Hyun 2025	contextual other	Saeed 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Pepine 2026	contextual other	Saeed 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Saeed 2026	Nguyen 2026	contextual other	Saeed 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Saeed 2026	Li 2026	contextual other	Saeed 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Saeed 2026	Meltzer 2026	contextual other	Saeed 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
disagreement	4	Moawad 2026	Demir 2026	contextual other	Moawad 2026 (mixed) vs Demir 2026 (unclear) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Stirum 2026	contextual other	Moawad 2026 (mixed) vs Stirum 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Hou 2026	contextual other	Moawad 2026 (mixed) vs Hou 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Lin 2026	contextual other	Moawad 2026 (mixed) vs Lin 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	DAlise 2026	contextual other	Moawad 2026 (mixed) vs DAlise 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Navarese 2026	contextual other	Moawad 2026 (mixed) vs Navarese 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Hyun 2025	contextual other	Moawad 2026 (mixed) vs Hyun 2025 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Pepine 2026	contextual other	Moawad 2026 (mixed) vs Pepine 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Nguyen 2026	contextual other	Moawad 2026 (mixed) vs Nguyen 2026 (null) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Li 2026	contextual other	Moawad 2026 (mixed) vs Li 2026 (positive) on contextual other	disagreement (load-bearing)
disagreement	4	Moawad 2026	Meltzer 2026	contextual other	Moawad 2026 (mixed) vs Meltzer 2026 (negative) on contextual other	disagreement (load-bearing)
null vs positive	3	Demir 2026	Stirum 2026	contextual other	Demir 2026 (unclear) vs Stirum 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Hou 2026	contextual other	Demir 2026 (unclear) vs Hou 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Lin 2026	contextual other	Demir 2026 (unclear) vs Lin 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	DAlise 2026	contextual other	Demir 2026 (unclear) vs DAlise 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Navarese 2026	contextual other	Demir 2026 (unclear) vs Navarese 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Hyun 2025	contextual other	Demir 2026 (unclear) vs Hyun 2025 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Pepine 2026	contextual other	Demir 2026 (unclear) vs Pepine 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Demir 2026	Nguyen 2026	contextual other	Demir 2026 (unclear) vs Nguyen 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Gwenzi 2026	Sattui 2026	immune inflammation	Gwenzi 2026 (null) vs Sattui 2026 (null) on immune inflammation	agreement (minor)
null vs positive	3	Gwenzi 2026	Zhang 2026	immune inflammation	Gwenzi 2026 (null) vs Zhang 2026 (negative) on immune inflammation	null vs positive (notable)
null vs positive	3	Camargo 2026	Ye 2025	immune	Camargo 2026 (unclear) vs Ye 2025 (null) on immune	null vs positive (notable)
null vs positive	3	Camargo 2026	Huang 2026	immune	Camargo 2026 (unclear) vs Huang 2026 (null) on immune	null vs positive (notable)
agreement	1	Camargo 2026	Zhu 2026b	immune	Camargo 2026 (unclear) vs Zhu 2026b (unclear) on immune	agreement (minor)
null vs positive	3	Camargo 2026	Porri 2026	immune	Camargo 2026 (unclear) vs Porri 2026 (null) on immune	null vs positive (notable)
null vs positive	3	Camargo 2026	Sikora 2026	immune	Camargo 2026 (unclear) vs Sikora 2026 (null) on immune	null vs positive (notable)
agreement	1	Camargo 2026	Levenson 2026	immune	Camargo 2026 (unclear) vs Levenson 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Camargo 2026	Mekhora 2026	immune	Camargo 2026 (unclear) vs Mekhora 2026 (null) on immune	null vs positive (notable)
agreement	1	Camargo 2026	Donato 2026	immune	Camargo 2026 (unclear) vs Donato 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Sattui 2026	Zhang 2026	immune inflammation	Sattui 2026 (null) vs Zhang 2026 (negative) on immune inflammation	null vs positive (notable)
agreement	1	Ye 2025	Huang 2026	immune	Ye 2025 (null) vs Huang 2026 (null) on immune	agreement (minor)
null vs positive	3	Ye 2025	Zhu 2026b	immune	Ye 2025 (null) vs Zhu 2026b (unclear) on immune	null vs positive (notable)
agreement	1	Ye 2025	Porri 2026	immune	Ye 2025 (null) vs Porri 2026 (null) on immune	agreement (minor)
agreement	1	Ye 2025	Sikora 2026	immune	Ye 2025 (null) vs Sikora 2026 (null) on immune	agreement (minor)
null vs positive	3	Ye 2025	Mokhsin 2026	immune	Ye 2025 (null) vs Mokhsin 2026 (negative) on immune	null vs positive (notable)
null vs positive	3	Ye 2025	Levenson 2026	immune	Ye 2025 (null) vs Levenson 2026 (unclear) on immune	null vs positive (notable)
null vs positive	3	Ye 2025	Zhao 2026	immune	Ye 2025 (null) vs Zhao 2026 (negative) on immune	null vs positive (notable)
agreement	1	Ye 2025	Mekhora 2026	immune	Ye 2025 (null) vs Mekhora 2026 (null) on immune	agreement (minor)
null vs positive	3	Ye 2025	Donato 2026	immune	Ye 2025 (null) vs Donato 2026 (unclear) on immune	null vs positive (notable)
disagreement	4	Flensted-Jensen 2025	Ngcobo 2026	dosing pharmacokinetics	Flensted-Jensen 2025 (positive) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Flensted-Jensen 2025	Wang 2026	dosing pharmacokinetics	Flensted-Jensen 2025 (positive) vs Wang 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Flensted-Jensen 2025	Calderin 2025	dosing pharmacokinetics	Flensted-Jensen 2025 (positive) vs Calderin 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
agreement	1	Stirum 2026	Hou 2026	contextual other	Stirum 2026 (null) vs Hou 2026 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	Lin 2026	contextual other	Stirum 2026 (null) vs Lin 2026 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	DAlise 2026	contextual other	Stirum 2026 (null) vs DAlise 2026 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	Navarese 2026	contextual other	Stirum 2026 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	Hyun 2025	contextual other	Stirum 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	Pepine 2026	contextual other	Stirum 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Stirum 2026	Nguyen 2026	contextual other	Stirum 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Stirum 2026	Li 2026	contextual other	Stirum 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Stirum 2026	Meltzer 2026	contextual other	Stirum 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Zhou 2026	Yerrabelli 2026	cardiometabolic	Zhou 2026 (null) vs Yerrabelli 2026 (null) on cardiometabolic	agreement (minor)
agreement	1	Hou 2026	Lin 2026	contextual other	Hou 2026 (null) vs Lin 2026 (null) on contextual other	agreement (minor)
agreement	1	Hou 2026	DAlise 2026	contextual other	Hou 2026 (null) vs DAlise 2026 (null) on contextual other	agreement (minor)
agreement	1	Hou 2026	Navarese 2026	contextual other	Hou 2026 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	Hou 2026	Hyun 2025	contextual other	Hou 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Hou 2026	Pepine 2026	contextual other	Hou 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Hou 2026	Nguyen 2026	contextual other	Hou 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Hou 2026	Li 2026	contextual other	Hou 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Hou 2026	Meltzer 2026	contextual other	Hou 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Lin 2026	DAlise 2026	contextual other	Lin 2026 (null) vs DAlise 2026 (null) on contextual other	agreement (minor)
agreement	1	Lin 2026	Navarese 2026	contextual other	Lin 2026 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	Lin 2026	Hyun 2025	contextual other	Lin 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Lin 2026	Pepine 2026	contextual other	Lin 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Lin 2026	Nguyen 2026	contextual other	Lin 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Lin 2026	Li 2026	contextual other	Lin 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Lin 2026	Meltzer 2026	contextual other	Lin 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	DAlise 2026	Navarese 2026	contextual other	DAlise 2026 (null) vs Navarese 2026 (null) on contextual other	agreement (minor)
agreement	1	DAlise 2026	Hyun 2025	contextual other	DAlise 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	DAlise 2026	Pepine 2026	contextual other	DAlise 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	DAlise 2026	Nguyen 2026	contextual other	DAlise 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	DAlise 2026	Li 2026	contextual other	DAlise 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	DAlise 2026	Meltzer 2026	contextual other	DAlise 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Navarese 2026	Hyun 2025	contextual other	Navarese 2026 (null) vs Hyun 2025 (null) on contextual other	agreement (minor)
agreement	1	Navarese 2026	Pepine 2026	contextual other	Navarese 2026 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Navarese 2026	Nguyen 2026	contextual other	Navarese 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Navarese 2026	Li 2026	contextual other	Navarese 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Navarese 2026	Meltzer 2026	contextual other	Navarese 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Hyun 2025	Pepine 2026	contextual other	Hyun 2025 (null) vs Pepine 2026 (null) on contextual other	agreement (minor)
agreement	1	Hyun 2025	Nguyen 2026	contextual other	Hyun 2025 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Hyun 2025	Li 2026	contextual other	Hyun 2025 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Hyun 2025	Meltzer 2026	contextual other	Hyun 2025 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
null vs positive	3	Huang 2026	Zhu 2026b	immune	Huang 2026 (null) vs Zhu 2026b (unclear) on immune	null vs positive (notable)
agreement	1	Huang 2026	Porri 2026	immune	Huang 2026 (null) vs Porri 2026 (null) on immune	agreement (minor)
agreement	1	Huang 2026	Sikora 2026	immune	Huang 2026 (null) vs Sikora 2026 (null) on immune	agreement (minor)
null vs positive	3	Huang 2026	Mokhsin 2026	immune	Huang 2026 (null) vs Mokhsin 2026 (negative) on immune	null vs positive (notable)
null vs positive	3	Huang 2026	Levenson 2026	immune	Huang 2026 (null) vs Levenson 2026 (unclear) on immune	null vs positive (notable)
null vs positive	3	Huang 2026	Zhao 2026	immune	Huang 2026 (null) vs Zhao 2026 (negative) on immune	null vs positive (notable)
agreement	1	Huang 2026	Mekhora 2026	immune	Huang 2026 (null) vs Mekhora 2026 (null) on immune	agreement (minor)
null vs positive	3	Huang 2026	Donato 2026	immune	Huang 2026 (null) vs Donato 2026 (unclear) on immune	null vs positive (notable)
agreement	1	Pepine 2026	Nguyen 2026	contextual other	Pepine 2026 (null) vs Nguyen 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Pepine 2026	Li 2026	contextual other	Pepine 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Pepine 2026	Meltzer 2026	contextual other	Pepine 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
null vs positive	3	Nguyen 2026	Li 2026	contextual other	Nguyen 2026 (null) vs Li 2026 (positive) on contextual other	null vs positive (notable)
null vs positive	3	Nguyen 2026	Meltzer 2026	contextual other	Nguyen 2026 (null) vs Meltzer 2026 (negative) on contextual other	null vs positive (notable)
disagreement	4	Beydon 2026	Ngcobo 2026	dosing pharmacokinetics	Beydon 2026 (unclear) vs Ngcobo 2026 (mixed) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Beydon 2026	Wang 2026	dosing pharmacokinetics	Beydon 2026 (unclear) vs Wang 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Beydon 2026	Calderin 2025	dosing pharmacokinetics	Beydon 2026 (unclear) vs Calderin 2025 (null) on dosing pharmacokinetics	null vs positive (notable)
disagreement	5	Li 2026	Meltzer 2026	contextual other	Li 2026 (positive) vs Meltzer 2026 (negative) on contextual other	disagreement (load-bearing)
disagreement	4	Ngcobo 2026	Wang 2026	dosing pharmacokinetics	Ngcobo 2026 (mixed) vs Wang 2026 (null) on dosing pharmacokinetics	disagreement (load-bearing)
disagreement	4	Ngcobo 2026	Calderin 2025	dosing pharmacokinetics	Ngcobo 2026 (mixed) vs Calderin 2025 (null) on dosing pharmacokinetics	disagreement (load-bearing)
null vs positive	3	Zhu 2026b	Porri 2026	immune	Zhu 2026b (unclear) vs Porri 2026 (null) on immune	null vs positive (notable)
null vs positive	3	Zhu 2026b	Sikora 2026	immune	Zhu 2026b (unclear) vs Sikora 2026 (null) on immune	null vs positive (notable)
agreement	1	Zhu 2026b	Levenson 2026	immune	Zhu 2026b (unclear) vs Levenson 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Zhu 2026b	Mekhora 2026	immune	Zhu 2026b (unclear) vs Mekhora 2026 (null) on immune	null vs positive (notable)
agreement	1	Zhu 2026b	Donato 2026	immune	Zhu 2026b (unclear) vs Donato 2026 (unclear) on immune	agreement (minor)
agreement	1	Porri 2026	Sikora 2026	immune	Porri 2026 (null) vs Sikora 2026 (null) on immune	agreement (minor)
null vs positive	3	Porri 2026	Mokhsin 2026	immune	Porri 2026 (null) vs Mokhsin 2026 (negative) on immune	null vs positive (notable)
null vs positive	3	Porri 2026	Levenson 2026	immune	Porri 2026 (null) vs Levenson 2026 (unclear) on immune	null vs positive (notable)
null vs positive	3	Porri 2026	Zhao 2026	immune	Porri 2026 (null) vs Zhao 2026 (negative) on immune	null vs positive (notable)
agreement	1	Porri 2026	Mekhora 2026	immune	Porri 2026 (null) vs Mekhora 2026 (null) on immune	agreement (minor)
null vs positive	3	Porri 2026	Donato 2026	immune	Porri 2026 (null) vs Donato 2026 (unclear) on immune	null vs positive (notable)
null vs positive	3	Sikora 2026	Mokhsin 2026	immune	Sikora 2026 (null) vs Mokhsin 2026 (negative) on immune	null vs positive (notable)
null vs positive	3	Sikora 2026	Levenson 2026	immune	Sikora 2026 (null) vs Levenson 2026 (unclear) on immune	null vs positive (notable)
null vs positive	3	Sikora 2026	Zhao 2026	immune	Sikora 2026 (null) vs Zhao 2026 (negative) on immune	null vs positive (notable)
agreement	1	Sikora 2026	Mekhora 2026	immune	Sikora 2026 (null) vs Mekhora 2026 (null) on immune	agreement (minor)
null vs positive	3	Sikora 2026	Donato 2026	immune	Sikora 2026 (null) vs Donato 2026 (unclear) on immune	null vs positive (notable)
agreement	1	Mokhsin 2026	Zhao 2026	immune	Mokhsin 2026 (negative) vs Zhao 2026 (negative) on immune	agreement (minor)
null vs positive	3	Mokhsin 2026	Mekhora 2026	immune	Mokhsin 2026 (negative) vs Mekhora 2026 (null) on immune	null vs positive (notable)
agreement	1	Wang 2026	Calderin 2025	dosing pharmacokinetics	Wang 2026 (null) vs Calderin 2025 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Levenson 2026	Mekhora 2026	immune	Levenson 2026 (unclear) vs Mekhora 2026 (null) on immune	null vs positive (notable)
agreement	1	Levenson 2026	Donato 2026	immune	Levenson 2026 (unclear) vs Donato 2026 (unclear) on immune	agreement (minor)
null vs positive	3	Zhao 2026	Mekhora 2026	immune	Zhao 2026 (negative) vs Mekhora 2026 (null) on immune	null vs positive (notable)
null vs positive	3	Mekhora 2026	Donato 2026	immune	Mekhora 2026 (null) vs Donato 2026 (unclear) on immune	null vs positive (notable)

Table 4 (supplemental): Design-Level Evidence Weighting Heuristic

Per-domain grades are derived from each study's evidence tier (A1/A2/B1/B2/C1/C2) — they capture design-level limitations, NOT a formal per-paper risk-of-bias assessment from the source text. Domains follow design-family categories for randomized, observational, animal, and systematic-review evidence; n/a indicates the domain is not meaningful for that design (e.g. blinding for an observational cohort). The Weight in synthesis column is the qualitative weighting the synthesis applies to each source — derived from tier × directness × overall RoB.

Citation	Tier	Tool	Allocation	Blinding	Attrition	Outcome measurement	Reporting	Confounding control	Generalizability	Overall RoB	Weight in synthesis	Effect direction notes
Flensted-Jensen 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Saeed 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Zhu 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Navarese 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Yan 2024	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Alsulami 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Haibier 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Moawad 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Beydon 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Demir 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Hou 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Sriranjan-Rothwell 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Abassi 2026	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	primary endpoint did not reach significance
Madurasinghe 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Li 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Handono 2025	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	internal contradiction across endpoints
Yang 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Li 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Zheng 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	primary endpoint did not reach significance
Phyo 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Sikora 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Areia 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Stirum 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Zhang 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Liu 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
DAlise 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Ngcobo 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Bruun 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Gwenzi 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Huang 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Zhou 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Calderin 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Nguyen 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Mokhsin 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Lin 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Meltzer 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Khander 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Camargo 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Pepine 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Zhu 2026b	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Espinoza 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Ye 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Kanwal 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Hyun 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Sattui 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Wang 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
He 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Nouni-Garcia 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Ibrahim 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Husain 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Porri 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Levenson 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Zhao 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	negative effect — see Tables 1/2
Donato 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Lu 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Yerrabelli 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Mekhora 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	primary endpoint did not reach significance

Table 5 (supplemental): Per-Paper Numeric Index

Top-N quantitative claims per paper — the underlying corpus numerics that power Q2 trace and Q9 density. One row per (paper × claim) tuple, prioritised by claim type (p-value > percentage > ratio > unit-value).

Citation	Section	Type	Value	Units
Flensted-Jensen 2025	abstract	p-value	P < 0.05	—
Flensted-Jensen 2025	results	percentage	2.2%	%
Flensted-Jensen 2025	results	unit value	3.3 kg	kg
Flensted-Jensen 2025	results	mean ± SD	1.7 ± 2.2	—
Flensted-Jensen 2025	results	mean ± SD	1.7 ± 2.1	—
Yan 2024	results	unit value	34 weeks	weeks
Yan 2024	results	unit value	37 weeks	weeks
Beydon 2026	abstract	percentage	36%	%
Sriranjan-Rothwell 2026	abstract	p-value	P = 0.015	—
Sriranjan-Rothwell 2026	abstract	percentage	7.7%	%
Sriranjan-Rothwell 2026	abstract	percentage	95%	%
Sriranjan-Rothwell 2026	abstract	percentage	8.3%	%
Sriranjan-Rothwell 2026	abstract	p-value	P = 0.009	—
Abassi 2026	discussion	unit value	10 weeks	weeks
Handono 2025	abstract	p-value	P = 0.06	—
Handono 2025	abstract	hazard ratio	HR: 1.00	—
Handono 2025	abstract	confidence interval	95% CI: 0.92-1.07	95%CI
Handono 2025	abstract	hazard ratio	HR: 1.00	—
Handono 2025	abstract	confidence interval	95% CI: 0.94-1.07	95%CI
Li 2025	results	p-value	P < 0.001	—
Li 2025	results	percentage	2.9%	%
Li 2025	results	percentage	7.5%	%
Li 2025	results	percentage	95%	%
Zheng 2026	results	confidence interval	95% CI 0.54 to 0.93	95%CI
Zheng 2026	results	confidence interval	95% CI 1.11 to 1.77	95%CI
Zheng 2026	results	confidence interval	95% CI 1.02 to 3.38	95%CI
Zheng 2026	results	confidence interval	95% CI 0.41 to 0.93	95%CI
Zheng 2026	results	confidence interval	95% CI 0.26 to 0.75	95%CI
Phyo 2025	abstract	unit value	4.7 years	years
Phyo 2025	abstract	confidence interval	95% CI: -0.004 to 0.005	95%CI
Phyo 2025	abstract	confidence interval	95% CI: -0.010 to 0.001	95%CI
Phyo 2025	introduction	unit value	4.7 years	years
Sikora 2026	results	p-value	P < 0.01	—
Sikora 2026	results	unit value	8 weeks	weeks
Sikora 2026	results	p-value	P < 0.01	—
Sikora 2026	results	p-value	P < 0.01	—
Sikora 2026	results	p-value	P < 0.01	—
Meltzer 2026	discussion	p-value	P = 0.01	—
Meltzer 2026	discussion	percentage	95%	%
Meltzer 2026	discussion	percentage	95%	%
He 2026	discussion	unit value	50 years	years
Ibrahim 2026	abstract	hazard ratio	HR: 0.60	—
Ibrahim 2026	abstract	confidence interval	95% CI 0.45-0.82	95%CI
Ibrahim 2026	abstract	hazard ratio	HR: 0.65	—
Ibrahim 2026	abstract	confidence interval	95% CI 0.49-0.88	95%CI
Levenson 2026	abstract	percentage	0.05%	%
Levenson 2026	abstract	unit value	3 weeks	weeks
Zhao 2026	abstract	p-value	P = 0.003	—
Zhao 2026	abstract	percentage	42.9%	%
Donato 2026	abstract	confidence interval	95% CI 1.75-2.82	95%CI
Donato 2026	abstract	confidence interval	95% CI 2.70-4.38	95%CI
Lu 2026	abstract	unit value	30 mg/kg/day	mg/kg/day
Mekhora 2026	abstract	p-value	P = 0.03	—

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Li 2025. Differential Effect of Ticagrelor Versus Clopidogrel by Causative Classification of Stroke Classification and Vascular Cellular Adhesion Molecule‐1 Level on the Risk of Recurrent Stroke: A Post Hoc Analysis of the CHANCE‐2 Trial. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.125.042259. PMID: 41413755.
Zheng 2026. Efficacy and safety of off-label low-dose compared with standard-dose antiplatelet agents in patients with coronary heart disease: a meta-analysis. Open Heart, 2026. DOI: 10.1136/openhrt-2025-003839. PMID: 41617356.
Phyo 2025. Effect of aspirin on grip strength and gait speed in community-dwelling older adults in the ASPirin in Reducing Events in the Elderly (ASPREE) Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2025. DOI: 10.1093/gerona/glaf198. PMID: 40929147.
Sikora 2026. Long-term anakinra therapy in Schnitzler syndrome: real-world evidence on remission of neutrophilic dermatitis and systemic inflammation, safety, biomarker insights and dose optimization. Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1830866. PMID: 42158864.
Areia 2025. Modulation of Immune Cells by Aspirin During Pregnancy. Immunology, 2025. DOI: 10.1111/imm.70051. PMID: 41087834.
Stirum 2026. Long‐term child outcomes after prenatal aspirin exposure: A 4‐year follow‐up of a randomized controlled trial (the APRIL study). International Journal of Gynaecology and Obstetrics, 2026. DOI: 10.1002/ijgo.70581. PMID: 41137531.
Zhang 2026. Preprocedural systemic immune-inflammation index predicts atrial fibrillation recurrence after catheter ablation: A systematic review and meta-analysis. Biomolecules and Biomedicine, 2026. DOI: 10.17305/bb.2026.13614. PMID: 41637736.
Liu 2026. The Efficacy and Safety of Indobufen-Based DAPT in ACS Patients with a History of Gastrointestinal Damage Undergoing PCI: A Single-Center, Observational Study. Clinical and Applied Thrombosis/Hemostasis, 2026. DOI: 10.1177/10760296251408060. PMID: 41729598.
DAlise 2026. Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial. Nature Medicine, 2026. DOI: 10.1038/s41591-025-04182-9. PMID: 41545594.
Ngcobo 2026. The impact of low‐dose aspirin on hemoglobin levels in pregnancy: A secondary analysis of a randomized controlled trial for prevention of hypertensive disorders of pregnancy. International Journal of Gynaecology and Obstetrics, 2026. DOI: 10.1002/ijgo.70710. PMID: 41321324.
Bruun 2025. No Effect of Low‐Dose Aspirin Versus Placebo as Add‐On Treatment in Bipolar Disorder—Results From a Randomised Controlled Trial (the A‐Bipolar RCT). Acta Psychiatrica Scandinavica, 2025. DOI: 10.1111/acps.70055. PMID: 41319159.
Gwenzi 2026. Effects of personalized vitamin D 3 on inflammation in colorectal cancer patients: a randomized trial. British Journal of Cancer, 2026. DOI: 10.1038/s41416-025-03333-6. PMID: 41507560.
Huang 2026. Effects of exercise intensity and volume on systemic inflammation in overweight and obese postmenopausal women: a dose-response meta-analysis. Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1801309. PMID: 41939882.
Zhou 2026. Mediterranean diet with high-phenolic EVOO slows kidney function decline and reduces inflammation in nondialysis CKD: a meta-analysis. Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1792390. PMID: 41847236.
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Background References

Canonical clinical thresholds cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

Studenski 2011. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58. DOI: 10.1001/jama.2010.1923. PMID: 21205966.
Cruz-Jentoft 2019. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31. DOI: 10.1093/ageing/afy169. PMID: 30312372.

Proof Trail

Decision: AcceptLiving evidence briefGate failures: 0

Topic: research

Author: Dominic Lynch

Author ORCID: 0009-0005-4286-8363

Institution: not supplied

ROR: not supplied

RAiD: not supplied

OSF DOI: 10.17605/OSF.IO/JQG95

AI co-writer: agent-v3-full-paper

Reviewer: reviewer-panel

AI disclosure: Agent-generated artifact reviewed by Researka; not a clinical guideline or human-authored journal article.

Integrity check: not recorded

Published: May 27, 2026

Provenance chain: Available → View

SHA-256: sha256:088139d96ab...

Publication ID: 4ff5f065-8b09-4580...

Machine-readable exports

Claim Cards Passport JSON RO-Crate JSON

RESEARKA

Research Synthesis: Aspirin Geroprotection

Certification Timeline

Abstract

Review Summary

Evidence Transparency

Living Evidence Brief

Research Question

Search Summary

Review type and protocol

Information sources

Search strategy

Eligibility criteria

Selection of sources of evidence

source admission funnel

Exclusion reasons

Data items

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

Evidence Landscape

Cardiometabolic Outcomes

Contextual / ancillary Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Safety and Comorbidity Outcomes

Frailty Outcomes

Longevity Outcomes

Skeletal, Fracture, and Bone Outcomes

Key Findings

Cardiometabolic Outcomes

Contextual / ancillary Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Safety and Comorbidity Outcomes

Frailty Outcomes

Longevity Outcomes

Skeletal, Fracture, and Bone Outcomes

Limitations

Gaps Identified

Interpretation constraints

Confidence calibration

Conclusion

Research Synthesis: Aspirin Geroprotection

Abstract

Introduction

Background

Methods

Review type and protocol

Information sources

Search strategy

Eligibility criteria

Selection of sources of evidence

source admission funnel

Exclusion reasons

Data items

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

Results

Cardiometabolic Outcomes

Contextual / ancillary Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Safety and Comorbidity Outcomes

Frailty Outcomes

Longevity Outcomes

Skeletal, Fracture, and Bone Outcomes

Cross-Domain Synthesis

Endpoint-Sensitivity Framework

Discussion

Interpretation constraints

Confidence calibration

Limitations

Conclusion