{"publication_id":"4ff5f065-8b09-4580-9cbc-da14dbcaa1fa","screening":{"identified":57,"screened":57,"excluded":0,"included":57,"included_or_retained":57,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"57 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["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","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.","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.","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.","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.","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.","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."]}