{"publication_id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","screening":{"identified":71,"screened":71,"excluded":0,"included":71,"included_or_retained":71,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"71 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 Arbs Longevity and human geroscience? This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. 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","Mechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).","Mechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.","Quantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.","A tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.","Quantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).","Mechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).","Within the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).","A tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.","The evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).","Mechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.","Mechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025)."]}