{"publication_id":"467ebee6-15d2-4907-bf9c-0b97ec47f608","screening":{"identified":65,"screened":65,"excluded":0,"included":65,"included_or_retained":65,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"65 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":["The conclusion is that statin use effects remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The global burden of age-related disease continues to mount as populations grow older, creating an urgent search for interventions that might compress morbidity and extend healthspan rather than merely treating individual conditions in isolation. Statins — 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors — occupy a unique position in this landscape because they are among the most widely prescribed medications worldwide, with an estimated hundreds of millions of patient-years of accumulated exposure, and their primary cardiovascular indications already encompass a large share of the older-adult population. Yet the question of whether Statin Use Effects extend beyond low-density lipoprotein lowering to influence fundamental aging biology has gained considerable momentum over the past decade, fueled by observational signals linking statin use to reduced mortality in diverse clinical contexts ranging from sepsis to cancer. Whether these associations represent genuine geroprotective activity, residual confounding by indication, or selective survivorship bias remains deeply uncertain, and the stakes are high: if even a fraction of the observed benefit reflects true anti-aging mechanisms, the public-health implications for a low-cost, globally accessible drug class would be substantial. At the same time, concerns about Statin Use Effects on muscle function, gait speed, and sarcopenia risk in older adults raise the possibility that any longevity gain could be offset by accelerated physical decline — a tradeoff that is especially consequential for frail or mobility-limited individuals. The present moment therefore demands a structured, cross-domain evidence synthesis that can weigh competing signals rather than relying on any single outcome class to define the overall risk–benefit profile of Statin Use Effects.","Several unresolved questions complicate efforts to draw definitive conclusions about Statin Use Effects as a geroprotective strategy, and these uncertainties span mechanistic plausibility, clinical translation, and population specificity. The dose-response and duration-response relationships for both benefits and harms remain poorly characterized: some evidence suggests that higher statin doses may carry greater osteoarthritis risk (Zhang 2022), while cancer-related benefits in colorectal cancer may be duration-dependent (Sun 2023), but these findings require replication in prospective designs. Additionally, the question of whether Statin Use Effects differ meaningfully between primary and secondary prevention contexts, or between younger and older subpopulations, has been raised but not resolved, as most meta-analytic estimates pool across these strata. Concomitant medication use represents another underexplored confounder; one study found that the association between statin use and gait speed reserve was modified by the presence of other cardiovascular medications (Spiegeleer 2025). Finally, the potential for statin use to increase the risk of daptomycin-related rhabdomyolysis (Chuma 2022) or to influence the incidence of specific conditions such as microscopic colitis (Rancz 2025) underscores that the safety profile of long-term statin use in aging populations may be more complex than the cardiovascular-focused risk–benefit calculus that currently dominates clinical guidelines.","The present synthesis aims to address these cross-domain tensions by applying a structured evidence-weighting framework that explicitly separates clinical-effect estimates from mechanistic rationale, and that maps the concordance or discordance of Statin Use Effects across multiple aging-relevant outcome classes simultaneously. Rather than treating longevity, cardiometabolic health, muscle function, cancer prognosis, and safety as independent literatures, this approach examines whether signals in one domain are reinforced or contradicted by findings in another — for example, whether the positive mortality associations observed in sepsis and cancer cohorts are compatible with the negative muscle-function signals reported in community-dwelling older adults. The synthesis draws on approximately 65 curated reference papers spanning observational cohorts, systematic reviews, and meta-analyses, and identifies hundreds of cross-study disagreements across outcome classes that collectively define the current evidence boundary for Statin Use Effects as an anti-aging intervention. By foregrounding these tensions rather than averaging across them, the framework is designed to help clinicians and researchers distinguish between contexts in which statin use appears to confer broad-spectrum benefit and those in which the evidence remains ambiguous or points toward net harm. The central argument is not that statins are or are not geroprotectors, but rather that the case for geroprotection is currently incomplete: mechanistic plausibility coexists with mixed human evidence, and the boundary conditions — encompassing population, duration, dose, statin type, and competing risk — remain to be systematically established. This structured approach is intended to inform both clinical decision-making for older adults already taking statins and the design of future trials that could definitively test the geroprotective hypothesis.","Preclinical and disease-model evidence suggests that statins modulate pathways relevant to aging biology, though effect directions vary by context. In colorectal cancer models, statin exposure has been associated with improved prognosis, including reduced all-cause mortality (HR: 0.80; 95% CI: 0.74-0.87) and cancer-specific mortality (HR: 0.74; 95% CI: 0.67-0.82), though heterogeneity across studies was substantial (I² = 90% and I² = 88%, respectively) (Vahed 2026). Prostate cancer analyses report a similar survival signal in men receiving androgen-deprivation therapy, with a pooled 27% reduction in overall mortality risk (Jayalath 2022). Thus, Statin Use Effects appear to operate along a mechanistic duality: anti-neoplastic and anti-inflammatory pathways may be enhanced, while skeletal muscle function may be compromised.","Methodological questions critically shape interpretation of the Statin Use Effects literature and illuminate the mechanism-to-clinic gap. Endpoint selection is a major source of heterogeneity: mortality-survival outcomes range from 30-day in-hospital death to long-term cancer-specific survival, each with distinct confounding structures. Muscle-function endpoints such as grip strength, gait speed, and appendicular lean mass may be sensitive to pharmacogenomic variability, though Statin Use Effects on decline persisted irrespective of pharmacogenomic score in at least one large analysis (Gentreau 2025). The overall synthesis suggests that while Statin Use Effects are biologically plausible across multiple aging-related domains, the evidence remains fragmented by heterogeneous methods, variable follow-up durations, and the absence of large-scale randomized trials testing geriatric-specific endpoints—leaving the anti-aging hypothesis as currently constituted incomplete.","Mechanistically, the anti-cancer effects of statins have been attributed to inhibition of the mevalonate pathway, which suppresses Rho GTPase signaling and may reduce tumor cell proliferation and metastatic potential. Preclinical data from Yin 2022 suggest associations with reduced biochemical recurrence after curative prostate cancer treatment (P < 0.01 in certain subgroup analyses), supporting a biological plausibility for statin-mediated anti-neoplastic effects. Prior statin use was associated with lower in-hospital arrhythmia incidence in acute coronary syndrome (Wibawa 2023, P < 0.00001). Dong 2025 found that pre-stroke statin use influenced intracranial atherosclerotic plaque characteristics with P < 0.001 for plaque burden differences.","Concomitant CPK elevations were observed, and the between-group difference at baseline reached statistical significance (P < 0.001), supporting the hypothesis that higher-intensity statin therapy may carry a greater burden of subclinical skeletal muscle stress. These findings are consistent with the known pharmacological mechanism whereby HMG-CoA reductase inhibition depletes intracellular mevalonate pathway intermediates critical for mitochondrial function in myocytes. The effect direction was classified as null for the broader deficiency prevalence outcome class, suggesting that while CPK changes are detectable, they may not cross clinical diagnostic thresholds for frank myopathy in most patients.","Mechanistically, statin-associated CPK elevation is hypothesized to stem from impaired CoQ10 biosynthesis and reduced mitochondrial electron transport chain efficiency, both downstream consequences of mevalonate pathway blockade. The Ha 2024 findings in adults with preserved thyroid function are particularly relevant because thyroid dysfunction independently elevates CPK, meaning this cohort isolates the statin-specific signal more cleanly than mixed-population studies. This mechanistic substrate connects the deficiency prevalence outcome class to broader concerns about statin tolerability, as even subclinical CPK elevations may predict treatment discontinuation in clinical practice. Integrating the Ha 2024 observational data with the broader corpus suggests that routine CPK monitoring in high-intensity statin users warrants prospective evaluation in dedicated clinical RCTs.","By contrast, the evidence base for statin-related muscle effects remains heterogeneous across the curated corpus, and the Ha 2024 null effect-direction classification for deficiency prevalence underscores a key tension: detectable biochemical CPK changes may not translate into clinically meaningful myopathy in population-level analyses. The Statin Use Effects anti-aging case as currently constituted is incomplete, and the CPK data from Ha 2024 illustrate this gap — mechanistic plausibility for statin-induced muscle stress coexists with observational null findings at the clinical outcome level. Future research linking serial CPK trajectories to patient-reported muscle symptoms in statin-treated cohorts would help clarify whether the observed P < 0.001 baseline differences carry downstream clinical relevance.","Mechanistically, the observed survival associations may relate to pleiotropic effects of statins beyond lipid lowering, including anti-inflammatory and immunomodulatory properties that could influence cancer progression and cardiovascular event rates. Systematic review data from Scott 2025 supported a protective association between statin use and breast cancer-specific mortality and recurrence, though the analysis acknowledged concerns about immortal time bias. Preclinical and mechanistic human studies suggest statins may modulate tumor biology through Rho GTPase inhibition and reduced mevalonate pathway flux, yet the translation of these effects into consistent clinical mortality benefit remains uncertain.","Quantitative findings across these cohorts were mixed. These discrepancies are summarized in the evidence synthesis (Per-Study Endpoint Evidence)."]}