{"publication_id":"9463fc73-49d4-41ec-b5f7-3087cedcb952","screening":{"identified":27,"screened":27,"excluded":0,"included":27,"included_or_retained":27,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"27 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":["Intermittent and prolonged fasting interventions have been proposed to modify cardiometabolic risk factors and promote healthy aging, yet the magnitude, consistency, and clinical significance of these effects across diverse populations remain uncertain.","Critically, cross-study disagreements were identified across the evidence base, with severity-4 disagreements between mixed-effect meta-analyses and positive-effect trials indicating that the fasting-effects cardiometabolic signal is context-dependent rather than uniform.","The global burden of age-related chronic disease has intensified interest in interventions that target fundamental biology rather than individual pathologies. Aging is the dominant risk factor for cardiovascular disease, metabolic dysfunction, neurodegeneration, and cancer, yet few therapeutic strategies address the underlying cellular processes that link these conditions. Fasting effects—encompassing intermittent fasting (IF), time-restricted eating (TRE), prolonged water-only fasting, and fasting-mimicking diets (FMDs)—have emerged as a candidate class with broad public accessibility and minimal regulatory barriers. The question of whether fasting effects can meaningfully extend human healthspan or lifespan remains unresolved, despite exponential growth in clinical investigation over the past decade. Understanding the scope and limitations of this evidence base is critical, given that millions of adults worldwide already practice some form of voluntary caloric restriction based on preliminary or mechanistic findings.","The geroscience hypothesis proposes that targeting the biological hallmarks of aging—cellular senescence, mitochondrial dysfunction, autophagy impairment, nutrient-sensing dysregulation—could simultaneously delay or prevent multiple age-related diseases. Fasting effects appear to engage several of these pathways, including AMPK activation, mTOR inhibition, and enhanced autophagic flux, positioning them as mechanistically plausible geroprotectors. This framework suggests that rather than developing novel pharmacological agents for each disease, repurposing behavioral interventions like fasting effects could offer a scalable anti-aging strategy with fewer off-target effects. However, it has been proposed that the translation from mechanistic promise to clinical benefit is far from guaranteed, as the magnitude and durability of these biological responses in humans remain uncertain. The tension between preclinical enthusiasm and clinical ambiguity is a defining feature of the fasting effects literature.","The regulatory and clinical history of fasting is unusual: it requires no prescription, carries no patent exclusivity, and has been practiced across cultures for millennia, yet its evidence base for health outcomes has only recently been subjected to systematic evaluation. Evidence suggests that the appeal of fasting effects lies partly in this accessibility, but the heterogeneity of protocols, durations, and comparators complicates synthesis. Whether fasting-mimicking formulations that replicate fasting biochemistry without complete food deprivation offer a more standardized therapeutic avenue remains an open empirical question.","Several unresolved questions constrain the clinical translation of fasting effects for aging populations. Third, the mechanistic translation problem persists: a fasting-mimicking diet was associated with a decrease of 2.5 years in median biological age using a validated algorithm (Brandhorst 2024), yet whether this surrogate endpoint predicts actual healthspan extension is unknown (Ioannidis 2005). Finally, the question of whether fasting effects interact with polypharmacy, frailty, or comorbid conditions common in aging has received almost no systematic investigation.","This synthesis addresses the fragmented evidence for fasting effects by applying structured evidence weighting across 27 curated reference papers spanning cardiometabolic, cognitive, anthropometric, safety, and functional outcomes. The evidence base reveals a context-dependent profile: positive signals emerge primarily in cardiometabolic domains, while null findings dominate in contextual and deficiency-prevalence outcomes. Across outcome classes, the synthesis identifies cross-study disagreements—including severity-level-4 disagreements between reviews reporting mixed effects and those reporting null effects—underscoring the heterogeneity that limits confident clinical recommendation. We separate mechanistic evidence from clinical trial evidence throughout, recognizing that fasting effects' biological plausibility (autophagy induction, metabolic switching, reduced oxidative stress) does not automatically translate to patient-relevant benefit. The fasting effects anti-aging case as currently constituted appears incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions under which fasting may benefit or harm older adults remain to be established.","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.","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.","Mechanistically, the positive signals from clinical RCTs like Burns 2025 suggest that periods of nutrient deprivation, even when mimicked by a low-calorie diet, can transiently improve glucose homeostasis and lipid profiles. This aligns with proposed pathways involving enhanced insulin sensitivity and metabolic switching. However, the null findings from meta-analyses like Wang 2025 indicate that these acute benefits may not consistently translate into long-term changes in body composition when compared to control diets. The review by Couto-Alfonso 2026, which found mixed effects with multiple significant p-values (e.g., P = 0.001, P < 0.001) across its included studies, underscores that the cardiometabolic benefits of IF may be highly dependent on the specific protocol, population, and comparator used.","Within the corpus, clear tensions exist regarding the strength and consistency of cardiometabolic evidence. The positive effect direction reported by Qudah 2026 and Burns 2025 contrasts with the null findings of Wang 2025 and the mixed conclusions of several meta-analyses. Furthermore, the RCT by Grant 2025, which found a novel fasting mimetic reduced total and LDL cholesterol (P < 0.05), presents an alternative intervention approach whose findings are not directly comparable to the dietary IF protocols synthesized in the other reviews, highlighting the heterogeneous nature of the evidence base.","A clear tension exists within the corpus regarding the magnitude and consistency of effects. By contrast, several other reports, including those synthesizing shorter-duration or intermittent protocols, found null or mixed effects (Dai 2025, Wen 2026, Camli 2026). This disagreement is further illustrated by the null effect direction assigned to Gabriel 2024, which contrasts with the positive or mixed signals in Scharf 2022 and Chen 2022. The tension between the positive findings in prolonged fasting cohorts and the null or unclear findings in many systematic reviews and other cohorts underscores the critical influence of fasting duration and protocol design on outcomes."]}