{"publication_id":"e64257d3-7980-4e68-9b2d-12e06cf91b11","content_hash":"sha256:d1081645009b2a6aa6825e72470f8d186d685428562cb2bd0eafc9ae85566a8a","nodes":[{"id":"e64257d3-7980-4e68-9b2d-12e06cf91b11","type":"publication","title":"Research Synthesis: Fasting Regimens — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 11/14 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_2","type":"claim","text":"This paper synthesizes evidence on fasting regimens across 14 included source papers and 557 high-confidence extracted claims."},{"id":"claim_3","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 3 mechanistic or model-system sources, with 8 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, cardiometabolic and deficiency prevalence outcome classes, and negative signals cluster in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that fasting regimens should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_6","type":"claim","text":"This manuscript is reported as a Evidence brief. 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-fasting_regimens-v06-DAILY-2026-06-16T19-52-05Z`."},{"id":"claim_7","type":"claim","text":"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. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_8","type":"claim","text":"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)."},{"id":"claim_9","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_10","type":"claim","text":"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."},{"id":"claim_11","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_12","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_13","type":"claim","text":"| Contextual Adjacent Evidence | n=10; claims=418 | no extracted directional signal in 8/10 sources | 5 indirect; 1 mechanistic; 4 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_15","type":"claim","text":"10 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=8. Directness coding: indirect=5, mechanistic=1, review=4."},{"id":"claim_16","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: mechanistic=2, review=1."},{"id":"claim_17","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1."},{"id":"claim_18","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_19","type":"claim","text":"The corpus assembled for this synthesis is dominated by short-duration, indirect-outcome designs and does not contain a definitive long-term mortality or hard-cardiovascular-endpoint randomized trial of any fasting regimen in non-diabetic older adults. Monda 2026 reported a population descriptor of 12 months. Several entries that would normally be expected in a mature evidence base — large pragmatic trials of time-restricted eating in primary-prevention cardiometabolic cohorts, head-to-head regimen comparisons with hard endpoints, and adequately powered trials in frail or sarcopenic populations — are absent. The eight partial conflicts catalogued in the cross-study disagreement map, all of which are between Monda 2026 and a null or mixed finding from a different design, reflect this gap: without a long-horizon randomized anchor, the corpus cannot adjudicate whether the negative signals on contextual endpoints in Monda 2026 will attenuate, persist, or amplify with extended follow-up. Consequently, the headline conclusion that the Fasting anti-aging case is \"incomplete\" is a direct consequence of the trial record itself, not a rhetorical hedge; the missing study designs are the missing page of the evidence base, and the synthesis cannot manufacture them."},{"id":"claim_20","type":"claim","text":"Several clinically relevant outcomes are touched by only a single source, which means they cannot be triangulated within the corpus and should be treated as hypothesis-generating rather than as synthesis-level findings. Shi 2025 is the sole source for the time-restricted-fasting + nicotinamide-mononucleotide combination on exercise capacity, and the underlying experiment is murine. Quan 2025 stands alone for the alternate-day-fasting / intestinal-epithelial-function claim in aging, again in animal tissue. Luciano 2026 provides the only genetic-modulation analysis of fasting-induced longevity, restricted to ten Collaborative Cross inbred mouse strains. Wang 2025 is the only entry anchoring adipose inositol monophosphate metabolism as a candidate mediator. When an outcome is supported by exactly one source, any single methodological caveat in that source — sample size, indirectness label, or population mismatch — propagates unchecked into the synthesis, and the reader should not interpret convergence across paragraphs as independent replication. The cross-study disagreement map further compounds this risk because several of the eight null-vs-negative conflicts are between Monda 2026 and a mechanistically adjacent but non-overlapping dataset, so within-corpus replication is structurally unavailable for the most contested claims."},{"id":"claim_21","type":"claim","text":"The population specificity of the included sources narrows external validity in several clinically important directions. Monda 2026 enrolled adults with obesity and a BMI at or above the WHO 2000 obesity threshold, which limits generalization to normal-weight, metabolically healthy, or older underweight adults who might in principle benefit from — or be harmed by — fasting-induced sarcopenia. Jiao 2026 restricts its synthesis to middle-aged adults with overweight or obesity and does not provide stratum-specific estimates for older adults — the very population in which age-related gait-speed decline of approximately 0.05 m/s (Bohannon 1997) and sarcopenia cutoffs of 27 kg for men and 16 kg for women (Cruz-Jentoft 2019) would be the relevant functional endpoints. Trials in adolescents, pregnant or lactating women, patients with chronic kidney disease or hepatic impairment, and adults with established eating-disorder risk are not represented, and the corpus offers no randomized evidence in frail older adults whose gait speed has already fallen below the 0.8 m/s mobility-risk threshold (Studenski 2011) or the 0.6 m/s severe-frailty cutoff (Cesari 2009). The translation of any headline effect to these groups is therefore a projection, not an inference supported by the curated data."},{"id":"claim_22","type":"claim","text":"Several of the most attractive claims in the synthesis are supported only by mechanistic or preclinical evidence and therefore carry a documented mechanism-to-clinic gap. The synaptic-function and α-synuclein findings in Maleki 2026 are restricted to an acute amyloid-β rat model and cannot be transported to human Alzheimer disease prevention without an intermediate human biomarker study. Parnas 2026 frames β-hydroxybutyrate signaling and chromatin remodeling as cytoprotective, but its tissue source is murine and the eight p-values highlighted in the sources (e.g., P = 0.0025, P = 0.0161) describe molecular rather than clinical readouts. Zhang 2026 uses a persimthan-tannin mimetic of alternate-day fasting in obese mice, which adds an additional translational layer. Shi 2025 again is murine for the NMN-augmented time-restricted feeding signal. Across these entries, the synthesis is forced to report mechanism, not clinical effect, and the reader should not interpret the P < 0.01 and P < 0.001 results in the preclinical sources as evidence that any human anti-aging endpoint will move in the corresponding direction. Until the mechanistic findings are paired with adequately powered human trials on hard endpoints, the mechanism-to-clinic distance remains a binding limitation of every claim the synthesis puts forward."},{"id":"claim_23","type":"claim","text":"Across the 14 curated references, the evidence base for fasting regimens as an anti-aging or geroprotective intervention remains context-dependent rather than consolidated, and the integrating thesis — that mechanistic plausibility coexists with mixed or sparse human-RCT evidence, with boundary conditions still to be established — is supported by the weight of the sources. A central unresolved question, and one that the available sources do not answer, is whether surrogate-endpoint improvements observed over the typical 3–12 month follow-up windows translate into hard outcomes such as incident frailty, sarcopenia, or mortality, a caution consistent with the broader methodological concern that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005)."},{"id":"claim_24","type":"claim","text":"For clinical practice today, the current evidence does not support marketing intermittent fasting, time-restricted feeding, or alternate-day fasting as a proven standalone anti-aging or geroprotective intervention, and pending further trials with hard endpoints in older adults, any off-label geroprotective use of these regimens should be considered investigational; this boundary is consistent with the pattern of mixed findings and the dominance of null or surrogate-only results in the sources. The evidence does support a hypothesis that fasting regimens may yield modest improvements in intermediate cardiometabolic markers in selected adults, particularly those with overweight, obesity, or metabolic syndrome, but the magnitude and durability of these effects across age strata, sexes, and genotypes remain to be confirmed (Xing 2026; Song 2025). General-health guidance — that adults who already wish to adopt a time-restricted eating pattern and tolerate it well can do so as one of several reasonable dietary approaches — is a separate question from claiming an evidence-based anti-aging effect, and clinicians should distinguish between these two framings when counseling patients. In short, the practice message is conservative: support tolerated, patient-preferred dietary patterns as part of standard cardiometabolic and general-health counseling, but do not promote fasting regimens as a validated anti-aging therapy outside the context of registered clinical trials."},{"id":"claim_25","type":"claim","text":"This synthesis maps 14 included sources on Fasting across 3 outcome classes and 8 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."},{"id":"claim_26","type":"claim","text":"Across 14 curated reference papers, the evidence base for Fasting shows a context-dependent profile. Negative signals appear in: contextual other. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Fasting 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."},{"id":"claim_27","type":"claim","text":"The strongest unresolved contrast is the null vs negative between Msane 2024 and Monda 2026 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_28","type":"claim","text":"Prior reviews in the corpus (Song 2025) emphasize convergent signals on Fasting. 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."},{"id":"claim_29","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"claim_30","type":"claim","text":"| cardiometabolic | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |"},{"id":"source_1","type":"source","study":"Metabolic and Orexin-A Responses to Ketogenic Diet and Intermittent Fasting: A 12-Month Randomized Trial in Adults with Obesity","year":2026,"doi":"10.3390/nu18020238","url":"https://doi.org/10.3390/nu18020238","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_2","type":"source","study":"Age-Specific Analysis of the Effects of Intermittent Fasting on Body Composition and Cardiometabolic Markers in Healthy Adults and Individuals with Overweight or Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","year":2026,"doi":"10.3390/nu18111799","url":"https://doi.org/10.3390/nu18111799","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_3","type":"source","study":"Intermittent fasting improves metabolic outcomes in metabolic syndrome: a systematic review and meta-analysis with GRADE evaluation","year":2025,"doi":"10.3389/fnut.2025.1664811","url":"https://doi.org/10.3389/fnut.2025.1664811","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_4","type":"source","study":"Time‐Restricted Feeding Preserves Synaptic Function and Modulates Reelin and α ‐Synuclein in an Acute Amyloid‐ β Rat Model: A Comparative Study With Alternate‐Day Fasting","year":2026,"doi":"10.1155/jnme/7185647","url":"https://doi.org/10.1155/jnme/7185647","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_5","type":"source","study":"Optimal dosage of exercise combined with intermittent fasting for body composition and cardiometabolic health in adults: a systematic review and multilevel meta-analysis","year":2026,"doi":"10.3389/fnut.2026.1772836","url":"https://doi.org/10.3389/fnut.2026.1772836","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_6","type":"source","study":"The effectiveness of fasting regimens on serum levels of some major weight regulating hormones: a GRADE-assessed systematic review and meta-analysis in randomized controlled trial","year":2025,"doi":"10.1186/s41043-025-00834-1","url":"https://doi.org/10.1186/s41043-025-00834-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_7","type":"source","study":"Effects of Time-Restricted Fasting–Nicotinamide Mononucleotide Combination on Exercise Capacity via Mitochondrial Activation and Gut Microbiota Modulation","year":2025,"doi":"10.3390/nu17091467","url":"https://doi.org/10.3390/nu17091467","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_8","type":"source","study":"Intermittent Fasting Enhances Genome Integrity and Cytoprotective Pathways via (BHB) β‐Hydroxybutyrate Signaling and Chromatin Remodeling","year":2026,"doi":"10.1096/fj.202503534R","url":"https://doi.org/10.1096/fj.202503534R","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_9","type":"source","study":"Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle","year":2026,"doi":"10.7554/eLife.107332","url":"https://doi.org/10.7554/eLife.107332","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_10","type":"source","study":"Genetic regulation of fasting-induced longevity effects","year":2026,"doi":"10.1093/genetics/iyag045","url":"https://doi.org/10.1093/genetics/iyag045","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_11","type":"source","study":"Simulation Effect and Mechanism of High-Polymeric Persimmon Tannin on Simulating Alternate-Day Fasting on Regulating Lipid Metabolism in Obese Mice","year":2026,"doi":"10.3390/nu18101608","url":"https://doi.org/10.3390/nu18101608","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_12","type":"source","study":"Alternate Day Fasting Enhances Intestinal Epithelial Function During Aging by Regulating Mitochondrial Metabolism","year":2025,"doi":"10.1111/acel.70052","url":"https://doi.org/10.1111/acel.70052","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"Adipose Inositol Monophosphate Metabolism Is Associated with Fasting Regimen-Elicited Metabolic Benefits","year":2025,"doi":"10.3390/biom15111514","url":"https://doi.org/10.3390/biom15111514","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_14","type":"source","study":"Therapeutic Potential of Various Intermittent Fasting Regimens in Alleviating Type 2 Diabetes Mellitus and Prediabetes: A Narrative Review","year":2024,"doi":"10.3390/nu16162692","url":"https://doi.org/10.3390/nu16162692","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_15","type":"source","study":"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_16","type":"source","study":"**Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_17","type":"source","study":"**Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_18","type":"source","study":"**Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_19","type":"source","study":"Studenski 2011","year":null,"doi":"10.1001/jama.2010.1923","url":"https://doi.org/10.1001/jama.2010.1923","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_20","type":"source","study":"Cesari 2009","year":null,"doi":"10.1093/gerona/glp012","url":"https://doi.org/10.1093/gerona/glp012","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_21","type":"source","study":"Perera 2006","year":null,"doi":"10.1111/j.1532-5415.2006.00701.x","url":"https://doi.org/10.1111/j.1532-5415.2006.00701.x","population":"not 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