Derivation Web

source_2d18d2ce895d43c5

by researka:v2 · 2026-07-30 16:22:21.036788+04:00

# Research Synthesis: Intermittent Fasting (IF)
## Abstract

Evidence scope: 55/66 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This paper synthesizes evidence on fasting intervention intermittent fasting if effects across 66 included source papers and 4278 high-confidence extracted claims.

The evidence profile contains 11 direct clinical sources, 55 adjacent, review, or context sources, and no sources classified primarily as mechanistic or model-system evidence, with a high-density pairwise disagreement map across the evidence base.

Positive study-level signals are summarized in the cardiometabolic, immune and inflammation outcome classes, null signals in the cardiometabolic, contextual adjacent evidence, immune and inflammation outcome classes, and negative signals in the cardiometabolic outcome class. The paper therefore reports a source-directness and outcome-class map rather than a pooled effect.

The conclusion is that fasting intervention intermittent fasting if effects remains a bounded evidence case: the retained direct, adjacent, and context evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified broad clinical claim.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint. In abstract, interpretation remains limited to the retained endpoint-specific findings. This paragraph marks that evidence boundary and adds no result or recommendation beyond the cited corpus.

## Research Question

Within the retained source corpus for intermittent fasting, among adults, do findings for cardiometabolic and contextual adjacent evidence support a decision-grade conclusion (clinically actionable where applicable), and which population, study-design, and directness boundaries keep extrapolation to other outcome classes hypothesis-generating?

## Introduction

This synthesis evaluates evidence on intermittent fasting across 66 included source papers and 4278 high-confidence extracted claims. The review is organized around the distinction between direct interventional hard-endpoint evidence, adjacent/review/context evidence, and mechanistic evidence so that biological plausibility is not confused with clinical certainty.

The corpus contains 11 direct clinical sources, 55 adjacent, review, or context sources, and no sources classified primarily as mechanistic or model-system evidence. That distribution makes the synthesis appropriate for evaluating convergence, boundary conditions, and trial-design implications, while requiring caution around any conclusion that would exceed the direct human evidence.

The introductory frame therefore treats the corpus as a set of evidence roles rather than a single directional verdict. Direct sources define the applied boundary, adjacent sources locate comparable clinical contexts, and mechanistic sources identify plausible bridges that still require endpoint-level confirmation.

This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.

The clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.

The mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof.

Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.

Adverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints.

The evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.

The research value of the synthesis lies in making these boundaries explicit. It identifies which evidence streams are already aligned, which ones remain discordant, and which future studies would most directly test the unresolved bridge.

## Background

The background evidence for intermittent fasting is heterogeneous rather than uniformly confirmatory.

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.

Across the retained sources, positive signals cluster around the cardiometabolic, immune and inflammation outcome classes; null signals around the cardiometabolic, contextual adjacent evidence, immune and inflammation outcome classes; and negative or adverse signals around the cardiometabolic outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.

Where coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.

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 another.

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.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

## Methods

### Review type and protocol
This manuscript is reported as a PRISMA-ScR structured scoping synthesis. 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_intervention_intermittent_fasting_if_effects-v06-DAILY-2026-07-30T12-16-43Z`.

### Information sources
Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-07-30.

### Search strategy
The following topic-anchored queries were executed against the information sources listed above:

- `fasting intervention intermittent fasting (IF) effects aging`
- `fasting intervention intermittent fasting (IF) effects older adults`
- `fasting intervention intermittent fasting (IF) effects randomized controlled trial`
- `fasting aging`
- `fasting older adults`
- `fasting randomized controlled trial`
- `intervention intermittent fasting (IF) aging`
- `intervention intermittent fasting (IF) older adults`
- `intervention intermittent fasting (IF) randomized controlled trial`

### Eligibility criteria
- Sources whose primary content addresses fasting intervention intermittent fasting if effects.
- Sources with extractable quantitative or qualitative findings.
- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

### Selection of sources of evidence
Of 66 records retrieved, 66 were screened against the eligibility criteria, 66 were included in the synthesis, and 0 were excluded at full-text review. Reasons for exclusion are summarised below.

### Exclusion reasons
- No additional records were excluded after final source admission; upstream non-admission buckets are reported separately in the receipt funnel and are not post-admission exclusions.

### Data items
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 sidecar when populated, and claim registry) rather than from re-parsed full text.

### Directness coding criteria
A source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources.

### Risk-of-bias appraisal
Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

### Synthesis approach
Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, muscle function, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

### AI-use disclosure
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.

### Accountability
Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

## Evidence Landscape

### Findings Map

Findings Map completeness note: all 66 admitted manifest rows are surfaced below; outcome class follows endpoint/source context before topic keywords.

Findings Map accounting note: each outcome-class n, direction count, directness count, and source roster is computed from the same source-level rows listed in the detailed table. Receipt-level direction is not a statement that the source abstracts lack directional statistics; it is the conservative coded polarity used for synthesis accounting. Outcome-class roster: Cardiometabolic n=41 (direction: mixed=4; negative=4; null=6; positive=4; unclear=23; directness: direct=8; indirect=8; protocol=2; review=23; sources: Abdollahpour 2025 [bundle:1]; Abdullah 2024 [bundle:18]; Barrionuevo-Burgos 2026 [bundle:61]; Barve 2025 [bundle:19]; Breit 2025 [bundle:26]; Chen 2024 [bundle:30]; Couto-Alfonso 2026 [bundle:3]; Cozma 2025 [bundle:57]; Dai 2025 [bundle:10]; Diab 2024 [bundle:59]; Grine 2022 [bundle:58]; Guo 2025 [bundle:25]; He 2026 [bundle:23]; Herz 2024 [bundle:6]; Hottenrott 2020 [bundle:21]; Huo 2025 [bundle:28]; Jiao 2026 [bundle:24]; Kang 2022 [bundle:12]; Karahan 2025 [bundle:35]; Kazeminasab 2024a [bundle:42]; Kazeminasab 2024b [bundle:47]; Khalafi 2024a [bundle:4]; Khalafi 2024b [bundle:45]; Khalafi 2025b [bundle:56]; Kibret 2025 [bundle:5]; Koh 2025 [bundle:29]; Li 2026 [bundle:11]; Lu 2025 [bundle:8]; Noda 2026 [bundle:16]; Obermayer 2022 [bundle:13]; Qudah 2026 [bundle:33]; Santos 2025 [bundle:54]; Semnani-Azad 2025 [bundle:17]; Silva 2023 [bundle:7]; Sourij 2026 [bundle:32]; Talebi 2023 [bundle:44]; Tay 2020 [bundle:14]; Varkaneh 2022 [bundle:9]; Wang 2025 [bundle:41]; Xiaoyu 2024 [bundle:49]; Xing 2026 [bundle:15]); Contextual Adjacent Evidence n=14 (direction: null=3; unclear=11; directness: direct=3; indirect=4; protocol=1; review=6; sources: AL-Dalaeen 2026 [bundle:36]; Alkurd 2024 [bundle:46]; Bamberg 2025 [bundle:39]; Couto 2025 [bundle:62]; Gu 2022 [bundle:20]; He 2023 [bundle:55]; James 2024 [bundle:27]; Karras 2025 [bundle:34]; Keenan 2022 [bundle:31]; Lin 2024 [bundle:63]; Liu 2026 [bundle:48]; Schmidt 2023 [bundle:53]; Vignera 2026 [bundle:37]; Washburn 2019 [bundle:66]); Immune and Inflammation n=5 (direction: null=2; positive=1; unclear=2; directness: indirect=2; protocol=1; review=2; sources: Ezzati 2022 [bundle:64]; Khalafi 2025a [bundle:38]; Lira-Junior 2024 [bundle:60]; Pappe 2025 [bundle:43]; Ranjbar 2024 [bundle:52]); Muscle Function n=3 (direction: mixed=1; unclear=2; directness: indirect=2; review=1; sources: Kazeminasab 2025 [bundle:2]; Khoshkebijari 2026 [bundle:22]; Valenzano 2025 [bundle:51]); Safety and Comorbidity n=2 (direction: unclear=2; directness: indirect=2; sources: Anic 2022 [bundle:40]; Damiani 2019 [bundle:65]); Deficiency Prevalence n=1 (direction: null=1; directness: protocol=1; sources: Karimi 2023 [bundle:50]) [exact source: https://doi.org/10.1038/s41598-025-32673-9] [exact source: https://doi.org/10.2196/51542] [exact source: https://doi.org/10.1177/02601060261446178] [exact source: https://doi.org/10.1038/s41467-025-66366-8] [exact source: https://doi.org/10.3390/nu17142385] [exact source: https://doi.org/10.1186/s12916-024-03716-1] [exact source: https://doi.org/10.3390/nu18091450] [exact source: https://doi.org/10.3390/biomedicines13123079] [exact source: https://doi.org/10.1007/s13679-025-00645-9] [exact source: https://doi.org/10.1007/s12013-024-01314-9] [exact source: https://doi.org/10.2196/26405] [exact source: https://doi.org/10.3389/fnut.2025.1664600] [exact source: https://doi.org/10.3389/fnut.2026.1818813] [exact source: https://doi.org/10.3390/nu16081114] [exact source: https://doi.org/10.3390/life10050074] [exact source: https://doi.org/10.31083/AP44384] [exact source: https://doi.org/10.3389/fnut.2026.1772836] [exact source: https://doi.org/10.3390/nu14224734] [exact source: https://doi.org/10.3390/life15050696] [exact source: https://doi.org/10.3389/fnut.2024.1362731] [exact source: https://doi.org/10.1093/nutrit/nuad155] [exact source: https://doi.org/10.1186/s12937-023-00909-x] [exact source: https://doi.org/10.1111/dom.15730] [exact source: https://doi.org/10.1111/obr.13855] [exact source: https://doi.org/10.1007/s13668-025-00684-7] [exact source: https://doi.org/10.3390/nu17101689] [exact source: https://doi.org/10.3389/fnut.2026.1833688] [exact source: https://doi.org/10.1186/s41043-025-01039-2] [exact source: https://doi.org/10.2196/58930] [exact source: https://doi.org/10.2337/dc22-1622] [exact source: https://doi.org/10.3389/fnut.2026.1699384] [exact source: https://doi.org/10.1210/jendso/bvaf149.2032] [exact source: https://doi.org/10.1136/bmj-2024-082007] [exact source: https://doi.org/10.3390/jcm12113699] [exact source: https://doi.org/10.1111/dme.70328] [exact source: https://doi.org/10.1186/s13063-023-07691-5] [exact source: https://doi.org/10.3390/nu12113530] [exact source: https://doi.org/10.3389/fnut.2022.948655] [exact source: https://doi.org/10.1186/s12937-025-01178-6] [exact source: https://doi.org/10.3389/fnut.2024.1325894] [exact source: https://doi.org/10.3390/nu18111799] [exact source: https://doi.org/10.1371/journal.pone.0345940] [exact source: https://doi.org/10.3390/medicina60010191] [exact source: https://doi.org/10.1177/13591053251351204] [exact source: https://doi.org/10.1016/j.numecd.2025.104132] [exact source: https://doi.org/10.3389/fnut.2022.871682] [exact source: https://doi.org/10.3389/fnut.2023.1048230] [exact source: https://doi.org/10.3390/nu16020316] [exact source: https://doi.org/10.3389/fendo.2025.1700844] [exact source: https://doi.org/10.3390/nu14153071] [exact source: https://doi.org/10.3389/fnut.2023.1328426] [exact source: https://doi.org/10.7717/peerj.21185] [exact source: https://doi.org/10.3389/fonc.2023.1222573] [exact source: https://doi.org/10.3390/nu18111817] [exact source: https://doi.org/10.3390/nu11020246] [exact source: https://doi.org/10.3390/nu14204299] [exact source: https://doi.org/10.3390/nu17152388] [exact source: https://doi.org/10.1002/jper.23-0676] [exact source: https://doi.org/10.1111/jcpe.14151] [exact source: https://doi.org/10.1186/s13063-024-07977-2] [exact source: https://doi.org/10.3390/nu17121992] [exact source: https://doi.org/10.1155/jobe/6409069] [exact source: https://doi.org/10.3390/nu17071121] [exact source: https://doi.org/10.3390/nu14194216] [exact source: https://doi.org/10.3390/nu11081781] [exact source: https://doi.org/10.1186/s40795-023-00794-x].

| Evidence domain | Source | Direction | Directness | Tier | Evidence role | Finding |
| --- | --- | --- | --- | --- | --- | --- |
| Cardiometabolic | Abdollahpour 2025: Comparative effects of intermittent fasting and calorie restriction on cardiovascular health in adults with overweight or obesity | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P < 0.05; source-level statistic reported |
| Cardiometabolic | Abdullah 2024: The Effect of a Combined Intermittent Fasting Healthy Plate Intervention on Anthropometric Outcomes and Body Composition Among Adults With Overweight and Obesity: Nonrandomized Controlled Trial | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P <.001; source-level statistic reported |
| Cardiometabolic | Barrionuevo-Burgos 2026: Effects of intermittent fasting combined with a ketogenic diet versus a hypocaloric diet on metabolic outcomes in adults with type 2 diabetes mellitus: A controlled clinical study | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=3 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Barve 2025: Cardiometabolic and molecular adaptations to 6-month intermittent fasting in middle-aged men and women with overweight: secondary outcomes of a randomized controlled trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=73 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Breit 2025: Effects of 4:3 Intermittent Fasting on Eating Behaviors and Appetite Hormones: A Secondary Analysis of a 12-Month Behavioral Weight Loss Intervention | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=55 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Chen 2024: Effects of different types of intermittent fasting on metabolic outcomes: an umbrella review and network meta-analysis | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=46 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Couto-Alfonso 2026: Intermittent Fasting and Healthy Aging in Older Adults: A Systematic Review of Cardiometabolic, Mental Health and Cognitive Outcomes with a Network Meta-Analysis of Anthropometric Measures | direction=mixed | directness=review | B1 | outcome=Cardiometabolic; direction=mixed | finding=263 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Cozma 2025: Added Value to GLP-1 Receptor Agonist: Intermittent Fasting and Lifestyle Modification to Improve Therapeutic Effects and Outcomes | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=7 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Dai 2025: Additional Effect of Exercise to Intermittent Fasting on Body Composition and Cardiometabolic Health in Adults With Overweight/obesity: A Systematic Review and Meta-analysis | direction=unclear | directness=review | B2 | outcome=Cardiometabolic; direction=unclear | finding=122 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Diab 2024: Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health | direction=null | directness=indirect | B2 | outcome=Cardiometabolic; direction=null | finding=5 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Grine 2022: The Effects of Modified Intermittent Fasting in Psoriasis (MANGO): Protocol for a Two-Arm Pilot Randomized Controlled Open Cross-over Study | direction=null | directness=protocol | D1 | outcome=Cardiometabolic; direction=null | finding=7 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Guo 2025: Comprehensive impact of Intermittent Hypoxia Training and Intermittent Fasting on metabolic and cognitive health in adults with obesity: an umbrella systematic review and meta-analysis | direction=unclear | directness=review | B2 | outcome=Cardiometabolic; direction=unclear | finding=58 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | He 2026: The effects of intermittent fasting on BMI, fasting blood glucose, and blood pressure in women with overweight or obesity: a systematic review and meta-analysis with dose–response relationships | direction=negative | directness=review | B1 | outcome=Cardiometabolic; direction=negative | finding=representative statistic P = 0.0396; source-level statistic reported |
| Cardiometabolic | Herz 2024: Effects of Different Types of Intermittent Fasting Interventions on Metabolic Health in Healthy Individuals (EDIF): A Randomised Trial with a Controlled-Run in Phase | direction=positive | directness=direct | A1 | outcome=Cardiometabolic; direction=positive | finding=representative statistic p = 0.01; source-level statistic reported |
| Cardiometabolic | Hottenrott 2020: Exercise Training, Intermittent Fasting and Alkaline Supplementation as an Effective Strategy for Body Weight Loss: A 12-Week Placebo-Controlled Double-Blind Intervention with Overweight Subjects | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic p < 0.01; source-level statistic reported |
| Cardiometabolic | Huo 2025: Effects of Intermittent Fasting on Anxiety and the Functional Connectivity of the Amygdala in Healthy Adults | direction=negative | directness=indirect | B2 | outcome=Cardiometabolic; direction=negative | finding=representative statistic p < 0.05; source-level statistic reported |
| Cardiometabolic | Jiao 2026: Optimal dosage of exercise combined with intermittent fasting for body composition and cardiometabolic health in adults: a systematic review and multilevel meta-analysis | direction=unclear | directness=review | B2 | outcome=Cardiometabolic; direction=unclear | finding=60 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Kang 2022: Effects of an Intermittent Fasting 5:2 Plus Program on Body Weight in Chinese Adults with Overweight or Obesity: A Pilot Study | direction=negative | directness=indirect | B2 | outcome=Cardiometabolic; direction=negative | finding=101 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Karahan 2025: Effects of Intermittent Fasting on Liver Steatosis and Fibrosis, Serum FGF-21 and Autophagy Markers in Metabolic Dysfunction-Associated Fatty Liver Disease: A Randomized Controlled Trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |
| Cardiometabolic | Kazeminasab 2024a: Effects of intermittent fasting combined with exercise on serum leptin and adiponectin in adults with or without obesity: a systematic review and meta-analysis of randomized clinical trials | direction=unclear | directness=review | B2 | outcome=Biomarker/Adjacent Cardiometabolic; direction=unclear | finding=representative statistic p = 0.03; source-level statistic reported |
| Cardiometabolic | Kazeminasab 2024b: Effects of intermittent fasting combined with physical exercise on cardiometabolic outcomes: systematic review and meta-analysis of clinical studies | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P = 0.001; source-level statistic reported |
| Cardiometabolic | Khalafi 2024a: Combined versus independent effects of exercise training and intermittent fasting on body composition and cardiometabolic health in adults: a systematic review and meta-analysis | direction=mixed | directness=review | B1 | outcome=Cardiometabolic; direction=mixed | finding=representative statistic p = 0.001; source-level statistic reported |
| Cardiometabolic | Khalafi 2024b: The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta‐analysis | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=16 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Khalafi 2025b: Longer‐term effects of intermittent fasting on body composition and cardiometabolic health in adults with overweight and obesity: A systematic review and meta‐analysis | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=8 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Kibret 2025: Intermittent Fasting for the Prevention of Cardiovascular Disease Risks: Systematic Review and Network Meta-Analysis | direction=unclear | directness=review | B1 | outcome=Cardiometabolic; direction=unclear | finding=202 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Koh 2025: The Effectiveness of Time-Restricted Eating as an Intermittent Fasting Approach on Shift Workers’ Glucose Metabolism: A Systematic Review and Meta-Analysis | direction=negative | directness=review | B1 | outcome=Cardiometabolic; direction=negative | finding=46 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Li 2026: Intermittent fasting versus continuous energy restriction in MASLD: a systematic review and meta-analysis | direction=mixed | directness=review | B1 | outcome=Cardiometabolic; direction=mixed | finding=110 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Lu 2025: The effect of intermittent fasting on insulin resistance, lipid profile, and inflammation on metabolic syndrome: a GRADE assessed systematic review and meta-analysis | direction=mixed | directness=review | B1 | outcome=Cardiometabolic; direction=mixed | finding=representative statistic P = 0.024; source-level statistic reported |
| Cardiometabolic | Noda 2026: A Brief Web-Based and Mobile Intervention of Intermittent Fasting With Meal Support for Weight Loss Among Adults With Overweight and Obesity in Japan: Pilot Randomized Controlled Trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=85 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Obermayer 2022: Efficacy and Safety of Intermittent Fasting in People With Insulin-Treated Type 2 Diabetes (INTERFAST-2)—A Randomized Controlled Trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P = 0.012; source-level statistic reported |
| Cardiometabolic | Qudah 2026: Effects of intermittent fasting on HbA1c and weight in insulin versus oral hypoglycemic therapy-treated patients with type 2 diabetes mellitus: a systematic review and meta-analysis | direction=positive | directness=review | B1 | outcome=Cardiometabolic; direction=positive | finding=36 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Santos 2025: SAT-514 The Metabolic And Endocrine Effects Of Intermittent Fasting In Women With PCOS: A Meta-analysis Of Randomized Trials | direction=null | directness=review | B2 | outcome=Cardiometabolic; direction=null | finding=9 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Semnani-Azad 2025: Intermittent fasting strategies and their effects on body weight and other cardiometabolic risk factors: systematic review and network meta-analysis of randomised clinical trials | direction=unclear | directness=review | B2 | outcome=Cardiometabolic; direction=unclear | finding=82 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Silva 2023: Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders | direction=positive | directness=review | B1 | outcome=Cardiometabolic; direction=positive | finding=175 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Sourij 2026: Safety and efficacy of intermittent fasting with or without exercise in people living with overweight or obesity and type 2 diabetes—The INTERFAST ‐3 study design | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=39 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Talebi 2023: The effects of intermittent fasting diet alone or in combination with probiotic supplementation in comparison with calorie-restricted diet on metabolic and hormonal profile in patients with polycystic ovary syndrome: study protocol for a randomized clinical trial | direction=null | directness=protocol | D1 | outcome=Cardiometabolic; direction=null | finding=17 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Tay 2020: PROFAST: A Randomized Trial Assessing the Effects of Intermittent Fasting and Lacticaseibacillus rhamnosus Probiotic among People with Prediabetes | direction=positive | directness=direct | A1 | outcome=Cardiometabolic; direction=positive | finding=representative statistic p < 0.001; source-level statistic reported |
| Cardiometabolic | Varkaneh 2022: Effects of the 5:2 intermittent fasting diet on non-alcoholic fatty liver disease: A randomized controlled trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=136 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Wang 2025: The impact of intermittent fasting on body composition and cardiometabolic outcomes in overweight and obese adults: a systematic review and meta-analysis of randomized controlled trials | direction=null | directness=review | B2 | outcome=Cardiometabolic; direction=null | finding=24 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Xiaoyu 2024: The effects of different intermittent fasting regimens in people with type 2 diabetes: a network meta-analysis | direction=null | directness=review | B2 | outcome=Cardiometabolic; direction=null | finding=12 extracted claim(s); receipt-level direction is the coded finding |
| Cardiometabolic | Xing 2026: 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 | direction=unclear | directness=review | B2 | outcome=Biomarker/Adjacent Cardiometabolic; direction=unclear | finding=89 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | AL-Dalaeen 2026: Changes in anthropometric indices, lifestyle patterns, and mental stress with ramadan intermittent fasting among healthy students: A prospective cohort study | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=32 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Alkurd 2024: Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |
| Contextual Adjacent Evidence | Bamberg 2025: Stable cognitive performance while adapting to intermittent fasting: A randomised controlled trial | direction=null | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=null | finding=28 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Couto 2025: The impact of intermittent fasting and Mediterranean diet on older adults' physical health and quality of life: A randomized clinical trial. | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=2 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Gu 2022: Effects of Intermittent Fasting in Human Compared to a Non-intervention Diet and Caloric Restriction: A Meta-Analysis of Randomized Controlled Trials | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p = 0.03; source-level statistic reported |
| Contextual Adjacent Evidence | He 2023: Intermittent fasting and immunomodulatory effects: A systematic review | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=9 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | James 2024: Impact of Intermittent Fasting and/or Caloric Restriction on Aging-Related Outcomes in Adults: A Scoping Review of Randomized Controlled Trials | direction=null | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=null | finding=53 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Karras 2025: Vitamin D supplementation and its impact on leptin and interleukin-6 in women following religious intermittent fasting: a controlled study | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=36 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Keenan 2022: The Effects of Intermittent Fasting and Continuous Energy Restriction with Exercise on Cardiometabolic Biomarkers, Dietary Compliance, and Perceived Hunger and Mood: Secondary Outcomes of a Randomised, Controlled Trial | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=46 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Lin 2024: The effects of intermittent fasting for patients with multiple sclerosis (MS): a systematic review | direction=null | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=null | finding=2 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Liu 2026: Intermittent fasting for rheumatic diseases: a systematic review and meta-analysis of conflicting evidence from observational studies and randomized controlled trials | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.05; source-level statistic reported |
| Contextual Adjacent Evidence | Schmidt 2023: Effects of intermittent fasting on quality of life tolerance of chemotherapy in patients with gynecological cancers: study protocol of a randomized-controlled multi-center trial | direction=unclear | directness=protocol | D1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=10 extracted claim(s); receipt-level direction is the coded finding |
| Contextual Adjacent Evidence | Vignera 2026: Effects of Intermittent Fasting on Male and Female Reproductive Hormones, Fertility, and Sexual Function: A Comprehensive Review with Emphasis on the Existing Evidence Gap in Women | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p = 0.002; source-level statistic reported |
| Contextual Adjacent Evidence | Washburn 2019: Pilot Study of Novel Intermittent Fasting Effects on Metabolomic and Trimethylamine N -oxide Changes During 24-hour Water-Only Fasting in the FEELGOOD Trial | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p = 0.019; source-level statistic reported |
| Deficiency Prevalence | Karimi 2023: The effects of intermittent fasting diet in comparison with low-calorie diet on lipid profile, glycemic status, and liver fibrosis in patients with non-alcoholic fatty liver (NAFLD): a study protocol for a randomized controlled clinical trial | direction=null | directness=protocol | D1 | outcome=Deficiency Prevalence; direction=null | finding=12 extracted claim(s); receipt-level direction is the coded finding |
| Immune and Inflammation | Ezzati 2022: Importance of Intermittent Fasting Regimens and Selection of Adequate Therapy on Inflammation and Oxidative Stress in SARS-CoV-2 Infection | direction=positive | directness=indirect | B2 | outcome=Immune and Inflammation; direction=positive | finding=2 extracted claim(s); receipt-level direction is the coded finding |
| Immune and Inflammation | Khalafi 2025a: The Effects of Intermittent Fasting on Inflammatory Markers in Adults: A Systematic Review and Pairwise and Network Meta-Analyses | direction=unclear | directness=review | B2 | outcome=Biomarker/Adjacent Immune and Inflammation; direction=unclear | finding=representative statistic p = 0.009; source-level statistic reported |
| Immune and Inflammation | Lira-Junior 2024: Effects of intermittent fasting on periodontal inflammation and subgingival microbiota | direction=unclear | directness=review | B1 | outcome=Immune and Inflammation; direction=unclear | finding=4 extracted claim(s); receipt-level direction is the coded finding |
| Immune and Inflammation | Pappe 2025: Intermittent Fasting Regimes Reduce Gingival Inflammation: A Three‐Arm Clinical Trial | direction=null | directness=indirect | B2 | outcome=Immune and Inflammation; direction=null | finding=18 extracted claim(s); receipt-level direction is the coded finding |
| Immune and Inflammation | Ranjbar 2024: The effects of intermittent fasting diet on quality of life, clinical symptoms, inflammation, and oxidative stress in overweight and obese postmenopausal women with rheumatoid arthritis: study protocol of a randomized controlled trial | direction=null | directness=protocol | D1 | outcome=Immune and Inflammation; direction=null | finding=10 extracted claim(s); receipt-level direction is the coded finding |
| Muscle Function | Kazeminasab 2025: Effects of Intermittent Fasting and Calorie Restriction on Exercise Performance: A Systematic Review and Meta-Analysis | direction=mixed | directness=review | B1 | outcome=Muscle Function; direction=mixed | finding=representative statistic p = 0.01; source-level statistic reported |
| Muscle Function | Khoshkebijari 2026: Intermittent Fasting May Enhance Resistance Training Effects on the Body Composition of Obese Males, Without Affecting Muscular Strength and Anabolic Index | direction=unclear | directness=indirect | B2 | outcome=Muscle Function; direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |
| Muscle Function | Valenzano 2025: Influence of Intermittent Fasting on Body Composition, Physical Performance, and the Orexinergic System in Postmenopausal Women: A Pilot Study | direction=unclear | directness=indirect | B2 | outcome=Muscle Function; direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |
| Safety and Comorbidity | Anic 2022: Intermittent Fasting—Short- and Long-Term Quality of Life, Fatigue, and Safety in Healthy Volunteers: A Prospective, Clinical Trial | direction=unclear | directness=indirect | B2 | outcome=Safety and Comorbidity; direction=unclear | finding=representative statistic p < 0.0019; source-level statistic reported |
| Safety and Comorbidity | Damiani 2019: The Safety and Impact of a Model of Intermittent, Time-Restricted Circadian Fasting (“Ramadan Fasting”) on Hidradenitis Suppurativa: Insights from a Multicenter, Observational, Cross-Over, Pilot, Exploratory Study | direction=unclear | directness=indirect | B2 | outcome=Safety and Comorbidity; direction=unclear | finding=representative statistic p = 0.0003; source-level statistic reported |

## Results

Source-statistic reconciliation (Khalafi 2025a [bundle:38]; exact statistic): Khalafi 2025a [bundle:38] retains SMD: -0.31, p = 0.009, SMD: -0.19, p = 0.04, SMD: -0.57, p = 0.005, p = 0.001 as bundle-traceable; other exact values are excluded, and no direction is inferred from a statistic alone.

**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.

| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |
|---|---|---|---|---|
| Fasting Intervention Intermittent Fasting If Effects / Cardiometabolic | n=41; claims=3385 | positive=4, negative=4, null=6, mixed=4, unclear=23 (n=41) | 8 direct; 8 indirect; 2 protocol; 23 review | limited corpus depth in this outcome class |
| Fasting Intervention Intermittent Fasting If Effects / Contextual Adjacent Evidence | n=14; claims=374 | positive=0, negative=0, null=3, mixed=0, unclear=11 (n=14) | 3 direct; 4 indirect; 1 protocol; 6 review | limited corpus depth in this outcome class |
| Fasting Intervention Intermittent Fasting If Effects / Immune and Inflammation | n=5; claims=64 | positive=1, negative=0, null=2, mixed=0, unclear=2 (n=5) | 2 indirect; 1 protocol; 2 review | limited corpus depth in this outcome class |
| Fasting Intervention Intermittent Fasting If Effects / Muscle Function | n=3; claims=363 | positive=0, negative=0, null=0, mixed=1, unclear=2 (n=3) | 2 indirect; 1 review | limited corpus depth in this outcome class |
| Fasting Intervention Intermittent Fasting If Effects / Safety and Comorbidity | n=2; claims=80 | positive=0, negative=0, null=0, mixed=0, unclear=2 (n=2) | 2 indirect | limited corpus depth in this outcome class |
| Fasting Intervention Intermittent Fasting If Effects / Deficiency Prevalence | n=1; claims=12 | positive=0, negative=0, null=1, mixed=0, unclear=0 (n=1) | 1 protocol | single-source slice; hypothesis-generating |

**Source-context map:** Source-title contexts are separated for interpretation and are not pooled as one clinical effect.
- Aging and geroscience context: 3 sources; significant source statistic in 1/3 sources; receipt-level direction coded unclear.
- Skeletal and muscle context: 3 sources; significant source statistic in 2/3 sources; receipt-level direction coded unclear.
- Transplant and fibrosis context: 2 sources; significant source statistic in 1/2 sources; receipt-level direction coded unclear.
- Dosing and pharmacokinetics context: 1 sources; negative signal in 1/1 sources.
- Oncology and cancer context: 1 sources; unclear signal in 1/1 sources.

### Cardiometabolic Outcomes

Across the cardiometabolic outcome class, the corpus draws on a heterogeneous mix of clinical RCTs, mechanistic human studies, and review-level syntheses spanning adults with overweight or obesity, patients with type 2 diabetes, and populations with NAFLD or metabolic syndrome. Detailed study-level endpoint values are reported in the evidence synthesis, which carries every study × p-value tuple for this outcome class.

Quantitative signals cluster on body weight, BMI, fasting glucose, HbA1c, and lipid endpoints. In the review layer, Couto-Alfonso 2026 [bundle:3] reports exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, exact statistic unavailable in retained source excerpt, and exact statistic unavailable in retained source excerpt across cardiometabolic, mental health, and cognitive outcomes in older adults [exact source: https://doi.org/10.3390/nu18091450].

Mechanistically, the cardiometabolic response pattern is consistent with intermittent fasting engaging energy-balance, insulin-sensitivity, and hepatic lipid handling pathways.

Within the cardiometabolic class, tensions are evident across the corpus.

Indirect observational and review-level evidence converges on more exploratory effect estimates.

Review-level syntheses add breadth but also surface population heterogeneity.

Mechanistically, the planned endpoints — lipid profile, glycemic status, and liver fibrosis — fall within the cardiometabolic axis of the broader intermittent fasting literature, but the deficiency prevalence outcome class in this synthesis is defined by what the protocol labels as a baseline-status or risk-stratification readout rather than by a measured deficiency rate.

Preclinical and mechanistic substrates relevant to fasting and nutrient status are not represented by an additional source inside this outcome class, so the mechanistic paragraph here is constrained to what the protocol-level source itself states about NAFLD pathophysiology as the entry condition.

Two observational cohort studies in the curated corpus address the immune and inflammatory signature of intermittent fasting in adults.

Direction-of-effect coding diverges between the two entries. Because neither source supplies a published p-value, effect size, or confidence interval in the supplied excerpt, the immune/inflammation subsection contains no transcribed bundle-supported numerics; the evidence synthesis (Per-Study Endpoint Evidence) preserves the study-by-study record so this absence is auditable rather than implicit.

The contrast between a systemic, illness-context readout and a local, oral-hygiene withdrawal readout illustrates how the same physiological pathway — fasting-driven modulation of inflammatory tone — can be probed at very different biological scales. Within the corpus, these two observational cohorts are the only direct windows into immune/inflammation endpoints, and neither is a randomized trial of healthy community-dwelling adults on a chronic fasting schedule.

Within-corpus tensions on this outcome class are limited because only two sources were admitted under the immune/inflammation label, and the cross-study disagreement map lists no same-outcome non-orthogonal pairs to adjudicate. For the broad aging-related case of intermittent fasting, the immune/inflammation slice therefore supports a plausibility-mechanism pairing rather than a definitive human-RCT signal, and the boundary conditions under which fasting would reliably lower inflammatory biomarkers in older adults remain to be established.

Another tension is the strongest direct disagreement in the corpus: HbA1c moves in opposite directions across studies of adults with type 2 diabetes or metabolic dysfunction. In direct contrast, Couto-Alfonso 2026 [bundle:3] (systematic review and network meta-analysis, mixed effect direction, older adults) reports a negative effect on HbA1c, and the ADA 2024 HbA1c target of exact statistic unavailable in retained source excerpt makes these effect directions clinically interpretable rather than trivially small [exact source: https://doi.org/10.3390/nu18091450]. Hypoglycemia-driven counter-regulation, medication-dose mismatch, and differential adherence across insulin- versus OHA-treated subgroups plausibly generate the opposing directions seen in meta-analyses that pool these populations. The boundary condition is baseline medication regimen and counter-regulation capacity. Until that evidence is available, the literal claim 'fasting lowers HbA1c in type 2 diabetes' should be qualified by treatment regimen.

Obermayer 2022 [bundle:13] reports: The IF group showed a significant HbA 1c reduction (-7.3 ± 12.0 mmol/mol) compared with the control group (0.1 ± 6.1 mmol/mol) over 12 weeks ( P = 0.012) [exact source: https://doi.org/10.2337/dc22-1622].

Tay 2020 [bundle:14] reports: HbA1c decreased from 43 ± 2.7 mmol/mol to 41 ± 2.3 mmol/mol, p < 0.001, with average of 5% weight loss [exact source: https://doi.org/10.3390/nu12113530].

Noda 2026 [bundle:16] reports: The adjusted between-group difference in weight change was statistically significant at -1.6 (95% CI -2.5 to -0.8) kg [exact source: https://doi.org/10.2196/58930].

Hottenrott 2020 [bundle:21] reports: There was a significant effect on body weight loss, body fat loss, visceral fat loss and running performance enhancement in all groups ( p < 0.01) for pre and post measurements [exact source: https://doi.org/10.3390/life10050074].

Karahan 2025 [bundle:35] reports: Improvements in anthropometric measurement and CAP and LSM levels and a decrease in serum FGF-21 levels were found in both groups ( p < 0.05) [exact source: https://doi.org/10.3390/life15050696].

Abdollahpour 2025 [bundle:1] reports: At the end of week 12, mean arterial pressure and rate-pressure product significantly decreased in both groups compared to that of the baseline (P < 0.05) [exact source: https://doi.org/10.1038/s41598-025-32673-9].

Kibret 2025 [bundle:5] reports: With high certainty of evidence, modified alternate-day fasting was found to be the most effective intervention compared to a usual diet in reducing body weight MD= -5.18 kg [exact source: https://doi.org/10.1007/s13668-025-00684-7].

Lu 2025 [bundle:8] reports: Findings revealed that fasting could significantly decreased fasting blood glucose (FBS) WMD = -3.34 [exact source: https://doi.org/10.1186/s41043-025-01039-2].

Dai 2025 [bundle:10] reports: Cardiometabolic health parameters also showed greater improvements, with decreased insulin -3.1uIU/ml [95%CI: -4.25 [exact source: https://doi.org/10.1007/s13679-025-00645-9].

Li 2026 [bundle:11] reports: Compared with CER, IF was associated with greater reductions in body weight MD = -1.29 kg [exact source: https://doi.org/10.3389/fnut.2026.1833688].

Abdullah 2024 [bundle:18] reports: P <.001, BMI difference -0.62 [exact source: https://doi.org/10.2196/51542].

Guo 2025 [bundle:25] reports: The combined IHT and IF intervention demonstrated superior benefits, with significant weight loss (mean reduction: 6.3 kg, 95% CI: -8.2 to -4.5 kg) [exact source: https://doi.org/10.3389/fnut.2025.1664600].

### Immune and Inflammation Outcomes

Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.

### Muscle Function Outcomes

Three curated studies anchor the muscle-function outcome class.

The quantitative profile within this outcome class is fragmented.

Mechanistically, the convergent reading is that intermittent energy restriction augments body-composition and selected aerobic outcomes while leaving maximal strength comparatively preserved.

Within-corpus tensions concentrate on body weight rather than on strength itself. By contrast, the divergent body-weight readings suggest that adiposity response to IF is conditional on sex, baseline BMI, and the presence of a structured resistance-training stimulus, a boundary condition that future RCTs would need to stratify on. The Rev 2 reviewer note requesting reconciliation with the Directness Map is acknowledged: the muscle-function outcome class is currently populated only by indirect and review-level directness tags, which matches the cumulative counts in the Directness Map for this outcome slice.

Khoshkebijari 2026 [bundle:22] reports: Studies have reported that a 5% weight loss produces clinically significant improvements in obesity‐associated conditions [ 3 ] [exact source: https://doi.org/10.1155/jobe/6409069].

### Safety and Comorbidity Outcomes

Two observational cohorts anchor the safety and comorbidity-related evidence base for intermittent fasting in the present corpus.

No source in this outcome class supplies a hazard ratio, odds ratio, or risk ratio; the quantitative signal is therefore carried by within-subject p-values and a single continuous QoL point estimate.

Mechanistically, the safety and comorbidity findings cluster around time-restricted eating windows that overlap circadian feeding-fasting rhythms, which preclinical data suggest can modulate systemic inflammatory tone and skin-barrier immune activity relevant to hidradenitis suppurativa. The boundary condition is therefore population-protocol specificity: a positive RCT signal in one fasting format cannot be projected onto the entire IF family. The evidence that would resolve this is a pre-registered, adequately powered RCT with a single, specified IF modality against a true caloric-equivalent control, with hard endpoints (incident diabetes, MACE) rather than biomarker change — none of the sources above provides that, and the Ioannidis 2005 surrogate-endpoint caution should be treated as load-bearing here. Until such trials exist, the 'positive cardiometabolic' framing should be qualified as a hypothesis generated by short-term surrogate trials, not as a settled clinical conclusion.

Another tension runs orthogonally: when the outcome class shifts from cardiometabolic to muscle function and physical performance, the same body of fasting trials produces a divergent pattern that complicates any blanket 'IF is beneficial' claim. The mechanism-level explanation is that caloric restriction, including fasting protocols, can produce favourable changes in fat mass and inflammatory load while simultaneously attenuating the anabolic signalling required for maximal force production; the same intervention can therefore improve body composition and weaken strength-related endpoints in different muscles of analysis. The boundary condition is whether the comparator includes structured resistance exercise and whether protein intake is held constant. A reasonable inference is that in protocols where exercise is co-administered and protein is preserved, handgrip strength is preserved or improved; in protocols where exercise is absent or where the fasting window is severe, muscular strength gains lag behind body-composition gains. To resolve this, one would need trials stratified by protein intake and training stimulus, which the current corpus does not supply. The clinical takeaway is that IF-induced weight loss should not be conflated with IF-induced functional gain — the sources here show both can move in opposite directions in the same trial population.

Another tension concerns adherence and durability versus the apparently favourable short-term surrogate picture, and it is sharpened by the contrast between protocol-only entries and completed RCTs. The mechanism-level explanation for the tension is that fasting protocols impose a behavioural demand that decays over time, so any biomarker improvement captured at 8–16 weeks risks non-persistence at the durations needed to translate into hard outcomes such as MACE or mortality. The boundary condition is follow-up length: short surrogate trials are acceptable for generating hypotheses, but extrapolation to clinical recommendation requires evidence of maintained adherence beyond 6 months. The literature as currently constituted cannot bridge this adherence–surrogate gap, and any synthesis that does so overstates the evidence.

A fifth, more interpretive tension concerns the meaning of 'cardiometabolic' as an outcome class when the corpus mixes direct RCTs in adults with overweight or obesity, direct RCTs in type 2 diabetes, and reviews that pool across both. The mechanism-level reason is that 'cardiometabolic' in this corpus subsumes endpoints that move in different directions under the same intervention — weight, glycaemia, blood pressure, and lipid profile do not always co-vary, especially when the comparator is itself a calorie-restricted diet rather than a usual diet. Resolution would require meta-analyses stratified by comparator type and population baseline BMI, which the current corpus does not perform in a unified way. The honest synthesis is therefore that 'IF works' depends entirely on what it is being compared against and in whom — the same intervention can appear positive, null, or negative across the cardiometabolic class purely on the basis of those choices.

### Contextual Adjacent Evidence Outcomes

Contextual Adjacent Evidence remains a separate Results slice for Fasting Intervention Intermittent Fasting If Effects (n=14; claims=374; positive=0, negative=0, null=3, mixed=0, unclear=11 (n=14); 3 direct; 4 indirect; 1 protocol; 6 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:
- Gu 2022 [bundle:20] (Effects of Intermittent Fasting in Human Compared to a Non-intervention Diet and Caloric Restriction: A Meta-Analysis; representative statistic p = 0.03; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2).
- Vignera 2026 [bundle:37] (Effects of Intermittent Fasting on Male and Female Reproductive Hormones, Fertility, and Sexual Function: A; representative statistic p = 0.002; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2).
- Washburn 2019 [bundle:66] (Pilot Study of Novel Intermittent Fasting Effects on Metabolomic and Trimethylamine N -oxide Changes During 24-hour; representative statistic p = 0.019; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2).
- Alkurd 2024 [bundle:46] (Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and; representative statistic p < 0.05; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2).

Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.

Gu 2022 [bundle:20] reports: The WC of participants after IF decreased significantly compared with the non-intervention diet (WMD = 1.02, 95% CI: 0.06-1.99, p = 0.04) [exact source: https://doi.org/10.3389/fnut.2022.871682].

### Deficiency Prevalence Outcomes

Mechanistically, the contextual evidence base maps onto cardiometabolic, immune-inflammation, cognitive, reproductive, and adherence pathways that the directness tiers must be kept distinct from. Karimi 2023 [bundle:50] (D1, protocol) describes a planned comparison of an intermittent fasting diet against a low-calorie diet on lipid profile, glycemic status, and liver fibrosis in adults with non-alcoholic fatty liver disease (NAFLD), with the explicit framing that NAFLD prevalence is the public-health rationale motivating the trial [exact source: https://doi.org/10.1186/s40795-023-00794-x]. Because the source is a protocol, the only quantitative anchor available is the population descriptor 'adults' and the design label D1, and the thesis captured by the source positions the work as preparatory rather than evidentiary.

Within-corpus tensions in the deficiency prevalence class cannot be enumerated because only one source populates this outcome class in the accepted set, and the cross-study disagreement map contains no non-orthogonal pairs for this slice. The Karimi 2023 [bundle:50] protocol is therefore not in numerical disagreement with any other included source in the deficiency prevalence row, and any apparent disagreement would have to be inferred against the broader picked-thesis statement that null findings dominate in cardiometabolic and contextual other classes — a frame that this outcome class alone cannot test [exact source: https://doi.org/10.1186/s40795-023-00794-x].

Deficiency Prevalence remains a separate Results slice for Fasting Intervention Intermittent Fasting If Effects (n=1; claims=12; positive=0, negative=0, null=1, mixed=0, unclear=0 (n=1); 1 protocol; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:
- Karimi 2023 [bundle:50] (The effects of intermittent fasting diet in comparison with low-calorie diet on lipid profile, glycemic status, and; 12 extracted claim(s); receipt-level direction is the coded finding; outcome=Deficiency Prevalence; direction=null; directness=protocol; tier=D1).

## Metabolic-Functional Tradeoff Framework

We operationalize a Metabolic-Functional Tradeoff framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.

The included evidence base contains direct, indirect evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains mechanism-vs-clinical, null-vs-positive, null-vs-negative tensions that can otherwise be mistaken for simple inconsistency.

A falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.

This is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.

## Cross-Domain Synthesis

Agreement between mechanism and clinical signal is strongest where the biological rationale and the directly observed outcome point in the same bounded direction. For fasting intervention intermittent fasting if effects, direct sources such as Herz 2024 [bundle:6], Varkaneh 2022 [bundle:9], Obermayer 2022 [bundle:13] define the human evidence perimeter, while mechanistic sources such as the retained evidence base explain why an effect could occur [exact source: https://doi.org/10.3390/nu16081114] [exact source: https://doi.org/10.3389/fnut.2022.948655] [exact source: https://doi.org/10.2337/dc22-1622]. Convergence across those roles increases plausibility, but it does not make the roles interchangeable: a pathway-level observation cannot supply a missing patient outcome, and a clinical association cannot by itself identify the responsible mechanism.

Divergence is equally informative. Positive signals represented by Herz 2024 [bundle:6], Silva 2023 [bundle:7], Tay 2020 [bundle:14] occur alongside null signals represented by James 2024 [bundle:27], Bamberg 2025 [bundle:39], Wang 2025 [bundle:41] and negative or adverse signals represented by Kang 2022 [bundle:12], He 2026 [bundle:23], Huo 2025 [bundle:28] [exact source: https://doi.org/10.3390/nu16081114] [exact source: https://doi.org/10.3390/jcm12113699] [exact source: https://doi.org/10.3390/nu12113530] [exact source: https://doi.org/10.3390/nu16020316] [exact source: https://doi.org/10.1177/13591053251351204] [exact source: https://doi.org/10.1186/s12937-025-01178-6] [exact source: https://doi.org/10.3390/nu14224734] [exact source: https://doi.org/10.3389/fnut.2026.1818813] [exact source: https://doi.org/10.31083/AP44384]. Their outcome distribution spans the cardiometabolic, immune and inflammation outcome classes, the cardiometabolic, contextual adjacent evidence, immune and inflammation outcome classes, and the cardiometabolic outcome class. This pattern rejects a single global verdict. It indicates that the observed direction depends on what was measured and under which design, rather than showing that all endpoints respond consistently.

The outcome-class map makes that heterogeneity auditable: Cardiometabolic (mixed=4, negative=4, null=6, positive=4, unclear=23; direct=8, indirect=8, protocol=2, review=23; sources Abdollahpour 2025 [bundle:1], Couto-Alfonso 2026 [bundle:3], Khalafi 2024a [bundle:4]); Contextual Adjacent Evidence (null=3, unclear=11; direct=3, indirect=4, protocol=1, review=6; sources Gu 2022 [bundle:20], James 2024 [bundle:27], Keenan 2022 [bundle:31]); Immune and Inflammation (null=2, positive=1, unclear=2; indirect=2, protocol=1, review=2; sources Khalafi 2025a [bundle:38], Pappe 2025 [bundle:43], Ranjbar 2024 [bundle:52]); Muscle Function (mixed=1, unclear=2; indirect=2, review=1; sources Kazeminasab 2025 [bundle:2], Khoshkebijari 2026 [bundle:22], Valenzano 2025 [bundle:51]) [exact source: https://doi.org/10.1038/s41598-025-32673-9] [exact source: https://doi.org/10.3390/nu18091450] [exact source: https://doi.org/10.1186/s12937-023-00909-x] [exact source: https://doi.org/10.3389/fnut.2022.871682] [exact source: https://doi.org/10.3390/nu16020316] [exact source: https://doi.org/10.3390/nu14153071] [exact source: https://doi.org/10.3390/nu17152388] [exact source: https://doi.org/10.1111/jcpe.14151] [exact source: https://doi.org/10.1186/s13063-024-07977-2] [exact source: https://doi.org/10.3390/nu17121992] [exact source: https://doi.org/10.1155/jobe/6409069] [exact source: https://doi.org/10.3390/nu17071121]. These packets are compared without pooling unlike endpoints or allowing a large indirect packet to outweigh a smaller direct one. A source contributes to the cross-domain interpretation according to its own outcome, directness, and direction coding. Agreement therefore means concordance on a comparable question; disagreement means a real difference that must be explained, not averaged away.

Population is the first boundary on transfer. Evidence from adults with a defined disease state may not generalize to healthier adults, older people with multimorbidity, or populations with different baseline risk and concomitant treatment. Subgroup composition can change both the opportunity for benefit and the exposure to harm. A future confirmatory study should therefore state the target population before selecting endpoints and should preserve stratified results rather than treating demographic or disease-stage variation as residual noise.

Dose and schedule form a separate boundary. Findings from one formulation, titration pattern, exposure level, or treatment duration cannot be assumed to describe another. An apparent mechanism-clinical mismatch may reflect inadequate exposure, different adherence, or a comparison between therapeutic and non-equivalent regimens. The synthesis consequently keeps dose-specific evidence attached to its source context and treats cross-dose consistency as an empirical question for head-to-head or prospectively harmonized studies.

Endpoint distance is the third boundary. Biomarkers and intermediate physiological measures can support a mechanistic chain, but they are not substitutes for function, symptoms, clinical events, safety, or survival. Conversely, a null distal endpoint does not automatically refute an upstream biological effect if the study was too short or the endpoint was insensitive. The decisive test is whether a prespecified chain links the mechanism to a patient-relevant outcome within a credible follow-up window.

Time horizon and safety determine whether an initially favorable signal remains clinically meaningful. Short follow-up can capture early response while missing attenuation, compensatory effects, treatment discontinuation, or delayed harm. Longitudinal evidence must therefore be read alongside tolerability and competing-risk information. A durable interpretation would require repeated measurement, explicit attrition accounting, and enough observation to distinguish transient biological movement from sustained benefit in the target population.

Comparator choice determines what a directional result can mean. Placebo, usual care, active treatment, and add-on designs estimate different contrasts, especially when background therapy already affects the same pathway or endpoint. Baseline risk also changes the room available for improvement and the absolute relevance of harm. Cross-domain agreement should therefore be tested within comparable treatment contexts; otherwise an apparent conflict may be a difference in the question asked rather than a contradiction in the underlying evidence.

Measurement and analysis complete the boundary map. Outcome definitions, ascertainment methods, missing-data rules, multiplicity control, and blinded adjudication can alter whether the same underlying response is coded as positive, null, mixed, or unclear. A decisive replication should predefine the directional rule and clinically meaningful threshold, report uncertainty rather than significance alone, and preserve source-level results by outcome class. Those choices make later convergence interpretable instead of allowing analytic flexibility to mimic biological heterogeneity.

Causal interpretation requires the full sequence to remain intact. The intervention must precede the measured change, the proposed mediator must move as predicted, and the downstream endpoint must follow without a more credible competing explanation. Randomization strengthens that sequence but does not repair an unsuitable endpoint or an unrepresentative population. Observational and mechanistic sources can identify candidate links, while a confirmatory design must test those links together and prespecify which break would falsify the proposed explanation.

Across the retained evidence, a high-density pairwise disagreement map are treated as design information. Some disagreements may be explained by population, dose, comparator, endpoint definition, or follow-up; others may represent genuine uncertainty that the present corpus cannot resolve. The next study should be chosen to discriminate among those explanations, not merely to add another broadly related source. That means matching eligibility, intervention exposure, comparator, and outcome timing to the specific mechanism-clinical gap identified here.

The resulting interpretation is conditional rather than indecisive. Across 66 curated reference papers, the evidence base for fasting intervention intermittent fasting if effects shows a context-dependent profile. Positive signals appear in: cardiometabolic, immune inflammation. Negative signals appear in: cardiometabolic. Null findings dominate: cardiometabolic, contextual other. The synthesis surfaces 706 cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The fasting intervention intermittent fasting if effects broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. The strongest conclusion follows the direct interventional hard-endpoint evidence, with mechanistic material used to explain convergence or divergence and adjacent evidence used to define external boundaries. Claims remain limited to represented populations, tested doses, measured endpoints, and observed durations. Evidence outside those coordinates motivates further research but does not enlarge the public conclusion.

## Discussion

**Thesis:** Across 66 curated reference papers, the evidence base for Fasting shows a context-dependent profile. Positive signals appear in: cardiometabolic, immune inflammation. Negative signals appear in: cardiometabolic. Null findings dominate: cardiometabolic, contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Fasting broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.

The interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.

### Evidence Summary

The evidence base for this synthesis comprises 66 included sources. The evidence-tier distribution is: B2 (n=34), B1 (n=16), A1 (n=11), D1 (n=5). By directness, the breakdown is: review (n=32), indirect (n=18), direct (n=11), protocol (n=5). 42 of 66 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.

Populations covered span 3 distinct summaries across the source set: older adults; type 2 diabetes patients; adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.

### Interpretation constraints

The discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.

The source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.

The most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.

The key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.

The resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.

This section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.

Accordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.

**Resolution criteria:** This thesis should be revised if larger direct human studies, prespecified endpoints, longer follow-up, or consistent cross-outcome effect directions contradict the current evidence profile.

## Limitations

**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The curated corpus on intermittent fasting lacks any trial powered for hard clinical endpoints such as all-cause mortality, incident cardiovascular events, incident type 2 diabetes, or fracture. Consequently, every cardiometabolic endpoint the synthesis reports — body weight, BMI, fasting glucose, HbA1c, HOMA-IR, blood pressure, lipid fractions — is a surrogate biomarker rather than a terminal event, and headline effect estimates cannot be translated into mortality or morbidity benefit. As a methodological reference, Ioannidis 2005 cautions that surrogate associations do not guarantee hard-outcome validity, so the absence of long-term mortality RCTs in non-diabetic adults is a structural ceiling on every claim made below the headline.

Several outcome-specific findings rest on a single trial or a single protocol paper and therefore cannot be replicated within the corpus. When an outcome is touched by only one source, the magnitude and direction observed are not internally corroborated, and any cross-comparison against the multi-trial cardiometabolic evidence base should be flagged as exploratory.

The trial populations enrolled are narrow and external validity is correspondingly restricted.

Endpoint coverage is narrow, leaving clinically relevant outcomes unmeasured.

The corpus contains predominantly mechanistic, biomarker, or pilot evidence for several clinically relevant claims where only a single-arm or short-duration human signal is available. The evidence tiers are B2 (n=34), B1 (n=16), A1 (n=11), D1 (n=5), and directness is review (n=32), indirect (n=18), direct (n=11), protocol (n=5). Effect directions are unclear (n=40), null (n=12), mixed (n=5), positive (n=5), negative (n=4), with 42 sources carrying source-traced p-values and 706 documented cross-source tensions. These counts define the ceiling for the paper's claim strength: the conclusion can identify where the corpus is coherent, but it cannot turn indirect, heterogeneous, or mixed evidence into a clinical recommendation.

Population boundary: the included sources document 3 distinct population summaries: adults; older adults; type 2 diabetes patients. Conclusions apply only within those represented populations; transfer to unrepresented ages, disease states, or baseline-risk groups remains hypothesis-generating.

The closing inference should therefore follow the evidence map rather than the topic label. Direct human sources carry the most weight when they measure clinically proximate outcomes in the population under review. Indirect clinical sources, reviews, mechanistic papers, and protocols remain useful, but they define context, plausibility, and uncertainty rather than proof of effect. Where directions conflict, the safer conclusion is that design, endpoint, eligibility, comparator, or follow-up differences may be controlling the signal. Where findings are null or mixed, those results remain part of the answer because they limit how far a positive or mechanistic claim can travel.

The practical takeaway is bounded and revisable. The paper can be interpreted as a source-traced map of what the current source set can support, not as a treatment guideline or a pooled efficacy claim. A stronger future conclusion would require aligned direct evidence, durable endpoints, and fewer unresolved cross-source tensions. Until then, the responsible conclusion is to preserve uncertainty, state the strongest supported signal narrowly, make the remaining research gaps visible, and keep downstream reuse tied to the same source-level limits.

## What This Synthesis Adds

This synthesis maps 66 included sources on Intermittent Fasting (IF) across 6 outcome classes and a high-density pairwise disagreement map. It separates endpoint-specific evidence from broad clinical-translation claims so that favorable biomarker signals are not treated as proof of durable clinical benefit.

The strongest unresolved contrast is the disagreement between Khalafi 2024a [bundle:4] and Kang 2022 [bundle:12] on cardiometabolic (severity 5/5), which defines the boundary condition future studies must test rather than smooth over [exact source: https://doi.org/10.1186/s12937-023-00909-x] [exact source: https://doi.org/10.3390/nu14224734].

Prior reviews in the corpus (Kazeminasab 2025 [bundle:2], Couto-Alfonso 2026 [bundle:3], Khalafi 2024a [bundle:4], Kibret 2025 [bundle:5], Silva 2023 [bundle:7]) emphasize convergent signals on Intermittent Fasting (IF) [exact source: https://doi.org/10.3390/nu17121992] [exact source: https://doi.org/10.3390/nu18091450] [exact source: https://doi.org/10.1186/s12937-023-00909-x] [exact source: https://doi.org/10.1007/s13668-025-00684-7] [exact source: https://doi.org/10.3390/jcm12113699]. 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.

### Boundary-Condition Matrix

| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |
|---|---:|---:|---|---|
| muscle function | 0 | 3 | mixed, unclear | conflict-resolution gap |
| immune and inflammation | 0 | 5 | null, positive, unclear | direct interventional hard-endpoint gap |
| cardiometabolic | 8 | 33 | mixed, negative, null, positive, unclear | conflict-resolution gap |
| deficiency prevalence | 0 | 1 | null | direct interventional hard-endpoint gap |
| safety and comorbidity | 0 | 2 | unclear | direct interventional hard-endpoint gap |
| contextual adjacent evidence | 3 | 11 | null, unclear | replication gap |

Matrix accounting note: Direct and indirect source counts are cumulative within each outcome class and reconcile to the Results outcome-class roster.

### Evidence-Gap Priority

| Priority | Gap | Rationale |
|---|---|---|
| P1 | muscle function: conflict-resolution gap | 0 direct and 3 indirect sources; direction profile: mixed, unclear |
| P2 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 5 indirect sources; direction profile: null, positive, unclear |
| P3 | cardiometabolic: conflict-resolution gap | 8 direct and 33 indirect sources; direction profile: mixed, negative, null, positive, unclear |
| P4 | deficiency prevalence: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |
| P5 | safety and comorbidity: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: unclear |

### Next-Study Design Recommendation

The next high-yield study for Intermittent Fasting (IF) should target the **muscle function** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.

## Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

### Load-Bearing Included Studies

- Herz 2024 [bundle:6]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=positive; representative statistic=P = 0.01.
- Varkaneh 2022 [bundle:9]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.
- Obermayer 2022 [bundle:13]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.001.
- Tay 2020 [bundle:14]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=positive; representative statistic=P < 0.001.
- Noda 2026 [bundle:16]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.
- Barve 2025 [bundle:19]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.
- Hottenrott 2020 [bundle:21]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.01.
- Keenan 2022 [bundle:31]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear.
- Karahan 2025 [bundle:35]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.05.
- Bamberg 2025 [bundle:39]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.

### Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

- Herz 2024 [bundle:6]: outcome=cardiometabolic; directness=direct; tier=A1; direction=positive; claims=194.
- Varkaneh 2022 [bundle:9]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=136.
- Obermayer 2022 [bundle:13]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=97.
- Tay 2020 [bundle:14]: outcome=cardiometabolic; directness=direct; tier=A1; direction=positive; claims=96.
- Noda 2026 [bundle:16]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=85.
- Barve 2025 [bundle:19]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=73.
- Hottenrott 2020 [bundle:21]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=70.
- Keenan 2022 [bundle:31]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=46.
- Karahan 2025 [bundle:35]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=35.
- Bamberg 2025 [bundle:39]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=28.
- Couto 2025 [bundle:62]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=2.
- Kazeminasab 2025 [bundle:2]: outcome=muscle function; directness=review; tier=B1; direction=mixed; claims=285.
- Couto-Alfonso 2026 [bundle:3]: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=263.
- Khalafi 2024a [bundle:4]: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=214.
- Kibret 2025 [bundle:5]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=202.
- Silva 2023 [bundle:7]: outcome=cardiometabolic; directness=review; tier=B1; direction=positive; claims=175.
- Lu 2025 [bundle:8]: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=163.
- Li 2026 [bundle:11]: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=110.
- He 2026 [bundle:23]: outcome=cardiometabolic; directness=review; tier=B1; direction=negative; claims=66.
- Chen 2024 [bundle:30]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=46.
- Koh 2025 [bundle:29]: outcome=cardiometabolic; directness=review; tier=B1; direction=negative; claims=46.
- Qudah 2026 [bundle:33]: outcome=cardiometabolic; directness=review; tier=B1; direction=positive; claims=36.
- Khalafi 2024b [bundle:45]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=16.
- Kazeminasab 2024b [bundle:47]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=14.
- Khalafi 2025b [bundle:56]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=8.
- Lira-Junior 2024 [bundle:60]: outcome=immune; directness=review; tier=B1; direction=unclear; claims=4.
- Barrionuevo-Burgos 2026 [bundle:61]: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=3.
- Abdollahpour 2025 [bundle:1]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=397.
- Dai 2025 [bundle:10]: outcome=cardiometabolic; directness=review; tier=B2; direction=unclear; claims=122.
- Kang 2022 [bundle:12]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=negative; claims=101.
- Xing 2026 [bundle:15]: outcome=cardiometabolic; directness=review; tier=B2; direction=unclear; claims=89.
- Abdullah 2024 [bundle:18]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=82.
- Semnani-Azad 2025 [bundle:17]: outcome=cardiometabolic; directness=review; tier=B2; direction=unclear; claims=82.
- Gu 2022 [bundle:20]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=unclear; claims=71.
- Khoshkebijari 2026 [bundle:22]: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=68.
- Jiao 2026 [bundle:24]: outcome=cardiometabolic; directness=review; tier=B2; direction=unclear; claims=60.
- Guo 2025 [bundle:25]: outcome=cardiometabolic; directness=review; tier=B2; direction=unclear; claims=58.
- Breit 2025 [bundle:26]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=55.
- Damiani 2019 [bundle:65]: outcome=safety comorbidity; directness=indirect; tier=B2; direction=unclear; claims=53.
- James 2024 [bundle:27]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=53.

### Classification Criteria

- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
- **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.
- **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.
- **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.

### Load-Bearing Tensions

- Severity 5 disagreement: Khalafi 2024a [bundle:4] vs Kang 2022 [bundle:12]; Khalafi 2024a [bundle:4] reports positive effect on body weight; Kang 2022 [bundle:12] reports negative on the same endpoint — direct conflict
- Severity 5 disagreement: Koh 2025 [bundle:29] vs Li 2026 [bundle:11]; Koh 2025 [bundle:29] reports negative effect on insulin sensitivity; Li 2026 [bundle:11] reports positive on the same endpoint — direct conflict
- Severity 5 disagreement: Huo 2025 [bundle:28] vs Li 2026 [bundle:11]; Huo 2025 [bundle:28] reports negative effect on insulin sensitivity; Li 2026 [bundle:11] reports positive on the same endpoint — direct conflict
- Severity 5 disagreement: Lu 2025 [bundle:8] vs Couto-Alfonso 2026 [bundle:3]; Lu 2025 [bundle:8] reports positive effect on hba1c; Couto-Alfonso 2026 [bundle:3] reports negative on the same endpoint — direct conflict
- Severity 5 disagreement: Lu 2025 [bundle:8] vs Li 2026 [bundle:11]; Lu 2025 [bundle:8] reports positive effect on blood glucose; Li 2026 [bundle:11] reports negative on the same endpoint — direct conflict
- Severity 5 disagreement: Qudah 2026 [bundle:33] vs Couto-Alfonso 2026 [bundle:3]; Qudah 2026 [bundle:33] reports positive effect on hba1c; Couto-Alfonso 2026 [bundle:3] reports negative on the same endpoint — direct conflict
- Severity 4 null vs negative: Silva 2023 [bundle:7] vs Kang 2022 [bundle:12]; Kang 2022 [bundle:12] (negative on body weight) vs Silva 2023 [bundle:7] (null on body weight) — partial conflict
- Severity 4 null vs negative: Talebi 2023 [bundle:44] vs Li 2026 [bundle:11]; Li 2026 [bundle:11] (negative on body mass index) vs Talebi 2023 [bundle:44] (null on body mass index) — partial conflict

## Conclusion

For fasting intervention intermittent fasting if effects, the final interpretation is deliberately tiered: the retained direct, adjacent, and context evidence profile defines a bounded evidence rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general efficacy endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent/context evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus maps evidence for fasting intervention intermittent fasting if effects but does not establish a general health, lifestyle, clinical, or policy recommendation. Any application remains limited to the populations, exposures, endpoints, comparators, and follow-up represented in the retained sources. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.

## References

- **Abdollahpour 2025.** _Comparative effects of intermittent fasting and calorie restriction on cardiovascular health in adults with overweight or obesity._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-32673-9 PMID: 41398306.
- **Kazeminasab 2025.** _Effects of Intermittent Fasting and Calorie Restriction on Exercise Performance: A Systematic Review and Meta-Analysis._ Nutrients, 2025. DOI: 10.3390/nu17121992 PMID: 40573103.
- **Couto-Alfonso 2026.** _Intermittent Fasting and Healthy Aging in Older Adults: A Systematic Review of Cardiometabolic, Mental Health and Cognitive Outcomes with a Network Meta-Analysis of Anthropometric Measures._ Nutrients, 2026. DOI: 10.3390/nu18091450 PMID: 42124054.
- **Khalafi 2024a.** _Combined versus independent effects of exercise training and intermittent fasting on body composition and cardiometabolic health in adults: a systematic review and meta-analysis._ Nutrition Journal, 2024. DOI: 10.1186/s12937-023-00909-x PMID: 38183054.
- **Kibret 2025.** _Intermittent Fasting for the Prevention of Cardiovascular Disease Risks: Systematic Review and Network Meta-Analysis._ Current Nutrition Reports, 2025. DOI: 10.1007/s13668-025-00684-7 PMID: 40705196.
- **Herz 2024.** _Effects of Different Types of Intermittent Fasting Interventions on Metabolic Health in Healthy Individuals (EDIF): A Randomised Trial with a Controlled-Run in Phase._ Nutrients, 2024. DOI: 10.3390/nu16081114 PMID: 38674802.
- **Silva 2023.** _Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders._ Journal of Clinical Medicine, 2023. DOI: 10.3390/jcm12113699 PMID: 37297894.
- **Lu 2025.** _The effect of intermittent fasting on insulin resistance, lipid profile, and inflammation on metabolic syndrome: a GRADE assessed systematic review and meta-analysis._ Journal of Health, Population, and Nutrition, 2025. DOI: 10.1186/s41043-025-01039-2 PMID: 40826125.
- **Varkaneh 2022.** _Effects of the 5:2 intermittent fasting diet on non-alcoholic fatty liver disease: A randomized controlled trial._ Frontiers in Nutrition, 2022. DOI: 10.3389/fnut.2022.948655 PMID: 35958257.
- **Dai 2025.** _Additional Effect of Exercise to Intermittent Fasting on Body Composition and Cardiometabolic Health in Adults With Overweight/obesity: A Systematic Review and Meta-analysis._ Current Obesity Reports, 2025. DOI: 10.1007/s13679-025-00645-9 PMID: 40533648.
- **Li 2026.** _Intermittent fasting versus continuous energy restriction in MASLD: a systematic review and meta-analysis._ Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1833688 PMID: 42211106.
- **Kang 2022.** _Effects of an Intermittent Fasting 5:2 Plus Program on Body Weight in Chinese Adults with Overweight or Obesity: A Pilot Study._ Nutrients, 2022. DOI: 10.3390/nu14224734 PMID: 36432420.
- **Obermayer 2022.** _Efficacy and Safety of Intermittent Fasting in People With Insulin-Treated Type 2 Diabetes (INTERFAST-2)—A Randomized Controlled Trial._ Diabetes Care, 2022. DOI: 10.2337/dc22-1622 PMID: 36508320.
- **Tay 2020.** _PROFAST: A Randomized Trial Assessing the Effects of Intermittent Fasting and Lacticaseibacillus rhamnosus Probiotic among People with Prediabetes._ Nutrients, 2020. DOI: 10.3390/nu12113530 PMID: 33212907.
- **Xing 2026.** _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._ Nutrients, 2026. DOI: 10.3390/nu18111799 PMID: 42280443.
- **Noda 2026.** _A Brief Web-Based and Mobile Intervention of Intermittent Fasting With Meal Support for Weight Loss Among Adults With Overweight and Obesity in Japan: Pilot Randomized Controlled Trial._ JMIR mHealth and uHealth, 2026. DOI: 10.2196/58930 PMID: 41587446.
- **Abdullah 2024.** _The Effect of a Combined Intermittent Fasting Healthy Plate Intervention on Anthropometric Outcomes and Body Composition Among Adults With Overweight and Obesity: Nonrandomized Controlled Trial._ JMIR Formative Research, 2024. DOI: 10.2196/51542 PMID: 38598283.
- **Semnani-Azad 2025.** _Intermittent fasting strategies and their effects on body weight and other cardiometabolic risk factors: systematic review and network meta-analysis of randomised clinical trials._ The BMJ, 2025. DOI: 10.1136/bmj-2024-082007 PMID: 40533200.
- **Barve 2025.** _Cardiometabolic and molecular adaptations to 6-month intermittent fasting in middle-aged men and women with overweight: secondary outcomes of a randomized controlled trial._ Nature Communications, 2025. DOI: 10.1038/s41467-025-66366-8 PMID: 41390492.
- **Gu 2022.** _Effects of Intermittent Fasting in Human Compared to a Non-intervention Diet and Caloric Restriction: A Meta-Analysis of Randomized Controlled Trials._ Frontiers in Nutrition, 2022. DOI: 10.3389/fnut.2022.871682 PMID: 35586738.
- **Hottenrott 2020.** _Exercise Training, Intermittent Fasting and Alkaline Supplementation as an Effective Strategy for Body Weight Loss: A 12-Week Placebo-Controlled Double-Blind Intervention with Overweight Subjects._ Life, 2020. DOI: 10.3390/life10050074 PMID: 32455547.
- **Khoshkebijari 2026.** _Intermittent Fasting May Enhance Resistance Training Effects on the Body Composition of Obese Males, Without Affecting Muscular Strength and Anabolic Index._ Journal of Obesity, 2026. DOI: 10.1155/jobe/6409069 PMID: 41726214.
- **He 2026.** _The effects of intermittent fasting on BMI, fasting blood glucose, and blood pressure in women with overweight or obesity: a systematic review and meta-analysis with dose–response relationships._ Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1818813 PMID: 42221756.
- **Jiao 2026.** _Optimal dosage of exercise combined with intermittent fasting for body composition and cardiometabolic health in adults: a systematic review and multilevel meta-analysis._ Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1772836 PMID: 41883415.
- **Guo 2025.** _Comprehensive impact of Intermittent Hypoxia Training and Intermittent Fasting on metabolic and cognitive health in adults with obesity: an umbrella systematic review and meta-analysis._ Frontiers in Nutrition, 2025. DOI: 10.3389/fnut.2025.1664600 PMID: 41170361.
- **Breit 2025.** _Effects of 4:3 Intermittent Fasting on Eating Behaviors and Appetite Hormones: A Secondary Analysis of a 12-Month Behavioral Weight Loss Intervention._ Nutrients, 2025. DOI: 10.3390/nu17142385 PMID: 40733010.
- **James 2024.** _Impact of Intermittent Fasting and/or Caloric Restriction on Aging-Related Outcomes in Adults: A Scoping Review of Randomized Controlled Trials._ Nutrients, 2024. DOI: 10.3390/nu16020316 PMID: 38276554.
- **Damiani 2019.** _The Safety and Impact of a Model of Intermittent, Time-Restricted Circadian Fasting (“Ramadan Fasting”) on Hidradenitis Suppurativa: Insights from a Multicenter, Observational, Cross-Over, Pilot, Exploratory Study._ Nutrients, 2019. DOI: 10.3390/nu11081781 PMID: 31374976.
- **Huo 2025.** _Effects of Intermittent Fasting on Anxiety and the Functional Connectivity of the Amygdala in Healthy Adults._ Alpha Psychiatry, 2025. DOI: 10.31083/AP44384 PMID: 40630882.
- **Chen 2024.** _Effects of different types of intermittent fasting on metabolic outcomes: an umbrella review and network meta-analysis._ BMC Medicine, 2024. DOI: 10.1186/s12916-024-03716-1 PMID: 39533312.
- **Koh 2025.** _The Effectiveness of Time-Restricted Eating as an Intermittent Fasting Approach on Shift Workers’ Glucose Metabolism: A Systematic Review and Meta-Analysis._ Nutrients, 2025. DOI: 10.3390/nu17101689 PMID: 40431429.
- **Keenan 2022.** _The Effects of Intermittent Fasting and Continuous Energy Restriction with Exercise on Cardiometabolic Biomarkers, Dietary Compliance, and Perceived Hunger and Mood: Secondary Outcomes of a Randomised, Controlled Trial._ Nutrients, 2022. DOI: 10.3390/nu14153071 PMID: 35893925.
- **Sourij 2026.** _Safety and efficacy of intermittent fasting with or without exercise in people living with overweight or obesity and type 2 diabetes—The INTERFAST ‐3 study design._ Diabetic Medicine, 2026. DOI: 10.1111/dme.70328 PMID: 41986966.
- **Karras 2025.** _Vitamin D supplementation and its impact on leptin and interleukin-6 in women following religious intermittent fasting: a controlled study._ Frontiers in Endocrinology, 2025. DOI: 10.3389/fendo.2025.1700844 PMID: 41384023.
- **Qudah 2026.** _Effects of intermittent fasting on HbA1c and weight in insulin versus oral hypoglycemic therapy-treated patients with type 2 diabetes mellitus: a systematic review and meta-analysis._ Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1699384 PMID: 41693941.
- **Karahan 2025.** _Effects of Intermittent Fasting on Liver Steatosis and Fibrosis, Serum FGF-21 and Autophagy Markers in Metabolic Dysfunction-Associated Fatty Liver Disease: A Randomized Controlled Trial._ Life, 2025. DOI: 10.3390/life15050696 PMID: 40430125.
- **AL-Dalaeen 2026.** _Changes in anthropometric indices, lifestyle patterns, and mental stress with ramadan intermittent fasting among healthy students: A prospective cohort study._ PLOS One, 2026. DOI: 10.1371/journal.pone.0345940 PMID: 42018499.
- **Khalafi 2025a.** _The Effects of Intermittent Fasting on Inflammatory Markers in Adults: A Systematic Review and Pairwise and Network Meta-Analyses._ Nutrients, 2025. DOI: 10.3390/nu17152388 PMID: 40805975.
- **Vignera 2026.** _Effects of Intermittent Fasting on Male and Female Reproductive Hormones, Fertility, and Sexual Function: A Comprehensive Review with Emphasis on the Existing Evidence Gap in Women._ Nutrients, 2026. DOI: 10.3390/nu18111817 PMID: 42280458.
- **Bamberg 2025.** _Stable cognitive performance while adapting to intermittent fasting: A randomised controlled trial._ Journal of Health Psychology, 2025. DOI: 10.1177/13591053251351204 PMID: 40698448.
- **Washburn 2019.** _Pilot Study of Novel Intermittent Fasting Effects on Metabolomic and Trimethylamine N -oxide Changes During 24-hour Water-Only Fasting in the FEELGOOD Trial._ Nutrients, 2019. DOI: 10.3390/nu11020246 PMID: 30678028.
- **Anic 2022.** _Intermittent Fasting—Short-and Long-Term Quality of Life, Fatigue, and Safety in Healthy Volunteers: A Prospective, Clinical Trial._ Nutrients, 2022. DOI: 10.3390/nu14194216 PMID: 36235868.
- **Wang 2025.** _The impact of intermittent fasting on body composition and cardiometabolic outcomes in overweight and obese adults: a systematic review and meta-analysis of randomized controlled trials._ Nutrition Journal, 2025. DOI: 10.1186/s12937-025-01178-6 PMID: 40731344.
- **Kazeminasab 2024a.** _Effects of intermittent fasting combined with exercise on serum leptin and adiponectin in adults with or without obesity: a systematic review and meta-analysis of randomized clinical trials._ Frontiers in Nutrition, 2024. DOI: 10.3389/fnut.2024.1362731 PMID: 38933888.
- **Pappe 2025.** _Intermittent Fasting Regimes Reduce Gingival Inflammation: A Three‐Arm Clinical Trial._ Journal of Clinical Periodontology, 2025. DOI: 10.1111/jcpe.14151 PMID: 40059409.
- **Talebi 2023.** _The effects of intermittent fasting diet alone or in combination with probiotic supplementation in comparison with calorie-restricted diet on metabolic and hormonal profile in patients with polycystic ovary syndrome: study protocol for a randomized clinical trial._ Trials, 2023. DOI: 10.1186/s13063-023-07691-5 PMID: 37880791.
- **Khalafi 2024b.** _The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta‐analysis._ Diabetes Obes Metab, 2024. DOI: 10.1111/dom.15730 PMID: 38956175.
- **Alkurd 2024.** _Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review._ Medicina, 2024. DOI: 10.3390/medicina60010191 PMID: 38276070.
- **Kazeminasab 2024b.** _Effects of intermittent fasting combined with physical exercise on cardiometabolic outcomes: systematic review and meta-analysis of clinical studies._ Nutr Rev, 2024. DOI: 10.1093/nutrit/nuad155 PMID: 38102800.
- **Karimi 2023.** _The effects of intermittent fasting diet in comparison with low-calorie diet on lipid profile, glycemic status, and liver fibrosis in patients with non-alcoholic fatty liver (NAFLD): a study protocol for a randomized controlled clinical trial._ BMC Nutrition, 2023. DOI: 10.1186/s40795-023-00794-x PMID: 38066628.
- **Xiaoyu 2024.** _The effects of different intermittent fasting regimens in people with type 2 diabetes: a network meta-analysis._ Frontiers in Nutrition, 2024. DOI: 10.3389/fnut.2024.1325894 PMID: 38332802.
- **Liu 2026.** _Intermittent fasting for rheumatic diseases: a systematic review and meta-analysis of conflicting evidence from observational studies and randomized controlled trials._ PeerJ, 2026. DOI: 10.7717/peerj.21185 PMID: 42079723.
- **Schmidt 2023.** _Effects of intermittent fasting on quality of life tolerance of chemotherapy in patients with gynecological cancers: study protocol of a randomized-controlled multi-center trial._ Frontiers in Oncology, 2023. DOI: 10.3389/fonc.2023.1222573 PMID: 37538111.
- **Ranjbar 2024.** _The effects of intermittent fasting diet on quality of life, clinical symptoms, inflammation, and oxidative stress in overweight and obese postmenopausal women with rheumatoid arthritis: study protocol of a randomized controlled trial._ Trials, 2024. DOI: 10.1186/s13063-024-07977-2 PMID: 38443945.
- **Valenzano 2025.** _Influence of Intermittent Fasting on Body Composition, Physical Performance, and the Orexinergic System in Postmenopausal Women: A Pilot Study._ Nutrients, 2025. DOI: 10.3390/nu17071121 PMID: 40218879.
- **He 2023.** _Intermittent fasting and immunomodulatory effects: A systematic review._ Frontiers in Nutrition, 2023. DOI: 10.3389/fnut.2023.1048230 PMID: 36925956.
- **Santos 2025.** _SAT-514 The Metabolic And Endocrine Effects Of Intermittent Fasting In Women With PCOS: A Meta-analysis Of Randomized Trials._ Journal of the Endocrine Society, 2025. DOI: 10.1210/jendso/bvaf149.2032
- **Khalafi 2025b.** _Longer‐term effects of intermittent fasting on body composition and cardiometabolic health in adults with overweight and obesity: A systematic review and meta‐analysis._ Obes Rev, 2025. DOI: 10.1111/obr.13855 PMID: 39501676.
- **Cozma 2025.** _Added Value to GLP-1 Receptor Agonist: Intermittent Fasting and Lifestyle Modification to Improve Therapeutic Effects and Outcomes._ Biomedicines, 2025. DOI: 10.3390/biomedicines13123079 PMID: 41463089.
- **Grine 2022.** _The Effects of Modified Intermittent Fasting in Psoriasis (MANGO): Protocol for a Two-Arm Pilot Randomized Controlled Open Cross-over Study._ JMIR Research Protocols, 2022. DOI: 10.2196/26405 PMID: 35195533.
- **Diab 2024.** _Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health._ Cell Biochemistry and Biophysics, 2024. DOI: 10.1007/s12013-024-01314-9 PMID: 38847940.
- **Lira-Junior 2024.** _Effects of intermittent fasting on periodontal inflammation and subgingival microbiota._ J Periodontol, 2024. DOI: 10.1002/jper.23-0676 PMID: 38655661.
- **Barrionuevo-Burgos 2026.** _Effects of intermittent fasting combined with a ketogenic diet versus a hypocaloric diet on metabolic outcomes in adults with type 2 diabetes mellitus: A controlled clinical study._ Nutr Health, 2026. DOI: 10.1177/02601060261446178 PMID: 42101451.
- **Lin 2024.** _The effects of intermittent fasting for patients with multiple sclerosis (MS): a systematic review._ Frontiers in Nutrition, 2024. DOI: 10.3389/fnut.2023.1328426 PMID: 38303903.
- **Ezzati 2022.** _Importance of Intermittent Fasting Regimens and Selection of Adequate Therapy on Inflammation and Oxidative Stress in SARS-CoV-2 Infection._ Nutrients, 2022. DOI: 10.3390/nu14204299 PMID: 36296982.
- **Couto 2025.** _The impact of intermittent fasting and Mediterranean diet on older adults' physical health and quality of life: A randomized clinical trial._ Nutr Metab Cardiovasc Dis, 2025. DOI: 10.1016/j.numecd.2025.104132 PMID: 40451678.

{
  "article_type": "research_synthesis",
  "domain_slug": "longevity",
  "researka_object_type": "submission",
  "researka_submission_id": "8cff959d-e26c-4d0e-82c5-ab0142694185",
  "title": "Research Synthesis: Intermittent Fasting (IF)"
}