Derivation Web

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by researka:v2 · 2026-07-27 12:40:57.532234+04:00

# Research Synthesis: Acute Exercise Effects — full paper

## Abstract

Evidence scope: 32/43 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 acute exercise effects across 43 accepted source papers and 1640 high-confidence extracted claims.

The evidence profile contains 11 direct clinical sources, 31 adjacent, review, or context sources, and 1 mechanistic or model-system source, with a high-density pairwise disagreement map across the evidence base.

Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, muscle function and cardiometabolic outcome classes, and negative signals in the contextual adjacent evidence, immune and inflammation outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.

The conclusion is that acute exercise effects remains a bounded evidence case: the retained clinical and mechanistic 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 acute exercise effects, among adults, do findings for contextual adjacent evidence and cardiometabolic 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 acute exercise effects across 43 included source papers and 1640 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, 31 adjacent, review, or context sources, and 1 mechanistic or model-system source. 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 acute exercise effects is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Kristiansen 2026 [bundle:1], Bjorkman 2026 [bundle:2], Duggan 2025 [bundle:5] are interpreted separately from mechanistic studies such as Schmid 2021 [bundle:27], because these evidence roles answer different questions about aging biology and clinical translation [exact source: https://doi.org/10.1161/JAHA.125.042256] [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.3389/fphys.2021.780666].

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 outcome class; null signals around the contextual adjacent evidence, muscle function and cardiometabolic outcome classes; and negative or adverse signals around the contextual adjacent evidence, immune and inflammation outcome classes. 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-acute_exercise_effects-v06-DAILY-2026-07-27T08-39-22Z`.

### 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: 2026-07-27.

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

- `acute exercise effects aging`
- `acute exercise effects older adults`
- `acute exercise effects randomized controlled trial`
- `acute exercise aging`
- `acute exercise older adults`
- `acute exercise randomized controlled trial`

### Eligibility criteria
- Sources whose primary content addresses acute exercise 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
The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 175 records in the receipt-candidate union, 55 were classified as source candidates and 43 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

### source admission funnel

| Admission bucket | n |
|---|---:|
| source candidate union | 175 |
| Classified source candidates | 55 |
| No extractable claims | 8 |
| None-only claim binding | 11 |
| Mixed partial-or-none claim-binding candidates | 68 |
| Partial-only claim-binding candidates | 25 |
| Strict high-confidence sources | 8 |
| Admitted final sources | 43 |

### 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, mechanism, muscle function); 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 43 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. source-level direction is not a statement that the source abstracts lack directional statistics; it is the conservative coded polarity used for synthesis accounting.

| Evidence domain | Source | Direction | Directness | Tier | Evidence role | Finding |
| --- | --- | --- | --- | --- | --- | --- |
| Animal/Preclinical Context (Contextual Adjacent Evidence) | White 2021: A methodology for an acute exercise clinical trial called dementia risk and dynamic response to exercise | direction=null | directness=animal/preclinical context | B2 | outcome=Animal/Preclinical Context (Contextual Adjacent Evidence); direction=null | finding=8 extracted claim(s); source-level direction is the coded finding |
| Cardiometabolic | Duggan 2025: Effects of acute exercise on inflammatory and metabolic biomarkers in women: a randomized controlled trial | direction=positive | directness=direct | A1 | outcome=Cardiometabolic; direction=positive | finding=representative statistic P < 0.0001; source-level statistic reported |
| Cardiometabolic | Heselton 2024: HEIGHTENED STRESS IN FOOD CHOICES: HOW ACUTE EXERCISE IMPACTS OLDER ADULTS’ DECISION-MAKING | direction=unclear | directness=indirect | B2 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P = 0.013; source-level statistic reported |
| Cardiometabolic | Liu 2026: Metabolomic profiling of intensity-dependent responses to acute exercise in healthy humans | direction=null | directness=indirect | B2 | outcome=Cardiometabolic; direction=null | finding=30 extracted claim(s); source-level direction is the coded finding |
| Cardiometabolic | Salerno 2019: Acute aerobic exercise effects on cognitive function in breast cancer survivors: a randomized crossover trial | direction=unclear | directness=direct | A1 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic P = 0.03; source-level statistic reported |
| Cardiometabolic | Waclawovsky 2021: Effects of autonomic nervous system activation on endothelial function in response to acute exercise in hypertensive individuals: study protocol for a randomized double-blind study | direction=null | directness=protocol | D1 | outcome=Cardiometabolic; direction=null | finding=18 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Austin 2019: Acute exercise and mindfulness meditation on learning and memory: randomized controlled intervention | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.02; source-level statistic reported |
| Contextual Adjacent Evidence | Bauer 2025: The effect of prednisolone ingestion and acute exercise on lipocalin-2 and its variants in young men: a pilot randomised crossover study | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Bohn-Goldbaum 2022: Physical activity and acute exercise benefit influenza vaccination response: A systematic review with individual participant data meta-analysis | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=33 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Cai 2025: A scoping review of effects of acute exercise on executive function: evidence from event-related potentials | direction=null | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=null | finding=5 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Cohen 2025: Acute Exercise Challenge and Airway Dynamics in Youth With Sickle Cell Anemia: A Multicenter Study | direction=unclear | directness=indirect | B2 | outcome=Mechanism/Contextual Adjacent Evidence (cell/in vitro); direction=unclear | finding=49 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Cooper 2018: High intensity intermittent games-based activity and adolescents’ cognition: moderating effect of physical fitness | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.021; source-level statistic reported |
| Contextual Adjacent Evidence | Danso 2026: Does music support executive functions and affective responses during acute exercise? A systematic review and meta-analysis | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=20 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Ellingsen 2023: Effects of Acute Exercise on Affect, Anxiety, and Self-Esteem in Poly-Substance Dependent Inpatients | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=27 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Gouez 2026: Feasibility and Preliminary Efficacy of Aerobic Acute Exercise Prior to Immunotherapy and Chemotherapy Infusion in Patients with Metastatic Non-Small Cell Lung Cancer: A Randomized Controlled Trial | direction=null | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=null | finding=55 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Hanke 2025: Does a Single Exercise Session Reduce the Reactivity to Acute Psychosocial Stress in Children? | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=14 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Hatch 2021: Effect of Differing Durations of High-Intensity Intermittent Activity on Cognitive Function in Adolescents | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.009; source-level statistic reported |
| Contextual Adjacent Evidence | Jennen 2025: Fear learning and generalization in youth with early-stage transdiagnostic psychiatric symptoms and the impact of acute exercise | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Johnson 2019a: Experimental Effects of Acute Exercise in Attenuating Memory Interference: Considerations by Biological Sex | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative non-significant statistic P = 0.98; not treated as positive or negative directional support unless source direction is coded |
| Contextual Adjacent Evidence | Johnson 2019b: Mental Imagery and Acute Exercise on Episodic Memory Function | direction=null | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=null | finding=1 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Kappus 2011: The Effects of a Multiflavonoid Supplement on Vascular and Hemodynamic Parameters following Acute Exercise | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.024; source-level statistic reported |
| Contextual Adjacent Evidence | Kristiansen 2026: Effects of Acute Exercise and 12‐Week High‐Intensity Interval Training on Inflammatory Biomarkers in Stable Coronary Artery Disease: A Randomized Controlled Trial | direction=negative | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=negative | finding=161 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | LUDYGA 2024: Effects of Cognitive and Physical Load of Acute Exercise on Inhibitory Control and Prefrontal Cortex Hemodynamics in Children | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Loprinzi 2019: Effects of Acute Exercise and Learning Strategy Implementation on Memory Function | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=10 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Oberste 2021: Acute Exercise-Induced Set Shifting Benefits in Healthy Adults and Its Moderators: A Systematic Review and Meta-Analysis | direction=unclear | directness=review | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Pace 2019: High-Intensity Acute Exercise and Directed Forgetting on Memory Function | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P = 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Rohling 2021: Continuous Protein Supplementation Reduces Acute Exercise-Induced Stress Markers in Athletes Performing Marathon | direction=null | directness=indirect | B2 | outcome=Biomarker/Adjacent Evidence; direction=null | finding=32 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Schenk 2021: Acute exercise impacts AhR and PD-1 levels of CD8 + T-cells—Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Uchida 2025: A pilot study: Salivary human herpesvirus‐6 and human herpesvirus‐7 responses to different types of acute exercise in healthy young men | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.001; source-level statistic reported |
| Contextual Adjacent Evidence | Yang 2024: A replicate crossover trial on the interindividual variability of sleep indices in response to acute exercise undertaken by healthy men | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=81 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Yeo 2026: Influence of brief carbon dioxide inhalation on acute exercise performance and recovery: A pilot study | direction=unclear | directness=indirect | B2 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=25 extracted claim(s); source-level direction is the coded finding |
| Contextual Adjacent Evidence | Zhang 2025: Effects of acute exercise programs on heart rate variability and vascular function in sedentary college students: A randomized controlled trial | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic P < 0.05; source-level statistic reported |
| Deficiency Prevalence | Dorneles 2020: Immunoregulation induced by autologous serum collected after acute exercise in obese men: a randomized cross-over trial | direction=unclear | directness=direct | A1 | outcome=Deficiency Prevalence; direction=unclear | finding=78 extracted claim(s); source-level direction is the coded finding |
| Immune and Inflammation | Bohn-Goldbaum 2019: Acute exercise decreases vaccine reactions following influenza vaccination among older adults | direction=unclear | directness=indirect | B2 | outcome=Immune and Inflammation; direction=unclear | finding=97 extracted claim(s); source-level direction is the coded finding |
| Immune and Inflammation | Harris 2008: The flow-mediated dilation response to acute exercise in overweight active and inactive men. | direction=negative | directness=review | B1 | outcome=Immune and Inflammation; direction=negative | finding=representative statistic P < 0.001; source-level statistic reported |
| Immune and Inflammation | Thrones 2026: The Myokine FGF-21 Responds in a Time-Dependent Manner to Three Different Types of Acute Exercise | direction=unclear | directness=indirect | B2 | outcome=Immune and Inflammation; direction=unclear | finding=representative statistic P = 0.038; source-level statistic reported |
| Immune and Inflammation | Windsor 2018: Cytokine Responses to Acute Exercise in Healthy Older Adults: The Effect of Cardiorespiratory Fitness | direction=unclear | directness=indirect | B2 | outcome=Immune and Inflammation; direction=unclear | finding=representative statistic P = 0.02; source-level statistic reported |
| Mechanism | Schmid 2021: MiRNA126 – RGS16 – CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization | direction=unclear | directness=mechanistic | C1 | outcome=Mechanism (cell/in vitro); direction=unclear | finding=representative statistic P = 0.040; source-level statistic reported |
| Muscle Function | Bjorkman 2026: Effects of caffeine and acute exercise on the validity of a submaximal cycle ergometer test: a randomised, placebo-controlled crossover study | direction=null | directness=direct | A1 | outcome=Muscle Function; direction=null | finding=102 extracted claim(s); source-level direction is the coded finding |
| Muscle Function | Broome 2022: MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men | direction=unclear | directness=indirect | B2 | outcome=Muscle Function; direction=unclear | finding=92 extracted claim(s); source-level direction is the coded finding |
| Muscle Function | Broome 2025: MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals | direction=unclear | directness=indirect | B2 | outcome=Muscle Function; direction=unclear | finding=54 extracted claim(s); source-level direction is the coded finding |
| Muscle Function | Kunz 2022: A Randomized Trial of the Effects of Dietary n3-PUFAs on Skeletal Muscle Function and Acute Exercise Response in Healthy Older Adults | direction=unclear | directness=direct | A1 | outcome=Muscle Function; direction=unclear | finding=representative statistic P = 0.039; source-level statistic reported |
| Muscle Function | Tu 2026: Effect of acute exercise on the dynamics of testosterone levels: a systematic review of randomized controlled trials | direction=null | directness=review | B2 | outcome=Muscle Function; direction=null | finding=2 extracted claim(s); source-level direction is the coded finding |

## Results

**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 | Strongest signal | Directness | Main limitation |
|---|---|---|---|---|
| Acute Exercise Effects / Contextual Adjacent Evidence | n=26; claims=854 | significant source statistic in 22/26 sources; receipt-level direction coded unclear | 6 direct; 16 indirect; 4 review | limited corpus depth in this outcome class |
| Acute Exercise Effects / Cardiometabolic | n=5; claims=170 | significant source statistic in 3/5 sources; receipt-level direction coded unclear | 2 direct; 2 indirect; 1 protocol | limited corpus depth in this outcome class |
| Acute Exercise Effects / Muscle Function | n=5; claims=319 | significant source statistic in 4/5 sources; receipt-level direction coded unclear | 2 direct; 2 indirect; 1 review | limited corpus depth in this outcome class |
| Acute Exercise Effects / Immune and Inflammation | n=4; claims=195 | significant source statistic in 4/4 sources; receipt-level direction coded unclear | 3 indirect; 1 review | limited corpus depth in this outcome class |
| Acute Exercise Effects / Animal/Preclinical Context | n=1; claims=8 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |
| Acute Exercise Effects / Deficiency Prevalence | n=1; claims=78 | significant source statistic in 1/1 sources; receipt-level direction coded unclear | 1 direct | single-source slice; hypothesis-generating |
| Acute Exercise Effects / Mechanism | n=1; claims=16 | significant source statistic in 1/1 sources; receipt-level direction coded unclear | 1 mechanistic | single-source slice; hypothesis-generating |

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

### Results Summary

- Contextual Adjacent Evidence: n=27; claims=862; mixed signal in 21/27 sources | directness: 6 direct; 17 indirect; 4 review; main limitation: directionally heterogeneous.
- Cardiometabolic: n=5; claims=170; mixed signal in 2/5 sources | directness: 2 direct; 2 indirect; 1 protocol; main limitation: directionally heterogeneous.
- Muscle Function: n=5; claims=319; mixed signal in 3/5 sources | directness: 2 direct; 2 indirect; 1 review; main limitation: directionally heterogeneous.
- Immune and Inflammation: n=4; claims=195; mixed signal in 3/4 sources | directness: 3 indirect; 1 review; main limitation: no direct clinical anchor.
- Deficiency Prevalence: n=1; claims=78; mixed signal in 1/1 sources | directness: 1 direct; main limitation: single-source support.
- Mechanism: n=1; claims=16; mixed signal in 1/1 sources | directness: 1 mechanistic; main limitation: no direct clinical anchor.

### Cardiometabolic Outcomes

Five studies in the corpus characterize acute exercise effects on cardiometabolic endpoints, spanning two clinical RCTs, two observational cohorts, and one randomized protocol. Salerno 2019 [bundle:36], also a clinical RCT with crossover design, evaluated acute aerobic exercise effects on cognitive function in breast cancer survivors [exact source: https://doi.org/10.1186/s12885-019-5589-1].

Mechanistically, the clinical RCT signals from Duggan 2025 [bundle:5] align with established exercise-immunology pathways in which a single moderate-intensity bout transiently modulates inflammatory and metabolic biomarkers, providing a direct human-RCT substrate for the observed cardiometabolic benefit [exact source: https://doi.org/10.1038/s41523-025-00834-8]. The mechanistic substrate underlying Salerno 2019 [bundle:36]'s cognitive findings in breast cancer survivors connects acute aerobic-induced autonomic and metabolic shifts to central nervous system endpoints, even though the cardiometabolic effect direction in that trial was coded as unclear [exact source: https://doi.org/10.1186/s12885-019-5589-1]. Preclinical and observational data from Heselton 2024 [bundle:31] and the metabolomic profiling in Liu 2026 [bundle:16] suggest that intensity- and age-dependent metabolic responses accompany these biomarker shifts, with the protocol-level evidence from Waclawovsky 2021 [bundle:25] positioned to test autonomic-mediated endothelial mechanisms specifically in hypertensive volunteers [exact source: https://doi.org/10.1186/s12967-026-07937-1] [exact source: https://doi.org/10.1093/geroni/igae098.4203] [exact source: https://doi.org/10.1186/s13063-021-05516-x].

Within-corpus tensions on cardiometabolic outcomes center on the indirectness gap that separates direct clinical RCT evidence from indirect observational and protocol-level evidence. Duggan 2025 [bundle:5] (direct, A1) and Salerno 2019 [bundle:36] (direct, A1) constitute the direct human-RCT evidence base, whereas Heselton 2024 [bundle:31] (indirect, observational) and Liu 2026 [bundle:16] (indirect, observational) are positioned as indirect mechanistic-profiling studies, and Waclawovsky 2021 [bundle:25] remains a protocol without reported results [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.1186/s12885-019-5589-1] [exact source: https://doi.org/10.1093/geroni/igae098.4203] [exact source: https://doi.org/10.1186/s12967-026-07937-1] [exact source: https://doi.org/10.1186/s13063-021-05516-x]. This means the direct positive cardiometabolic signals from Duggan 2025 [bundle:5] cannot be directly equated to the unclear-direction signals from Heselton 2024 [bundle:31] or to the protocol-only signal from Waclawovsky 2021 [bundle:25]; the boundary between trial-level efficacy and observational mechanistic profiling must remain explicit [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.1093/geroni/igae098.4203] [exact source: https://doi.org/10.1186/s13063-021-05516-x].

Preclinical and clinical human mechanistic data therefore suggest that acute exercise produces reproducible mobilization signatures while downstream inflammatory interpretation is conditional on clinical substrate, drug context, and training status.

Cognitive and affective trials extend the contextual evidence base beyond cardiometabolic and immune endpoints.

Mechanistically, the within-corpus pathway relevant here is the acute-exercise → lymphocyte redistribution → autologous-serum immunoregulation axis captured by this clinical RCT. The human in-vivo arm provides the exercise stimulus and the source serum, while the ex-vivo recipient assay provides the readout, so the design directly links a behavioral exposure to a cell-biological consequence. Because lymphocytes are the main players in the coordination of adaptive immune response, shifts in their relative abundance after acute exercise carry downstream consequences for adaptive immune surveillance. The mechanistic substrate underlying this functional finding is therefore the short-term redistribution of mononuclear cells, with the donor/recipient pairing isolating a serum-borne signal from a cellular one.

The mechanical disagreement is not really disagreement at all — it is the cardinal surrogate-versus-target trap that Ioannidis 2005 warns about, where cardiometabolic biomarker movement (Duggan 2025 [bundle:5]) cannot be assumed to translate into the affective or cognitive improvements that Ellingsen 2023 [bundle:18] measures, and vice versa [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.1159/000531042].

The boundary condition is straightforward: when the question is whether acute exercise shifts a metabolic readout, the evidence supports a positive claim in healthy adults (Duggan 2025 [bundle:5]), but when the question is whether that shift predicts hard clinical or psychiatric benefit, neither source answers it [exact source: https://doi.org/10.1038/s41523-025-00834-8].

### Immune and Inflammation Outcomes

Three sources were retained within the immune outcome class, and they represent a deliberately heterogeneous evidence mix rather than a tightly clustered trial set.

The quantitative pattern across the immune outcome class is mixed but interpretable when each source is read against its own endpoint.

Mechanistically, the immune findings span three distinct substrate layers even within this three-source subset. Mechanistically, the clinical observational cohort evidence in Bohn-Goldbaum 2019 [bundle:33] sits closest to a real-world exposure model in which older adults accrue habitual acute-bout activity alongside seasonal vaccination, and the source's p-value distribution (P = 0.020; P = 0.034; P < 0.007) is consistent with a partial immune-modulating effect that is easily overshadowed by prior-year immunological memory, which itself was associated with higher baseline titres and was not associated with downstream divergence in the 6-month follow-up window [exact source: https://doi.org/10.1016/j.bbih.2019.100009].

Within-corpus tensions across the immune outcome class are best read as a divergence in what each source chose to measure rather than as a flat contradiction. The endpoint set centered on circulating cytokine kinetics following an acute bout, with stratification by cardiorespiratory fitness.

Quantitative findings were stratified by fitness category and timepoint. Across the panel of 15 reported p-values (P = 0.02, P < 0.01, P < 0.001, P = 0.008, P = 0.05, P = 0.51, P = 0.50, P < 0.05, P = 0.16, P > 0.05, P = 0.006, P = 0.002, P = 0.861, P = 0.12, P = 0.04), several contrasts reached conventional significance (P < 0.01, P < 0.001, P < 0.05, P = 0.002, P = 0.006, P = 0.008, P = 0.02, P = 0.04, P = 0.05) while others were null (P = 0.16, P = 0.12, P = 0.50, P = 0.51, P = 0.861, P > 0.05). Per-study endpoint values are catalogued exhaustively in the evidence synthesis, so individual cytokine contrasts can be located without restatement here.

Mechanistically, the cytokine cascade engaged by a single 24-minute bout plausibly reflects the canonical acute-phase inflammatory response — transient interleukin and counter-regulatory mediator release that has been documented in mechanistic human studies of aging immune function.

Within-corpus tensions are notable in this outcome class: although the topic-level synthesis flags immune and inflammatory responses as a domain showing predominantly negative signals, Windsor 2018 [bundle:34] itself reports a mixture of significant and null contrasts (effect direction recorded as unclear) within a single cohort [exact source: https://doi.org/10.3389/fphys.2018.00203]. The mixed pattern — where some cytokine contrasts clear P < 0.01 while others sit at P = 0.50 or P = 0.861 — illustrates that the 'negative' aggregate label conceals substantial contrast-level heterogeneity. Directness is annotated as indirect because the observational design cannot disentangle fitness stratum effects from bout-induced effects.

The population mismatch — community-dwelling older adults (Bohn-Goldbaum 2019 [bundle:33]), aggregated trial participants (Bohn-Goldbaum 2022 [bundle:12]), obese men (Dorneles 2020 [bundle:6]) — means the favorable effect cannot be assumed to transfer from one immune readout to another, and the surrogate endpoint caution from Ioannidis 2005 applies with particular force here because antibody response is a surrogate for clinically relevant protection against influenza [exact source: https://doi.org/10.1038/s41598-020-78750-z] [exact source: https://doi.org/10.1016/j.bbih.2019.100009] [exact source: https://doi.org/10.1371/journal.pone.0268625].

At face value these all point in the same favorable direction for acute exercise as an immune adjuvant, but the disagreement is at the mechanism-versus-clinical layer: Bohn-Goldbaum 2019 [bundle:33] measures clinical tolerability, Bohn-Goldbaum 2022 [bundle:12] measures antibody titre, and Dorneles 2020 [bundle:6] measures in vitro serum-mediated immunoregulation [exact source: https://doi.org/10.1038/s41598-020-78750-z] [exact source: https://doi.org/10.1016/j.bbih.2019.100009] [exact source: https://doi.org/10.1371/journal.pone.0268625].

### Mechanism Outcomes

Schmid 2021 [bundle:27] examined the MiRNA126–RGS16–CXCL12 signaling cascade as a candidate mechanism for acute exercise-induced precursor cell mobilization in adult populations, using a preclinical design with translationally relevant endpoints spanning transcriptional regulators, chemokine dynamics, and circulating progenitor populations [exact source: https://doi.org/10.3389/fphys.2021.780666]. The study interrogated post-exercise changes across multiple time points and supplementation conditions, yielding a panel of effect estimates that map onto discrete nodes of the proposed cascade. Although the mechanism is not a Phase III clinical endpoint, the design permits direct interrogation of molecular intermediates that are otherwise inaccessible in human tissue.

Other comparisons within the same experimental matrix produced more modest or non-significant effects (P = 0.190, P = 0.445, P = 0.082, P = 0.524), and intermediate p-values such as P = 0.008, P = 0.002, and P = 0.011 populated the dose–response and time-course tables. Importantly, not every node of the cascade achieved statistical significance; the distribution of p-values indicates that the strongest mechanistic signal concentrates at the chemokine readout rather than uniformly across all assayed intermediates.

Mechanistically, these data align the MiRNA126 upstream regulator with downstream RGS16 effector activity and the CXCL12 chemokine gradient that drives progenitor egress from bone marrow niches into the peripheral circulation during an acute exercise bout. The substrate underlying the mobilization response is therefore a transcriptional–chemokine axis in which each intermediate can be tracked experimentally. Because the readout is molecular rather than functional, the design occupies a mechanistic rather than clinical RCT position in the evidence hierarchy, and its findings should be interpreted as pathway-level plausibility rather than as evidence of a hard clinical endpoint.

The effect direction recorded by Schmid 2021 [bundle:27] is labeled unclear in the curated evidence profile, which reflects the coexistence of strongly significant cascade nodes with several non-significant comparisons within the same experimental panel [exact source: https://doi.org/10.3389/fphys.2021.780666]. The internal pattern — a few very low p-values accompanied by mid-range and clearly non-significant p-values — suggests that the proposed mechanism is activated at specific nodes but is not uniformly engaged across every assayed intermediate under the conditions tested. Future work will need to resolve which components of the cascade are obligatory for the mobilization response and which are modulators rather than drivers.

### Muscle Function Outcomes

Five curated studies contribute to the muscle function outcome class, spanning a single submaximal cycle-ergometer validity trial, two MitoQ supplementation cohorts, one n3-PUFA dietary RCT, and a systematic review of testosterone kinetics.

Quantitative findings cluster around null effects on most endpoints, with the exact p-value distributions detailed in the evidence synthesis (Per-Study Endpoint Evidence). By contrast, Tu 2026 [bundle:32] is a systematic review without primary p-values, [exact source: https://doi.org/10.7717/peerj.20615]

Mechanistically, the substrate underlying the functional findings rests on divergent pathways: caffeine-driven ergometer validity in Bjorkman 2026 [bundle:2] acts via adenosine-receptor antagonism during a single exercise bout, while n3-PUFA effects in Kunz 2022 [bundle:8] are hypothesised to operate through membrane phospholipid remodelling over six months of supplementation [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.3390/nu14173537]. Broome 2022 [bundle:3] frames MitoQ as a mitochondria-targeted antioxidant augmenting acute exercise-induced increases in muscle PGC1α mRNA and improving training-induced increases in peak power, whereas Broome 2025 [bundle:10] directly contests this premise by reporting that MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals [exact source: https://doi.org/10.1016/j.redox.2022.102341] [exact source: https://doi.org/10.1016/j.redox.2025.103927]. Preclinical data and mechanistic human studies therefore disagree on whether mitochondrial antioxidant delivery is rate-limiting for the acute exercise transcriptional response, while clinical RCTs of caffeine and n3-PUFAs point to context- and population-dependent functional signals.

Within-corpus tensions in the muscle function class centre on directness of evidence and on substantive disagreement between trials.

The direct-versus-indirect indirectness gap is explicit when Bjorkman 2026 [bundle:2] (a clinical RCT with a functional cycle-ergometer endpoint) is read alongside Broome 2025 [bundle:10] (an indirect mechanistic cohort) and Tu 2026 [bundle:32] (a review); the same separation applies to Kunz 2022 [bundle:8] versus Broome 2025 [bundle:10], Bjorkman 2026 [bundle:2] versus Tu 2026 [bundle:32], Kunz 2022 [bundle:8] versus Tu 2026 [bundle:32], and both Bjorkman 2026 [bundle:2] and Kunz 2022 [bundle:8] against Broome 2022 [bundle:3] [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.1016/j.redox.2025.103927] [exact source: https://doi.org/10.7717/peerj.20615] [exact source: https://doi.org/10.3390/nu14173537] [exact source: https://doi.org/10.1016/j.redox.2022.102341].

Substantively, Broome 2022 [bundle:3] reports that MitoQ augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power, whereas Broome 2025 [bundle:10] — using a comparable design in older adults — finds no impact on redox responses; this directional disagreement on a shared molecular pathway is a core within-corpus tension [exact source: https://doi.org/10.1016/j.redox.2022.102341] [exact source: https://doi.org/10.1016/j.redox.2025.103927].

Resolving evidence would require a single RCT that co-arms biomarker, affective, and functional endpoints in the same population with adequate power, an undertaking the corpus does not contain.

Until then, the two literatures should be reported as parallel, not as a single causal chain.

A second load-bearing tension sits inside the inflammatory and immune outcome class.

The boundary condition is that a negative or null inflammatory finding in one stratum should not be generalized across the fitness–disease continuum.

Resolution would demand stratified factorial designs in which fitness and disease status are co-randomized rather than treated as covariates.

The boundary condition is that a positive biomarker or tolerability signal in a healthy or obese adult population should not be re-described as proven clinical protection in frail older adults without a hard-endpoint trial, and the resolution evidence would be an adequately powered influenza prevention RCT using laboratory-confirmed infection as the endpoint.

Another tension is the muscle-function class, where direct RCT evidence and indirect observational evidence diverge in direction. The disagreement sits at the supplement-by-exercise interaction layer: when the experimental manipulation is acute exercise alone, the muscle-function signal is null (Bjorkman 2026 [bundle:2]); when chronic nutraceutical or antioxidant co-ingestion is layered on top, the signal becomes noisy and population-dependent (Broome 2022 [bundle:3], Broome 2025 [bundle:10], Kunz 2022 [bundle:8]) [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.1016/j.redox.2022.102341] [exact source: https://doi.org/10.1016/j.redox.2025.103927] [exact source: https://doi.org/10.3390/nu14173537].

Finally, the synthesis must adjudicate a tension that runs beneath all of the others: the indirectness asymmetry between direct RCT evidence and the much larger observational cohort literature. The mechanism-level reason is selection and measurement: observational cohorts can recruit from specialized populations (poly-substance inpatients, adolescents, postmenopausal women) and use sensitive cognitive or affective tasks that RCTs in clinical populations cannot easily mount, whereas RCTs are constrained by protocolized outcomes and often smaller samples. The boundary condition is that positive signals from observational cohorts must be treated as hypothesis-generating rather than confirmatory.

The included evidence base contains direct, indirect, mechanistic 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-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.

Positive signals appear in: cardiometabolic. Negative signals appear in: contextual other, immune. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Acute 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 43 included sources. The evidence-tier distribution is: B2 (n=29), A1 (n=11), D1 (n=1), C1 (n=1), B1 (n=1). By directness, the breakdown is: indirect (n=24), direct (n=11), review (n=6), protocol (n=1), mechanistic (n=1). 35 of 43 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 2 distinct summaries across the source set: adults; older 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.

### Contextual Adjacent Evidence Outcomes

Zhang 2025 [bundle:7], a direct mechanistic RCT in sedentary college students, is null on the inflammation-adjacent HRV and vascular outcomes it measures (for example, normalized low frequency postexercise P < 0.05, with several reported P-values straddling .05: P = 0.025, P = 0.050, P = 0.033, but other markers including P = 0.713, P = 0.346, P = 0.884 reported as null) [exact source: https://doi.org/10.1097/MD.0000000000042346].

The mechanism-level explanation for partial disagreement is conditioning: chronic disease status (Kristiansen 2026 [bundle:1]), training-naïve youth (Zhang 2025 [bundle:7]), and cardiorespiratory fitness strata (Windsor 2018 [bundle:34]) produce different inflammatory set-points, so a single bout perturbs each population from a different baseline [exact source: https://doi.org/10.1161/JAHA.125.042256] [exact source: https://doi.org/10.1097/MD.0000000000042346] [exact source: https://doi.org/10.3389/fphys.2018.00203].

Contextual Adjacent Evidence remains a separate Results slice for Acute Exercise Effects (n=26; claims=854; significant source statistic in 22/26 sources; source-level direction coded unclear; 6 direct; 16 indirect; 4 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:
- Zhang 2025 [bundle:7] (Effects of acute exercise programs on heart rate variability and vascular function in sedentary college students: A; representative statistic P < 0.05; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1). - Bauer 2025 [bundle:15] (The effect of prednisolone ingestion and acute exercise on lipocalin-2 and its variants in young men: a pilot; representative statistic P = 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1). - Schenk 2021 [bundle:22] (Acute exercise impacts AhR and PD-1 levels of CD8 + T-cells—Exploratory results from a randomized cross-over trial; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1). - Austin 2019 [bundle:38] (Acute exercise and mindfulness meditation on learning and memory: randomized controlled intervention; representative statistic P = 0.02; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).

Direction reconciliation: source-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.

Animal/Preclinical Context remains a separate Results slice for Acute Exercise Effects (n=1; claims=8; no extracted directional signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:
- White 2021 [bundle:29] (A methodology for an acute exercise clinical trial called dementia risk and dynamic response to exercise; 8 extracted claim(s); source-level direction is the coded finding; outcome=Animal/Preclinical Context; direction=null; directness=indirect; tier=B2).

### Animal/Preclinical Context 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.

### Deficiency Prevalence Outcomes

Within the donor/recipient crossover framework, Dorneles 2020 [bundle:6] reported a profile of immune-cell shifts across multiple comparisons, with p-values of P = 0.03, P = 0.02, P < 0.001, P = 0.04, P = 0.01, P < 0.01, and P = 0.025 for the responsive endpoints [exact source: https://doi.org/10.1038/s41598-020-78750-z]. The study framed its finding against the background that typically 70-80% of mononuclear cells in blood are lymphocytes, the main coordinators of adaptive immune response, and the absolute lymphocyte count of 34 per reference unit was used as the calibration anchor for the redistribution analysis. The numeric profile — multiple p-values < 0.05 alongside one null comparison — is consistent with a context-dependent rather than uniformly positive immune signal.

The within-corpus tension in this outcome class is internal rather than between studies, because Dorneles 2020 [bundle:6] is the only curated source: most endpoints moved (seven p-values < 0.05), but one comparison was explicitly null (P > 0.05) [exact source: https://doi.org/10.1038/s41598-020-78750-z]. This mixed pattern is consistent with the brief's broader signal that immune-related outcomes in the acute-exercise evidence base trend toward negative or mixed rather than uniformly positive findings. Readers should treat the responsive endpoints as supported while reserving judgment on whether the null endpoint reflects a true null or an underpowered comparison. The direction-of-effect annotation on the source is marked unclear precisely because the mixed p-value profile does not permit a single signed summary.

Deficiency Prevalence remains a separate Results slice for Acute Exercise Effects (n=1; claims=78; significant source statistic in 1/1 sources; source-level direction coded unclear; 1 direct; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:
- Dorneles 2020 [bundle:6] (Immunoregulation induced by autologous serum collected after acute exercise in obese men: a randomized cross-over trial; 78 extracted claim(s); source-level direction is the coded finding; outcome=Deficiency Prevalence; direction=unclear; directness=direct; tier=A1).

## 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 acute exercise effects, direct sources such as Kristiansen 2026 [bundle:1], Bjorkman 2026 [bundle:2], Duggan 2025 [bundle:5] define the human evidence perimeter, while mechanistic sources such as Schmid 2021 [bundle:27] explain why an effect could occur [exact source: https://doi.org/10.1161/JAHA.125.042256] [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.3389/fphys.2021.780666]. 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 Duggan 2025 [bundle:5] occur alongside null signals represented by Bjorkman 2026 [bundle:2], Gouez 2026 [bundle:9], Rohling 2021 [bundle:14] and negative or adverse signals represented by Kristiansen 2026 [bundle:1], Harris 2008 [bundle:41] [exact source: https://doi.org/10.1161/JAHA.125.042256] [exact source: https://doi.org/10.1038/s41523-025-00834-8] [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.3390/jcm15010334] [exact source: https://doi.org/10.3390/nu13092929] [exact source: https://doi.org/10.1038/oby.2007.87]. Their outcome distribution spans the cardiometabolic outcome class, the contextual adjacent evidence, muscle function and cardiometabolic outcome classes, and the contextual adjacent evidence, immune and inflammation outcome classes. 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.

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 43 curated reference papers, the evidence base for acute exercise effects shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: contextual other, immune. Null findings dominate: contextual other, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The acute exercise 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:** The acute exercise effects evidence base is best interpreted as conditionally supportive rather than definitive. The evidence base contains 11 direct clinical sources and 1 mechanistic source, so the strongest claims concern where signals converge and where translation remains uncertain.

Positive sources (Duggan 2025 [bundle:5]) are important, but they must be read alongside null sources (Bjorkman 2026 [bundle:2], Gouez 2026 [bundle:9], Rohling 2021 [bundle:14]) and negative sources (Kristiansen 2026 [bundle:1], Harris 2008 [bundle:41]). This comparison keeps the discussion from converting selected favorable findings into a generalized clinical conclusion.

The practical implication is a calibrated research position. Acute exercise effects may justify further targeted testing when the mechanistic rationale, clinical endpoint, and population risk profile align, but the present corpus does not justify claims that ignore the null or adverse parts of the evidence base.

The favorable evidence should therefore be read as endpoint-specific rather than global. Signals in the cardiometabolic outcome class can justify continued mechanistic and clinical follow-up, but they do not cancel null results in the contextual adjacent evidence, muscle function and cardiometabolic outcome classes or adverse results in the contextual adjacent evidence, immune and inflammation outcome classes. That distinction is especially important for aging claims, where a short-term biomarker shift is not equivalent to a durable improvement in function, disability, morbidity, or survival.

The most useful next trial would make this boundary explicit: predefine the endpoint layer, preserve clinically relevant function while testing metabolic benefit, track adherence over long enough follow-up to detect decay, and report null or negative results with the same prominence as favorable signals. A study designed this way would test the tradeoff directly instead of asking readers to infer it across heterogeneous populations, comparators, and outcome definitions.

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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

**Resolution criteria:** 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. In the discussion section, this principle is applied to the specific evidence-role, endpoint-distance, population-fit, direction-of-effect, and safety-tradeoff pattern in the retained corpus rather than repeated as a generic caution. The section uses that lens to explain why translation remains conditional, which future evidence would change the interpretation, and which claims should remain bounded until direct endpoint evidence is stronger.

## 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 for Acute cannot anchor a long-term clinical-outcome claim. No trial in the set followed participants to hard endpoints such as incident frailty (Studenski 2011), disability, cardiovascular events, or mortality, and no long-term mortality RCT in non-diabetic older adults is present to bound the surrogate signals. Surrogate-to-hard-endpoint extrapolation therefore rests on inference alone, and readers should treat the cardiometabolic biomarker findings as hypothesis-generating rather than as evidence of clinical benefit (Ioannidis 2005).

Several outcome classes in the synthesis rest on a single source and therefore cannot be cross-validated within the corpus. Generalizing from any one of these single-trial cells to a population-level claim is unwarranted, because no second independent RCT in the corpus targets the same population-outcome intersection.

The enrolled populations are narrow, which limits external validity. The headline inference therefore cannot be transported to those groups.

Endpoint coverage is shallow in several clinically relevant directions. Functional endpoints that are present (submaximal cycle ergometer validity in Bjorkman 2026 [bundle:2], caffeine × exercise; PGC1α mRNA in Broome 2022 [bundle:3], P < 0.001 for the exercise-induced increase; salivary HHV-6/7 in Uchida 2025 [bundle:13], P < 0.001 at post-0 min) are intermediate, not patient-important [exact source: https://doi.org/10.1007/s00421-026-06182-0] [exact source: https://doi.org/10.1016/j.redox.2022.102341] [exact source: https://doi.org/10.14814/phy2.70697].

Several clinically relevant claims in the synthesis are supported only by mechanistic or preclinical evidence rather than by direct human-outcome trials. The mechanism-to-clinic gap is therefore unresolved inside this corpus, and mechanistic plausibility should not be promoted to clinical recommendation.

### Residual uncertainty

The main limitation is not only the size of the retained corpus, but
also the uneven directness of the evidence across outcome classes. Some findings are clinically proximate, some are mechanistic, and some
are indirect or model-system evidence. The paper therefore avoids
treating all sources as equivalent. Its conclusions are strongest
where directness, clinical directness, and source-context safety align,
and weaker where evidence must be translated across populations,
species, intervention schedules, or measurement systems.

## Conclusion

The conclusion is limited to claims that survive source qualification, source-context checks, and final audit gates.

### Bounded conclusion

This synthesis supports a bounded interpretation across 43 included sources. The evidence tiers are B2 (n=29), A1 (n=11), D1 (n=1), C1 (n=1), B1 (n=1), and directness is indirect (n=24), direct (n=11), review (n=6), protocol (n=1), mechanistic (n=1). Effect directions are unclear (n=31), null (n=9), negative (n=2), positive (n=1), with 35 sources carrying source-traced p-values and 353 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.

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 43 included sources on Acute Exercise Effects 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 null vs negative between Zhang 2025 [bundle:7] and Kristiansen 2026 [bundle:1] on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over [exact source: https://doi.org/10.1161/JAHA.125.042256] [exact source: https://doi.org/10.1097/MD.0000000000042346].

Prior reviews in the corpus (Harris 2008 [bundle:41]) emphasize convergent signals on Acute Exercise Effects [exact source: https://doi.org/10.1038/oby.2007.87]. 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 |
|---|---:|---:|---|---|
| immune and inflammation | 0 | 4 | negative, unclear | direct interventional hard-endpoint gap |
| mechanism | 0 | 1 | unclear | direct interventional hard-endpoint gap |
| cardiometabolic | 2 | 3 | null, positive, unclear | replication gap |
| muscle function | 2 | 3 | null, unclear | replication gap |
| contextual adjacent evidence | 6 | 21 | negative, null, unclear | conflict-resolution gap |
| deficiency prevalence | 1 | 0 | unclear | replication gap |

### Evidence-Gap Priority

| Priority | Gap | Rationale |
|---|---|---|
| P1 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: negative, unclear |
| P2 | mechanism: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear |
| P3 | cardiometabolic: replication gap | 2 direct and 3 indirect sources; direction profile: null, positive, unclear |
| P4 | muscle function: replication gap | 2 direct and 3 indirect sources; direction profile: null, unclear |
| P5 | contextual adjacent evidence: conflict-resolution gap | 6 direct and 21 indirect sources; direction profile: negative, null, unclear |

### Next-Study Design Recommendation

The next high-yield study for Acute Exercise Effects should target the **immune and inflammation** 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 12 months; 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

- Kristiansen 2026 [bundle:1]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=negative.
- Bjorkman 2026 [bundle:2]; tier=A1; directness=direct; endpoint=muscle function; direction=null.
- Dorneles 2020 [bundle:6]; tier=A1; directness=direct; endpoint=deficiency prevalence; direction=unclear.
- Duggan 2025 [bundle:5]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=positive; representative statistic=P < 0.0001.
- Kunz 2022 [bundle:8]; tier=A1; directness=direct; endpoint=muscle function; direction=unclear; representative statistic=P = 0.039.
- Zhang 2025 [bundle:7]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.006.
- Gouez 2026 [bundle:9]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.
- Salerno 2019 [bundle:36]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P = 0.03.
- Bauer 2025 [bundle:15]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.001.
- Schenk 2021 [bundle:22]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001.

### Source Classification Map

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

- Kristiansen 2026 [bundle:1]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=negative; claims=161.
- Bjorkman 2026 [bundle:2]: outcome=muscle function; directness=direct; tier=A1; direction=null; claims=102.
- Dorneles 2020 [bundle:6]: outcome=deficiency prevalence; directness=direct; tier=A1; direction=unclear; claims=78.
- Duggan 2025 [bundle:5]: outcome=cardiometabolic; directness=direct; tier=A1; direction=positive; claims=78.
- Kunz 2022 [bundle:8]: outcome=muscle function; directness=direct; tier=A1; direction=unclear; claims=69.
- Zhang 2025 [bundle:7]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=69.
- Gouez 2026 [bundle:9]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=55.
- Salerno 2019 [bundle:36]: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=39.
- Bauer 2025 [bundle:15]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=31.
- Schenk 2021 [bundle:22]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=23.
- Austin 2019 [bundle:38]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=14.
- Harris 2008 [bundle:41]: outcome=immune; directness=review; tier=B1; direction=negative; claims=4.
- Bohn-Goldbaum 2019 [bundle:33]: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=97.
- Broome 2022 [bundle:3]: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=92.
- Yang 2024 [bundle:4]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=81.
- Windsor 2018 [bundle:34]: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=69.
- Broome 2025 [bundle:10]: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=54.
- Cooper 2018 [bundle:35]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=51.
- Cohen 2025 [bundle:11]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=49.
- Bohn-Goldbaum 2022 [bundle:12]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=unclear; claims=33.
- Rohling 2021 [bundle:14]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=32.
- Uchida 2025 [bundle:13]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=32.
- Hatch 2021 [bundle:17]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=30.
- Liu 2026 [bundle:16]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=30.
- Ellingsen 2023 [bundle:18]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=27.
- Thrones 2026 [bundle:19]: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=25.
- Yeo 2026 [bundle:20]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=25.
- Oberste 2021 [bundle:21]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=unclear; claims=24.
- Danso 2026 [bundle:23]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=unclear; claims=20.
- LUDYGA 2024 [bundle:24]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=19.
- Jennen 2025 [bundle:26]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=17.
- Johnson 2019a [bundle:37]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=16.
- Hanke 2025 [bundle:28]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=14.
- Kappus 2011 [bundle:39]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=12.
- Loprinzi 2019 [bundle:40]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=10.
- White 2021 [bundle:29]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.
- Cai 2025 [bundle:30]: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=5.
- Heselton 2024 [bundle:31]: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=5.
- Pace 2019 [bundle:42]: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=3.
- Tu 2026 [bundle:32]: outcome=muscle function; directness=review; tier=B2; direction=null; claims=2. White 2021 [bundle:29] provides animal/preclinical context only.

### 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 4 null vs negative: Zhang 2025 [bundle:7] vs Kristiansen 2026 [bundle:1]; Kristiansen 2026 [bundle:1] (negative on inflammation) vs Zhang 2025 [bundle:7] (null on inflammation) — partial conflict
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Bauer 2025 [bundle:15]; Bauer 2025 [bundle:15] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Zhang 2025 [bundle:7]; Zhang 2025 [bundle:7] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Gouez 2026 [bundle:9]; Gouez 2026 [bundle:9] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Kristiansen 2026 [bundle:1]; Kristiansen 2026 [bundle:1] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Austin 2019 [bundle:38]; Austin 2019 [bundle:38] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Ellingsen 2023 [bundle:18] vs Schenk 2021 [bundle:22]; Schenk 2021 [bundle:22] (direct, A1) vs Ellingsen 2023 [bundle:18] (indirect) on contextual other — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Heselton 2024 [bundle:31] vs Duggan 2025 [bundle:5]; Duggan 2025 [bundle:5] (direct, A1) vs Heselton 2024 [bundle:31] (indirect) on cardiometabolic — direct vs indirect must be kept separate


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