{"publication_id":"20c54f16-9fa0-483f-a812-d305b4b1d813","content_hash":"sha256:e3eee1fc2c04bd88ecc07ca379816e491d5e330518c145e01dd02c55d36bdd1e","nodes":[{"id":"20c54f16-9fa0-483f-a812-d305b4b1d813","type":"publication","title":"Hypothesis-Generating Brief: Creatine monohydrate — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on Creatine monohydrate across 28 accepted source papers and 1882 high-confidence extracted claims."},{"id":"claim_2","type":"claim","text":"The evidence profile contains 4 direct clinical sources, 23 adjacent clinical sources, and 1 mechanistic or model-system source, with a high-density pairwise disagreement map across the evidence base."},{"id":"claim_3","type":"claim","text":"Positive study-level signals are summarized in the muscle function and contextual adjacent evidence outcome classes, null signals in the muscle function, contextual adjacent evidence and cardiometabolic outcome classes, and negative signals in the contextual adjacent evidence and muscle function outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_4","type":"claim","text":"The conclusion is that Creatine monohydrate remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_5","type":"claim","text":"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 the abstract 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."},{"id":"claim_6","type":"claim","text":"Creatine is a guanidino compound endogenously synthesized from arginine, glycine, and methionine, and it is consumed in the diet in meat and fish, with a typical mixed diet providing roughly 60%–80% of the creatine and phosphocreatine pool that can be further elevated by exogenous supplementation. The canonical mechanism relevant to aging biology is the phosphocreatine shuttle, in which creatine kinase catalyzes the regeneration of adenosine triphosphate from phosphocreatine during high-energy-demand states, supporting rapid ATP turnover in skeletal muscle, cardiac tissue, and the brain. Beyond this bioenergetic role, additional mechanisms have been proposed, including antioxidant effects, modulation of mitochondrial function, neuroprotection, and potential influence on sarcopenic and osteopenic processes, although the clinical relevance of these non-energy mechanisms in older adults remains uncertain. As a nutritional supplement, creatine occupies a regulatory category distinct from prescription drugs, which has both accelerated population-level adoption and complicated the generation of conventional randomized-trial evidence at scale, because large long-duration outcome trials funded by industry are uncommon for non-patentable compounds. The clinical history of creatine is dominated by sports-medicine research, with thousands of participants studied in short-term resistance-training contexts, and only more recently has attention shifted to older adults, to patient populations, and to non-muscle endpoints such as cognition. This trajectory leaves the field with a substantial body of mechanistic and performance evidence but a comparatively thin evidence base for the aging endpoints that matter most to public health, a gap that the present synthesis is designed to help clarify."},{"id":"claim_7","type":"claim","text":"Despite the volume of creatine research, several unresolved questions remain central to any claim that creatine may influence healthspan or lifespan in older adults. First, the translation from acute bioenergetic and performance effects to sustained functional change in older adults has not been established, and the boundary between reversible metabolic effects and durable structural or cognitive benefits remains uncertain. Second, the literature shows clear population specificity: signals in young resistance-trained men, in older adults undergoing structured training, in patients with Alzheimer's disease, and in vegan or vegetarian cohorts may have different magnitudes and directions, and a unified mechanistic story has not yet been articulated. Third, dose-response relationships are incompletely characterized, with most trials using a small number of fixed protocols and limited head-to-head comparisons, so the question of whether higher or lower doses, different forms, or co-ingestion with related compounds produces incremental benefit is open. Fourth, the duration of supplementation in most trials remains short relative to the time horizons over which anti-aging benefits would plausibly accrue, raising the question of whether observed short-term changes in strength or muscle cross-sectional area translate into reduced falls, hospitalization, or disability over years. Fifth, the tradeoff between putative benefits and reported signals of harm or null effect in some outcome classes, including dietary-intake analyses suggesting a negative association with one context (Jiang 2025), demands careful separation of contexts in which creatine has been evaluated. Each of these gaps is consequential for clinical decision-making, and the present synthesis is structured to make these gaps visible rather than to smooth them over."},{"id":"claim_8","type":"claim","text":"This synthesis addresses the gap between mechanistic plausibility and clinical evidence for creatine as a candidate geroprotective intervention by explicitly separating direct from indirect evidence, clinical from mechanistic data, and concordant from discordant findings. Across the curated reference set, positive signals appear in muscle function and several contextual outcomes, while negative signals surface in distinct contexts, and null findings dominate large portions of the evidence base, producing cross-study disagreements that any responsible synthesis must acknowledge rather than resolve by averaging. The contribution of this work is therefore not a single pooled effect estimate but a structured weighting of evidence across outcome classes, populations, and study designs, with explicit attention to where direct interventional hard-endpoint evidence, indirect surrogate evidence, and preclinical mechanistic evidence can and cannot speak to the same question. By treating creatine as a context-dependent intervention whose effects vary with age, training status, baseline intake, and outcome domain, the synthesis aims to provide a more clinically useful map than either an unconditional endorsement or dismissal. The framework developed here may also serve as a template for evaluating other nutritional supplements proposed as geroscience candidates, and the resulting map should help clinicians, trialists, and funders identify the specific studies and populations most likely to change the current state of evidence in the coming years."},{"id":"claim_9","type":"claim","text":"Geroscience reframes chronic disease as the clinical expression of shared biological aging processes, with the hallmarks of aging (updated 2023) supplying a mechanistic vocabulary that links cellular decline to late-life morbidity. A central regulatory implication is that interventions capable of modifying one or more hallmarks — mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, loss of proteostasis, and the like — may plausibly delay or compress morbidity across organ systems, even when individual chronic diseases have not yet manifested. Creatine monohydrate sits naturally inside this framework: it buffers and regenerates ATP via the phosphocreatine system, and downstream effects on cellular energetics, redox balance, and protein turnover intersect with several hallmark axes. As regulatory bodies (e. For example, EFSA under Regulation (EC) No 1924/2006, per Turck 2024) increasingly evaluate structure/function claims against aging biology, the geroscience lens provides the conceptual scaffold within which a nutritional supplement candidate like creatine is judged. The present Background therefore sets up (i) the preclinical mechanisms by which creatine interfaces with aging biology, (ii) the human RCT evidence base, (iii) the registered-trial landscape, and (iv) the methodological questions that condition interpretation of that evidence."},{"id":"claim_10","type":"claim","text":"Several methodological and clinical-design questions condition the interpretability of the creatine evidence base. Second, surrogate-to-hard-outcome translation is uncertain — a caution explicitly raised by Ioannidis 2005 for any surrogate-endpoint-driven claim, and directly relevant to the use of psoas muscle ratio or D₃-creatine dilution as proxies for disability and mortality. Finally, concurrent interventions (resistance training in Amiri 2023, Wang 2024, Gu 2026, Liu 2025, Sharifian 2025; HMB in Ramos-Hernandez 2026; calorie restriction in Beavers 2023; eccentric loading in Yamaguchi 2025) are rarely constant, so isolated creatine effects are difficult to extract. The synthesis must therefore adjudicate not only whether creatine 'works' but under what boundary conditions — population, dose, duration, co-intervention, and endpoint — a signal emerges."},{"id":"claim_11","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_12","type":"claim","text":"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."},{"id":"claim_13","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, dosing and pharmacokinetics, 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."},{"id":"claim_14","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_15","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_16","type":"claim","text":"| Contextual Adjacent Evidence | n=7; claims=491 | no extracted directional signal in 4/7 sources | 2 direct; 4 indirect; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_17","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_18","type":"claim","text":"Contextual Adjacent Evidence: n=7; claims=491; no extracted directional signal in 4/7 sources | directness: 2 direct; 4 indirect; 1 review; main limitation: directionally heterogeneous."},{"id":"claim_19","type":"claim","text":"The cardiometabolic evidence curated for this synthesis is anchored by two systematic reviews that pool creatine monohydrate trials across exercise and recovery contexts. Effects of Short-Term Creatine 2024 aggregated physical-fitness and hypertrophy endpoints in junior women wrestlers across three assessment time points, framing short-duration loading as a distinct exposure window (Effects of Short-Term Creatine 2024). Both reviews are rated as indirect/directness = review in the curated corpus, and they jointly define the cardiometabolic outcome class for the synthesis."},{"id":"claim_20","type":"claim","text":"Only a single contrast in the curated extracts reached the P < 0.001 threshold, while most markers clustered between P = 0.11 and P = 0.78 — a pattern consistent with mixed and largely null effects across muscle-damage surrogates. The accompanying p-values for the Effects of Short-Term Creatine 2024 review were not reported in the curated excerpts, so quantitative claims for that review are limited to its trial-level design features (Effects of Short-Term Creatine 2024)."},{"id":"claim_21","type":"claim","text":"Mechanistically, the cardiometabolic outcome class in this corpus is populated by indirect evidence: the populations are healthy or athletic adults, not patients with cardiometabolic disease, and the endpoints are surrogate biomarkers of muscle damage and training adaptation rather than hard cardiovascular events (Doma 2022). The mechanistic substrate — phosphocreatine resynthesis, cell-volumization, and attenuated oxidative stress — is plausible from preclinical work but is not directly tested in any enrolled cardiometabolic cohort within the curated set (Doma 2022; Effects of Short-Term Creatine 2024). Accordingly, the human evidence speaks to exercise-physiology adaptations, while mechanistic transfer to cardiometabolic risk reduction remains a translational inference rather than a demonstrated RCT finding."},{"id":"claim_22","type":"claim","text":"The brief characterizes the broader creatine evidence base as dominated by null findings with positive and negative signals appearing in both muscle function and contextual categories, and the cardiometabolic class reflects that pattern: a single significant contrast (P < 0.001) sits alongside 14 contrasts that fail to reach conventional significance. The disagreement is therefore one of framing — meta-analytic null synthesis versus short-duration positive summary — rather than a contradiction in direction of effect, and it leaves the cardiometabolic case for creatine anti-aging in the 'incomplete' state flagged in the brief."},{"id":"claim_23","type":"claim","text":"Smith 2025b is the single cognitive-outcome source in the corpus and frames the human evidence base as a pilot-scale, mechanism-anchored study in adults with Alzheimer's disease. The trial design is observational cohort rather than randomized, with an 8-week assessment window measuring serum creatine at baseline, 4 weeks, and 8 weeks alongside brain total creatine (tCr) and cognition on the NIH Toolbox battery. The source characterizes the work as a feasibility pilot rather than a definitive efficacy trial, which constrains the inferential weight that can be placed on its cognitive endpoints. Directness is rated indirect for the cognitive outcome class because the primary signal of interest is biochem."},{"id":"claim_24","type":"claim","text":"The source does not disambiguate which p-value attaches to which contrast — for example, whether P = 0.02 or P = 0.03 corresponds to a cognition composite versus an individual NIH Toolbox subscore — so the prose references the evidence synthesis for the per-endpoint mapping rather than reattributing values. Against the integrating thesis that null findings dominate the corpus, Smith 2025b is consistent with that pattern in the cognitive domain, while still leaving room for mechanism-positive secondary endpoints."},{"id":"claim_25","type":"claim","text":"Mechanistically, the cognitive signal in Smith 2025b is interpreted through the brain tCr trajectory rather than through a behavioral primary endpoint, so the inference chain runs from peripheral serum Cr to central tCr to NIH Toolbox performance. The source explicitly anchors this substrate–outcome chain by co-measuring serum Cr and brain tCr alongside the cognitive battery, allowing within-study mechanistic grounding even where the behavioral contrast is null. Preclinical data on creatine and brain bioenergetics are not separately receipted in this corpus, so the mechanistic narrative here is human-only and rests on Smith 2025b's paired biochemistry–cognition design rather than on animal triangulation."},{"id":"claim_26","type":"claim","text":"Because Smith 2025b is the only cognitive source, the within-corpus tension for this outcome class is one of sparsity rather than of disagreement: there is no second human RCT or observational cohort to contradict or replicate the null directional finding. The cross-study disagreement map confirms this, listing no non-orthogonal pairs for the cognitive outcome class. The integrating thesis is therefore consistent with the cognitive slice of the corpus — null findings dominate, mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and boundary conditions (dose, duration, disease stage) remain to be established in future trials."},{"id":"claim_27","type":"claim","text":"Mechanistically, the directly assessed clinical RCTs (Ramos-Hernandez 2026, Londono-Velasquez 2025) and the older-adult vascular pilot (Clarke 2024) point toward plausible functional and vascular substrates in trained or older populations, while the meta-analytic and review literature (Gu 2026) and the regulatory evaluation (Turck 2024) supply the broader, indirect contextual layer. By contrast, the large NHANES analytic cohort (Jiang 2025) frames a population-scale epidemiologic signal linking dietary creatine intake to cancer outcomes, and Desai 2025 contributes an intermediate-dose, mixed-sex resistance training randomised evaluation. Preclinical data and mechanistic human biomarker work converge on the principle that creatine augments phosphocreatine-driven ATP resynthesis and may influence endothelial and metabolic pathways, but the human evidence in this corpus is dominated by short-term, modest-sample, indirectness-tagged studies, with only Ramos-Hernandez 2026 and Londono-Velasquez 2025 carrying direct-design labels for the outcomes they tested. The mechanistic substrate underlying the contextual findings therefore remains anchored to small, targeted, often crossover designs rather than long-horizon outcome trials."},{"id":"claim_28","type":"claim","text":"Within-corpus tensions cluster on the contextual axis. A second, distinct tension separates directness of evidence: Ramos-Hernandez 2026 and Londono-Velasquez 2025 are direct, A1-tagged RCTs on contextual endpoints, whereas Turck 2024, Clarke 2024, Desai 2025, Gu 2026, and Jiang 2025 carry indirect, review, or observational cohort labels for the same outcome class, and these strata must be read separately rather than pooled (Ramos-Hernandez 2026; Londono-Velasquez 2025; Turck 2024; Clarke 2024; Desai 2025; Gu 2026; Jiang 2025). The endpoint battery centered on homocysteine and ancillary markers of cardiometabolic health, with chronic supplementation rather than a single bolus as the kinetic frame. Duration of exposure (six weeks) and adult population are the key design parameters reported."},{"id":"claim_29","type":"claim","text":"The evidence base on muscle function spans three study registers: direct clinical RCTs, indirect cohort or pilot work, and mechanistic/preclinical data. In a clinical RCT, Yamaguchi 2025 randomized adults to creatine monohydrate (CrM) or placebo (crystalline cellulose) over 33 days and tracked eccentric-exercise recovery endpoints, reporting p-values spanning P = 0.002 to P = 0.048 across recovery markers."},{"id":"claim_30","type":"claim","text":"Across the corpus, within-domain tensions are most visible on muscle function. Agreement clusters around Davies 2023 with Tam 2025 and Amiri 2023 with Tam 2025 on positive direction. The likely mechanistic explanation is a gene-by-supplementation interaction: Varillas-Delgado 2024 explicitly stratifies by genetic profile, and certain genotypes may blunt or even reverse the typical phosphocreatine-loading response, whereas Davies 2023 and Amiri 2023 pool across genotypes and dilute any signal in either direction. The boundary condition is therefore population-genetic: aggregate positive evidence applies to genetically unselected resistance-training cohorts, while negative evidence applies to the subset of professional athletes whose genotype does not support creatine-driven hypertrophy. What would resolve this tension is an adequately powered, genotype-stratified RCT comparing creatine versus placebo on lean mass and strength, with the genetic stratification pre-specified rather than post hoc; until such a trial is reported, the two literatures can be interpreted as complementary rather than contradictory, each applying to its own population."},{"id":"source_1","type":"source","study":"The Paradoxical Effect of Creatine Monohydrate on Muscle Damage Markers: A Systematic Review and Meta-Analysis","year":2022,"doi":"10.1007/s40279-022-01640-z","url":"https://doi.org/10.1007/s40279-022-01640-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_2","type":"source","study":"The impact of creatine supplementation associated with resistance training on muscular strength and lean tissue mass in the aged: a systematic review and meta-analysis","year":2025,"doi":"10.1186/s11556-025-00392-9","url":"https://doi.org/10.1186/s11556-025-00392-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_3","type":"source","study":"Creatine supplementation in young men under resistance versus non-resistance training: a systematic review and meta-analysis of strength, performance, and lean mass","year":2026,"doi":"10.3389/fnut.2026.1800546","url":"https://doi.org/10.3389/fnut.2026.1800546","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_4","type":"source","study":"The Effect of Creatine Supplementation on Lean Body Mass with and Without Resistance Training","year":2025,"doi":"10.3390/nu17061081","url":"https://doi.org/10.3390/nu17061081","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_5","type":"source","study":"Effects of Creatine Supplementation and Resistance Training on Muscle Strength Gains in Adults <50 Years of Age: A Systematic Review and Meta-Analysis","year":2024,"doi":"10.3390/nu16213665","url":"https://doi.org/10.3390/nu16213665","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_6","type":"source","study":"Effect of Creatine Monohydrate Supplementation on Macro- and Microvascular Endothelial Function in Older Adults: A Pilot Study","year":2024,"doi":"10.3390/nu17010058","url":"https://doi.org/10.3390/nu17010058","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_7","type":"source","study":"The association between dietary creatine intake and cancer in U.S. adults: insights from NHANES 2007–2018","year":2025,"doi":"10.3389/fnut.2024.1460057","url":"https://doi.org/10.3389/fnut.2024.1460057","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_8","type":"source","study":"Comparative Effects of Dietary Protein, Creatine, and Omega-3 Supplementation on Muscle Strength, Endurance, and Recovery in Trained Athletes: A Systematic Review and Network Meta-Analysis","year":2026,"doi":"10.3390/nu18060909","url":"https://doi.org/10.3390/nu18060909","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_9","type":"source","study":"Muscle creatine levels and sprint performance in young adult vegans and vegetarians after 7 days of creatine monohydrate supplementation","year":2025,"doi":"10.14814/phy2.70539","url":"https://doi.org/10.14814/phy2.70539","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_10","type":"source","study":"Impact of creatine supplementation and exercise training in older adults: a systematic review and meta-analysis","year":2025,"doi":"10.1186/s11556-025-00384-9","url":"https://doi.org/10.1186/s11556-025-00384-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_11","type":"source","study":"Application of the D 3 ‐creatine muscle mass assessment tool to a geriatric weight loss trial: A pilot study","year":2023,"doi":"10.1002/jcsm.13322","url":"https://doi.org/10.1002/jcsm.13322","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_12","type":"source","study":"Eight weeks of creatine monohydrate supplementation is associated with increased muscle strength and size in Alzheimer’s disease: data from a single-arm pilot study","year":2025,"doi":"10.3389/fnut.2025.1670641","url":"https://doi.org/10.3389/fnut.2025.1670641","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition","year":2025,"doi":"10.1002/trc2.70101","url":"https://doi.org/10.1002/trc2.70101","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_14","type":"source","study":"Association of Genetic Profile with Muscle Mass Gain and Muscle Injury Prevention in Professional Football Players after Creatine Supplementation","year":2024,"doi":"10.3390/nu16152511","url":"https://doi.org/10.3390/nu16152511","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_15","type":"source","study":"The role of resistance training and creatine supplementation on oxidative stress, antioxidant defense, muscle strength, and quality of life in older adults","year":2023,"doi":"10.3389/fpubh.2023.1062832","url":"https://doi.org/10.3389/fpubh.2023.1062832","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_16","type":"source","study":"Combined creatine and β-hydroxy-β-methylbutyrate supplementation with integral conditioning exercise enhances functional performance and metabolic health in physically active older adults: A randomized controlled crossover trial","year":2026,"doi":"10.1007/s40520-025-03312-0","url":"https://doi.org/10.1007/s40520-025-03312-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_17","type":"source","study":"The Effects of Creatine Monohydrate Supplementation on Recovery from Eccentric Exercise-Induced Muscle Damage: A Double-Blind, Randomized, Placebo-Controlled Trial Considering Sex and Age Differences","year":2025,"doi":"10.3390/nu17111772","url":"https://doi.org/10.3390/nu17111772","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_18","type":"source","study":"Effects of six weeks of high-dose creatine monohydrate supplementation with or without guanidinoacetic acid on homocysteine and markers of health","year":2025,"doi":"10.1080/15502783.2025.2550207","url":"https://doi.org/10.1080/15502783.2025.2550207","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_19","type":"source","study":"Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial","year":2024,"doi":"10.1186/s12885-024-12260-3","url":"https://doi.org/10.1186/s12885-024-12260-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_20","type":"source","study":"Effects of creatine supplementation on muscle strength gains—a meta-analysis and systematic review","year":2025,"doi":"10.7717/peerj.20380","url":"https://doi.org/10.7717/peerj.20380","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_21","type":"source","study":"Does Creatine Supplementation Enhance Performance in Active Females? 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