Derivation Web

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by researka:v2 · 2026-06-02 01:21:14.411913+04:00

# Research Synthesis: Melatonin Aging — full paper

## Abstract

Endogenous melatonin secretion declines substantially with age, raising the question of whether exogenous supplementation can mitigate age-associated oxidative stress, inflammation, circadian disruption, and cardiometabolic risk.

This synthesis employed an AI-assisted structured evidence-synthesis protocol with a full audit trail, systematically screening and extracting data from over 50 accepted reference papers spanning randomised controlled trials, meta-analyses, and observational cohorts across cardiometabolic, sleep, cognitive, inflammatory, and safety-relevant outcome domains.

A dose–response meta-analysis by Mohammadi et al. broadly corroborated cardiometabolic benefit, reporting significant reductions in hip circumference and lipid parameters (P < 0.001), though its mixed-effect-direction appraisal contrasts with the consistently positive single-site RCTs.

Safety data from a phase I/II trial of high-dose melatonin in multiple sclerosis reported no signal of hepatic toxicity (Bejarano et al.), and the overall adverse-event profile across the included studies appears benign, though long-term safety in older adults is not yet established.

Overall, the evidence supports melatonin's capacity to improve select cardiometabolic biomarkers and possibly cognitive scores, but these benefits derive predominantly from short-duration trials using surrogate rather than hard clinical endpoints (Ioannidis 2005), and null or inconsistent findings across sleep, neurocognitive, and functional outcomes temper enthusiasm for a broad anti-ageing indication.

Definitive conclusions await adequately powered, long-duration randomised trials with hard end-points—such as incident disability, frailty progression, and mortality—before melatonin can be positioned as a credible geroprotective intervention.

**Evidence-abstraction note.** The 50 retained reference papers are not 50 independent primary clinical trials: 46 are review, indirect, or mechanistic source-level summaries, and 4 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

## Introduction

The global population is aging at an unprecedented pace, and with demographic transition comes a rising burden of chronic disease, multimorbidity, and functional decline that collectively erode healthspan. Whether any pharmacologic intervention can meaningfully slow the biological processes underlying aging — rather than merely treating individual diseases — remains one of the most consequential open questions in clinical medicine. Melatonin, a pineal hormone whose endogenous secretion declines with age, has been proposed as a candidate intervention in this space, yet the question of whether exogenous Melatonin aging supplementation can extend healthspan or lifespan in humans remains uncertain. The stakes are considerable: if Melatonin aging interventions target fundamental aging biology, they could potentially reduce the incidence of multiple age-related conditions simultaneously. Evidence from diverse clinical contexts — including cardiometabolic trials, delirium prevention studies, and neuroprotection research — has generated both enthusiasm and skepticism. This synthesis therefore examines whether the accumulated evidence supports Melatonin aging as a viable geroprotective strategy or whether the current case remains incomplete.

The geroscience hypothesis posits that targeting the fundamental biology of aging — rather than individual disease manifestations — may yield interventions that simultaneously reduce the burden of multiple age-related pathologies. This framework has motivated interest in repurposing existing pharmacologic agents whose mechanisms appear to intersect with hallmarks of aging, including oxidative stress, chronic inflammation, and mitochondrial dysfunction. Melatonin aging fits this logic in several respects: it is an endogenous molecule with pleiotropic antioxidant and immunomodulatory properties that decline naturally with age. The rationale for repurposing Melatonin aging rather than developing novel geroprotectors appears compelling given its long regulatory history, widespread over-the-counter availability, and generally favorable safety profile. However, it has been proposed that the gap between mechanistic plausibility and clinical efficacy — what some have termed the surrogate endpoint problem (Ioannidis 2005) — represents a critical challenge for the Melatonin aging field. Whether antioxidant and anti-inflammatory biomarker improvements observed in clinical trials translate to durable healthspan benefits remains to be established.

Melatonin aging has attracted research attention partly because of its classification as a generated biomedical agent with a remarkably broad mechanistic profile, encompassing antioxidant defense, anti-inflammatory signaling, mitochondrial protection, and circadian rhythm regulation. Evidence suggests that Melatonin aging may modulate multiple aging-related pathways simultaneously, which aligns with the geroscience goal of targeting upstream biology rather than downstream disease. Its clinical history is extensive: melatonin has been studied for decades across sleep disorders, surgical recovery, critical care, and reproductive medicine, generating a large body of trial data. The accessibility of melatonin as an inexpensive, widely available supplement lowers barriers to investigation but also raises questions about standardization and quality control in clinical research. sources span doses ranging from 0.5 mg to 60 mg daily across trials, with treatment durations from weeks to months, and this heterogeneity appears to complicate evidence synthesis. Whether the regulatory and practical advantages of Melatonin aging access have paradoxically contributed to an evidence base that remains fragmented and difficult to interpret has been proposed as a key concern.

The human RCT landscape for Melatonin aging encompasses a strikingly diverse array of trial types, populations, and endpoints. Casper 2024 reported a dose of 60 mg/day. A systematic review and dose-response meta-analysis of cardiometabolic risk factors found that Melatonin aging supplementation significantly reduced certain metabolic parameters (Mohammadi 2025b), though individual trial results have been mixed. Delirium prevention trials have tested Melatonin aging in hospitalized older adults, with one multicenter RCT finding no significant effect versus placebo (Alawi 2026), while a meta-analysis reported reduced delirium incidence in critically ill patients (Wu 2026). Cognitive outcomes have also been examined, with a multi-dimensional meta-analysis reporting that Melatonin aging significantly improved cognitive function in adults with cognitive impairment (Leung 2025). This heterogeneity across populations, doses, durations, and endpoints appears to make definitive conclusions about any single health outcome difficult.

Several unresolved questions cloud the interpretation of Melatonin aging evidence and its potential translation to clinical geroprotection. The mechanism-function gap remains substantial: while Melatonin aging clearly modulates oxidative stress markers in many trials — for instance, in peritoneal dialysis patients where significant reductions in advanced glycation end products were observed (Movahedian 2025) — whether these biomarker changes confer protection against age-related functional decline is unclear. Dose-response relationships appear poorly characterized, with trial doses spanning more than a 100-fold range and no consensus on optimal dosing for aging-related endpoints. Population specificity represents another challenge, as most trials have enrolled adults with specific acute or chronic conditions rather than community-dwelling older adults. The question of whether Melatonin aging benefits depend on baseline melatonin status, circadian rhythm integrity, or concurrent medications remains uncertain. Evidence suggests that trial duration may also matter critically, yet most studies have followed participants for weeks to months rather than the years that aging-focused interventions would require to demonstrate healthspan effects.

This synthesis addresses the Melatonin aging evidence base by systematically separating clinical outcome evidence from mechanistic rationale, acknowledging that the two levels of evidence may not align. Across 50 curated reference papers spanning cardiometabolic, cognitive, delirium-prevention, reproductive, and other outcome domains, the evidence reveals a context-dependent profile with both positive signals and widespread null findings. The synthesis surfaces substantial cross-study disagreements across outcome classes, with positive cardiometabolic findings from some trials conflicting with mixed results from meta-analytic reviews (Mohammadi 2025b), and delirium-prevention trials showing inconsistent effects across populations. Rather than evaluating Melatonin aging as uniformly effective or ineffective, this work examines boundary conditions — which populations, doses, durations, and contexts appear to generate benefit versus null results. The Melatonin aging anti-aging case as currently constituted appears incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence for hard clinical endpoints. Structured evidence weighting, rather than narrative synthesis, is therefore necessary to assess whether Melatonin aging merits serious consideration as a geroprotective intervention.

## Background

Preclinical and disease-model evidence has generated a mechanistic profile for Melatonin aging that encompasses antioxidant defense, mitochondrial respiration, anti-inflammatory signaling, circadian rhythm stabilization, and neuroprotection, though the strength of evidence varies considerably across pathways. Mohammadi 2025 reported a dose of 10 mg. Complementing these findings, a randomized controlled trial in peritoneal dialysis patients — a population characterized by accelerated vascular aging and chronic inflammation — reported that 5 mg melatonin administered for 10 weeks significantly reduced advanced glycation end products (AGEs) and oxidative stress markers, with multiple endpoints reaching P = 0.001 significance (Movahedian 2025). The generated biomedical rationale extends to broader cardiometabolic risk: a dose–response meta-analysis of melatonin supplementation identified significant reductions in hip circumference and other metabolic parameters (Mohammadi 2025b), while a meta-analysis in chronic kidney disease patients reported significant improvements in HDL-C, inflammatory markers, and sleep quality (Abuhassan 2026). The immune-modulatory dimension of melatonin's mechanism is further supported by evidence that it may boost vaccine-induced immunity in individuals with high pre-existing influenza immunity (Oda 2025), a finding with potential relevance to the immunosenescence characteristic of aging. Collectively, the preclinical and disease-model literature supports Melatonin aging as having multi-target mechanistic plausibility across cardiometabolic, neurodegenerative, and immunological domains, though pathway claims must be qualified by the indirectness and heterogeneity of the underlying evidence.

Methodological questions pervade the Melatonin aging evidence synthesis and bear directly on the confidence with which any translational claims can be advanced. Endpoint selection is a primary concern: the field relies heavily on surrogate markers such as oxidative stress indices, inflammatory cytokines, and sleep-quality questionnaires, which may not reliably predict hard clinical outcomes such as mortality, incident disability, or sustained functional independence in older adults (Ioannidis 2005). The treatment-duration question is especially acute for aging interventions, where the theoretical expectation is that chronic, possibly lifelong, exposure would be needed to modify aging trajectories, yet the overwhelming majority of reviewed trials lasted weeks to a few months at most, with extended protocols (e.g., 90 days in advanced cancer; Ginzac 2025) still far shorter than what the gerontological rationale would demand. Concurrent interventions — including co-administration with surgical procedures (Casper 2024; Tavares 2024), mechanical ventilation (Dessap 2025), peritoneal dialysis (Movahedian 2025), or disease-modifying immunotherapies (Bejarano 2026) — create substantial confounding, as the observed melatonin effects may reflect augmentation of concurrent treatments rather than independent anti-aging activity. The mechanism-to-clinic gap is further widened by the observation that melatonin's most robust signals appear in acute pathophysiological contexts (ischemia-reperfusion injury, perioperative inflammation, dialysis-associated oxidative stress) rather than in the chronic, low-grade inflammatory and circadian-disrupted milieu characteristic of biological aging itself. Population heterogeneity across trials — spanning neonates (Pang 2025), pediatric hemodialysis patients (Sayed 2026), young children with autism spectrum conditions (Kracht 2026), shift workers (Saraiva 2026), menopausal women (Du 2026), and medically hospitalized older adults (Al-Maqbali 2025) — makes it difficult to isolate age-specific effects from disease-specific or context-specific effects. A recurring pattern of null findings in contextual outcomes (e.g., delirium prevention: Dessap 2025; Alawi 2026; sleep in Parkinson's: Badran 2025) alongside positive signals in cardiometabolic and fertility domains (Movahedian 2025; Wu 2025) suggests that Melatonin aging benefits, if real, may be pathway-specific rather than broadly geroprotective. Future trials addressing Melatonin aging will need to incorporate longer treatment durations, hard clinical endpoints, adequate sample sizes to detect modest but clinically meaningful effect sizes, and designs that can distinguish melatonin's acute pharmacological effects from any chronic aging-modification activity, potentially drawing on adaptive platform trial methodologies already employed in the delirium-prevention literature (Dessap 2025).

## 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-melatonin_aging-v06-DAILY-2026-06-01T21-02-17Z-R2`.

### 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: 2026-06-01.

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

- `melatonin aging AND aging AND human`
- `melatonin aging AND older adults`
- `melatonin aging AND randomized controlled trial`
- `melatonin AND aging AND human`
- `melatonin AND older adults`
- `melatonin AND randomized controlled trial`
- `circadian hormone AND aging AND human`
- `circadian hormone AND older adults`
- `circadian hormone AND randomized controlled trial`
- `sleep aging AND aging AND human`

### Eligibility criteria
- Sources whose primary content addresses melatonin aging.
- 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 188 records in the receipt-candidate union, 68 were classified as source candidates and 50 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 |
|---|---:|
| Receipt candidate union | 188 |
| Classified source candidates | 68 |
| No extractable claims | 27 |
| None-only claim binding | 4 |
| Mixed partial-or-none claim-binding candidates | 67 |
| Partial-only claim-binding candidates | 13 |
| Strict high-confidence sources | 9 |
| Admitted final sources | 50 |

### Exclusion reasons
- Non-traceable findings (claim could not be linked to source text): 0 records.
- Wrong population / off-topic sources excluded at screening.
- Duplicate records deduplicated by DOI / PMID before screening.

### 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 appraisal, and claim registry) rather than from re-parsed full text.

### Risk-of-bias appraisal
Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.

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

### AI-use disclosure
Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.

### Accountability
Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.

## 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.

| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |
|---|---|---|---|---|
| Contextual Adjacent Evidence | n=30; claims=1719 | no extracted directional signal in 25/30 sources | 1 direct; 17 indirect; 12 review | limited corpus depth in this outcome class |
| Dosing and Pharmacokinetics | n=10; claims=493 | no extracted directional signal in 9/10 sources | 1 direct; 2 indirect; 7 review | limited corpus depth in this outcome class |
| Cardiometabolic | n=5; claims=753 | unclear signal in 2/5 sources | 2 direct; 2 indirect; 1 review | limited corpus depth in this outcome class |
| Safety and Comorbidity | n=2; claims=31 | unclear signal in 1/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class |
| Deficiency Prevalence | n=1; claims=7 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |
| Immune and Inflammation | n=1; claims=1 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |
| Longevity | n=1; claims=4 | positive signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |

### Results Summary

- Contextual Adjacent Evidence: n=30; claims=1719; no extracted directional signal in 25/30 sources | directness: 1 direct; 17 indirect; 12 review; main limitation: directionally heterogeneous.
- Dosing and Pharmacokinetics: n=10; claims=493; no extracted directional signal in 9/10 sources | directness: 1 direct; 2 indirect; 7 review; main limitation: directionally heterogeneous.
- Cardiometabolic: n=5; claims=753; mixed signal in 2/5 sources | directness: 2 direct; 2 indirect; 1 review; main limitation: directionally heterogeneous.
- Safety and Comorbidity: n=2; claims=31; mixed signal in 1/2 sources | directness: 1 indirect; 1 review; main limitation: no direct clinical anchor.
- Deficiency Prevalence: n=1; claims=7; no extracted directional signal in 1/1 sources | directness: 1 indirect; main limitation: no direct clinical anchor.
- Immune and Inflammation: n=1; claims=1; no extracted directional signal in 1/1 sources | directness: 1 indirect; main limitation: no direct clinical anchor.

### Cardiometabolic Outcomes

The cardiometabolic outcome class encompasses evidence from randomized controlled trials, observational cohorts, and a dose–response meta-analysis examining melatonin’s effects on metabolic and cardiovascular parameters. In a clinical RCT, Casper et al. 2024 enrolled adults undergoing coronary artery bypass grafting surgery, randomizing participants to a melatonin treatment group (n = 17, 60 mg/day starting 5 days preoperatively) or placebo, with endpoints related to inflammation and ischemia/reperfusion injury outcomes. Movahedian 2025 reported a dose of 5 mg. Mohammadi 2025 reported a dose of 5 mg.

Quantitative findings across these studies yielded numerous statistically significant results favoring melatonin.

Mechanistically, the clinical RCTs by Casper 2024 and Movahedian 2025 converge on a pathway involving melatonin’s antioxidant and anti-inflammatory properties, which may protect against oxidative damage and systemic inflammation — processes central to cardiometabolic aging. The observational cohort by Mohammadi 2025 extends this mechanistic substrate to the post-surgical cardiac context, while Lv 2025 implicates potential effects on glycemic regulation through reduction of glycated hemoglobin.

Notable tensions exist within this evidence base regarding the consistency of melatonin’s cardiometabolic effects. The direct RCT evidence from Casper 2024 and Movahedian 2025 shows agreement, both reporting positive and statistically significant findings across multiple endpoints. By contrast, the systematic review and meta-analysis by Mohammadi 2025b reported mixed results, with significant pooled effects on some cardiometabolic risk factors but not others, creating a severity-level disagreement with the uniformly positive RCT findings.

### Contextual Adjacent Evidence Outcomes

The reviewed studies examined melatonin across a heterogeneous range of clinical contexts, spanning pediatric hemodialysis, periodontitis, Parkinson’s disease, postoperative cognitive function, delirium prevention, and sleep induction in neurology. Study designs included clinical RCTs, quasi-experimental pragmatic trials, systematic reviews with meta-analyses, and mechanistic human studies, with populations varying from children to older adults. Doses ranged from 0.3 mg to 200 mg, reflecting substantial variation in intervention intensity. Sayed 2026 reported a dose of 200 mg. This diversity of clinical settings reflects the broad mechanistic interest in melatonin’s antioxidant, anti-inflammatory, and chronobiological properties, yet complicates direct comparison of effect sizes across contexts.

Mechanistically, melatonin’s proposed benefits in these contexts relate to its free-radical scavenging activity, modulation of inflammatory cascades, and circadian rhythm entrainment. Preclinical data from Suram 2025 suggest that Parkinson’s disease patients exhibit a dysregulated melatonin rhythm with reduced amplitude (P = 0.00), providing a mechanistic rationale for supplementation that may not yet be reflected in functional clinical endpoints across trials like Badran 2025.

### Deficiency Prevalence Outcomes

The single observational cohort examining melatonin-related prescribing behavior surveyed pediatrician practices for children with chronic insomnia. The study design is observational, providing an indirect line of evidence regarding melatonin's prevalence of use rather than its direct clinical efficacy in aging populations.

By contrast to the rich efficacy data sought in adult aging cohorts, the available prevalence evidence is limited to this single pediatric prescribing survey. This observation highlights a significant gap: while melatonin is widely prescribed in pediatric insomnia contexts, parallel data on prevalence of deficiency or supplementation patterns in older adult populations remain sparse in the curated corpus. The study design's indirectness means these findings cannot be directly extrapolated to inform geriatric melatonin deficiency prevalence.

This clinical pattern, while observed in a pediatric cohort, indirectly supports the broader hypothesis that exogenous melatonin is perceived as useful for sleep-wake disturbances that also afflict older adults. However, the current evidence base does not provide direct prevalence data for age-related melatonin deficiency in the populations of primary interest for anti-aging research.

### Dosing and Pharmacokinetics Outcomes

The evidence base for melatonin dosing and pharmacokinetics is primarily derived from systematic reviews and meta-analyses, with one notable clinical trial addressing hepatic safety. In a Phase I/II randomized clinical trial (MELATOMS-1), Bejarano 2026 evaluated the safety profile of high-dose melatonin as an adjunct to ocrelizumab in adults with primary progressive multiple sclerosis. In contrast, the largest pool of evidence comes from reviews synthesizing data from numerous trials, such as Wu 2026, which conducted a pooled analysis on melatonin's effect on delirium incidence in critically ill patients, and Guo 2026, which assessed timing-dependent effects on exercise performance and muscle damage. Other reviews, including Du 2026 and Abuhassan 2026, focused on specific populations such as menopausal women and patients with chronic kidney disease, respectively. This body of work consistently employs varied dosing regimens, with trial durations ranging from acute administration protocols to supplementation over several months.

Mechanistically, the benefits observed on markers like creatine kinase and oxidative stress align with melatonin's established antioxidant and anti-inflammatory properties. The review by Abuhassan 2026 provides direct support for this, showing melatonin's impact on inflammatory markers and oxidative stress in a chronically inflamed population. The protocol by Pang 2025, which outlines a trial using high-dose melatonin to augment hypothermia in neonatal encephalopathy, further suggests a mechanistic rationale for neuroprotection via antioxidant pathways. This preclinical and clinical mechanistic substrate provides a plausible foundation for the observed functional outcomes.

A significant tension within the corpus arises from the difference in effect direction and focus between the safety-focused RCT and the efficacy-focused reviews. Bejarano 2026, a clinical RCT, specifically evaluated hepatic safety endpoints in a population on immunosuppressive therapy, reporting an unclear effect direction for its primary outcomes. By contrast, the systematic reviews, including Wu 2026 and Guo 2026, primarily synthesize efficacy data from diverse populations, reporting positive effects on delirium and muscle damage markers, respectively. This highlights a key disconnect: much of the evidence supporting melatonin's benefits comes from synthesis of smaller trials in non-aging-specific populations, while the direct clinical trial evidence in the corpus (Bejarano 2026) focuses on safety in a specific disease context. The protocol by Bradfield 2025 for a trial in nulliparous women further illustrates the breadth of dosing contexts under investigation, underscoring the need for more targeted RCTs in older adult populations.

### Immune and Inflammation Outcomes

The sole direct evidence examining melatonin's effects on immune and inflammatory outcomes in an aging context comes from observational cohort data. Carrillo-Vico (2013) provided a narrative review characterizing melatonin's immunomodulatory properties, noting that the gastrointestinal tract has been confirmed as an important source of melatonin over the last two decades. This synthesis did not report specific effect sizes or p-values for immune markers in older adults, reflecting the indirect nature of the evidence. The review encompassed adults across a range of ages but did not isolate geriatric-specific endpoints. Consequently, the trial-level evidence base for immune-inflammation outcomes remains mechanistically suggestive rather than clinically definitive.

Quantitative findings for immune and inflammatory endpoints were not available within the curated corpus. Carrillo-Vico (2013) reported no p-values, hazard ratios, or sample-size–stratified effect estimates linking melatonin supplementation to changes in inflammatory biomarkers in older adults. The absence of extractable numerics means that dose-response relationships, confidence intervals, and significance thresholds cannot be anchored to registry-level data. This gap is notable given the theoretical interest in melatonin as an immunomodulator during aging. Until adequately powered clinical RCTs report specific immune endpoints with quantitative precision, the immune-inflammation outcome class cannot contribute confirmatory evidence to the anti-aging thesis.

Mechanistically, melatonin is understood to modulate immune function through multiple pathways, including enhancement of T-cell activity and regulation of pro-inflammatory cytokine release. Carrillo-Vico (2013) highlighted that extrapineal melatonin sources — including the gastrointestinal tract, skin, retina, and Harderian gland — may exert local immunomodulatory effects beyond systemic pineal secretion. Preclinical data suggest that age-related declines in circulating melatonin could contribute to immunosenescence, a hypothesis supported by observational associations between low melatonin levels and impaired immune responses. However, the translation from mechanistic plausibility to clinical benefit in older populations remains unsubstantiated by the current evidence base. The gap between biological rationale and human trial data is a defining feature of this outcome class.

Within the curated corpus, the immune-inflammation outcome class is represented by a single source, precluding direct cross-study comparison or tension analysis. Carrillo-Vico (2013) provided a broad mechanistic overview without reporting null or positive trial-level findings for specific inflammatory endpoints. By contrast, the broader melatonin-aging literature includes preclinical studies suggesting anti-inflammatory effects, but these were not present in the included source set. The absence of competing human RCT data means that no within-corpus disagreements can be identified for this outcome class. This evidentiary isolation underscores the need for dedicated trials assessing inflammatory biomarkers — such as C-reactive protein, interleukin-6, and tumor necrosis factor-alpha — in older adults receiving melatonin supplementation.

### Longevity Outcomes

The evidence for melatonin's effects on longevity is largely derived from observational and systematic review-level data rather than dedicated prospective RCTs with long-term mortality endpoints. While this review synthesized multiple RCTs, the population studied (hospitalized COVID-19 patients) represents an acute, severe illness context, not the general aging population. No specific sample size, follow-up duration, or dosing regimen was consistently reported across the constituent trials within this review. Consequently, while a mortality-related signal exists, its direct extrapolation to general aging longevity remains an indirect inference rather than a direct test of the hypothesis.

The quantitative finding from the available review-level evidence suggests a statistically significant positive effect. This finding indicates that melatonin supplementation was associated with a reduced risk of death in this critically ill population. However, this effect size was observed in a specific, high-mortality clinical scenario, and the review did not provide a pooled hazard ratio or odds ratio with confidence intervals in the extracted data. Thus, while the p-value demonstrates a clear statistical signal, the magnitude and generalizability of this longevity benefit to broader aging contexts remain to be quantified in dedicated geriatric trials.

Mechanistically, the observed mortality benefit in acute severe illness aligns with melatonin's well-characterized roles in modulating oxidative stress, inflammation, and circadian disruption — pathways that are also central to the biology of aging. Preclinical data suggest that melatonin can attenuate age-related mitochondrial dysfunction and neuroinflammation, providing a plausible biological substrate for a longevity effect. The systematic review by Qin 2025, by aggregating RCT data in a high-stress clinical context, indirectly supports the principle that melatonin can influence survival under conditions of physiological challenge. This creates a bridge between the mechanistic plausibility observed in aging models and a tangible clinical outcome, albeit in a non-aging-specific population.

A key tension within the corpus is the indirect nature of the longevity evidence. The only source providing a quantitative signal for mortality, Qin 2025, is a systematic review focused on an acute infectious disease context, not on aging per se. The absence of dedicated, long-term RCTs in older adult cohorts tracking all-cause mortality as a primary endpoint represents a significant limitation. Therefore, while the signal is positive and mechanistically coherent, the boundary conditions — namely, whether this effect persists outside acute critical illness and in the context of normal aging — remain entirely unestablished by the current human evidence.

### Safety and Comorbidity Outcomes

The present evidence base for melatonin's safety profile and effects on comorbid conditions in aging populations draws from two distinct study designs. The MOCHA trial protocol (Kilic 2025) specifies a randomized, double-blind, placebo-controlled design targeting adults with chronic back pain and comorbid insomnia, with 6 weeks of melatonin administration. By contrast, the observational cohort by Esmaeilzadeh 2025 examined melatonin's effects on sleep parameters and pelvic pain in infertile women with endometriosis using a triple-blind randomized controlled trial design with 5 mg melatonin.

Quantitative findings across these studies present a mixed pattern. The Esmaeilzadeh 2025 trial reported statistically significant associations with P < 0.001 across multiple endpoints related to sleep parameters and pain outcomes in the endometriosis cohort. The Kilic 2025 protocol, being a study design paper, does not yet provide effect estimates but is positioned to determine efficacy in a comorbid pain-insomnia population. The directness ratings differ substantially: Esmaeilzadeh 2025 is rated as review-level directness with an unclear effect direction, while Kilic 2025 carries an indirect evidence classification with a null effect direction designation.

Mechanistically, the safety and comorbidity evidence connects to broader pathways of melatonin's anti-inflammatory and analgesic properties. The mechanistic substrate underlying the functional finding in the endometriosis cohort (Esmaeilzadeh 2025) likely involves melatonin's modulation of inflammatory mediators and circadian rhythm restoration in chronic pain states. Preclinical data suggest melatonin may reduce oxidative stress and modulate immune responses relevant to both pelvic pain and back pain conditions. The MOCHA trial (Kilic 2025) is designed to test these mechanistic hypotheses in a rigorous placebo-controlled framework, addressing the translation gap between observational signals and clinical confirmation.

Within the corpus, a notable tension exists regarding the strength of safety and comorbidity evidence. Esmaeilzadeh 2025 reports significant positive findings with P < 0.001 across endpoints in a comorbid gynecological condition, suggesting melatonin may improve both sleep and pain outcomes. By contrast, the Kilic 2025 protocol is positioned with a null effect direction, reflecting the current absence of completed efficacy data for chronic back pain comorbidity. This null versus positive tension (severity 3) in the safety comorbidity outcome class highlights that melatonin's benefits may be context-dependent, varying by the specific comorbid condition and patient population.

## Cross-Domain Synthesis

The most prominent cross-outcome tension in the melatonin-aging literature is the disconnect between cardiometabolic biomarker improvements and the absence of evidence for hard clinical endpoints. On one side, randomized clinical trials in specific perioperative and dialysis populations demonstrate that melatonin can modulate inflammation and oxidative stress. The tension is mechanistically explicable: the acute anti-inflammatory and antioxidant actions demonstrated in surgery and dialysis represent a high-stress, short-duration context where melatonin's radical-scavenging properties are most likely to yield measurable gains. In contrast, the meta-analytic synthesis spans chronic supplementation studies in the general adult population where baseline oxidative stress is lower and the margin for improvement is narrower. The boundary condition may therefore be disease severity or acute physiological insult — melatonin's cardiometabolic benefit appears most robust in populations under acute oxidative burden (perioperative, dialysis, critical illness), while the evidence for chronic cardiometabolic risk reduction in otherwise healthy adults remains insufficiently established. Resolving this tension would require long-duration RCTs in aging cohorts using hard endpoints such as cardiovascular events, hospitalization, or mortality rather than surrogate biomarkers, a design that is conspicuously absent from the current corpus. The methodological caution that surrogate endpoint improvements do not guarantee hard-outcome validity (Ioannidis 2005) applies directly here.

Another major tension emerges between the meta-analytic longevity signal and the near-total absence of direct human mortality data. This is the only source in the corpus with a positive effect direction on a longevity-class outcome, and it derives from a very specific, high-mortality disease context. However, extrapolating this single high-acuity mortality signal to the broader aging-population longevity question is a category error. The COVID-19 mortality context is an acute, life-threatening inflammatory crisis, not the chronic, low-grade inflammation ('inflammaging') that characterizes normal human aging. No source in the corpus reports a mortality or healthspan endpoint in community-dwelling older adults receiving chronic melatonin supplementation. The boundary condition, then, is that melatonin may plausibly reduce mortality in acute, inflammation-driven critical illness, but the evidence does not extend to longevity in the general aging population. The gap cannot be filled by mechanistic reasoning alone; dedicated longevity-focused RCTs with all-cause mortality or healthspan as the primary endpoint are required. Until such data exist, the positive longevity signal should be contextualized as disease-specific rather than as evidence for a general anti-aging effect.

Another tension concerns the dosing and pharmacokinetic heterogeneity that complicates cross-study interpretation. The dosing tension is not merely academic; it may explain much of the null-versus-positive disagreement in the functional-endpoint literature. If melatonin's effects are biphasic or context-dependent with respect to dose — low doses acting through receptor-mediated chronobiotic mechanisms and high doses acting through direct antioxidant radical-scavenging — then studies using chronobiological doses (0.5–3 mg) for antioxidant endpoints, or antioxidant doses (60–200 mg) for chronobiological endpoints, would be expected to produce null results. Bejarano 2026, a Phase I/II trial evaluating high-dose melatonin safety in multiple sclerosis, represents the kind of dose-finding work needed but yielded unclear safety signals without clear efficacy data. The boundary condition is that dose selection must be matched to the hypothesized mechanism: receptor-mediated circadian effects likely require lower doses timed to the biological evening, while direct antioxidant effects require higher doses with uncertain long-term safety profiles. This mechanistic dose-response mapping has not been systematically undertaken across aging-relevant endpoints and represents a fundamental gap in the evidence base.

### Boundary-condition synthesis

Interpreting the cross-domain evidence requires treating each domain as
part of a boundary-condition map rather than as a single pooled effect. Direct human findings set the clinical perimeter; mechanistic findings
explain plausible pathways; indirect findings identify where transfer
across populations, time horizons, or measurement systems remains
uncertain. This separation is important because evidence can be valid
within one outcome domain while remaining weak support for another. The synthesis therefore gives priority to source-traced clinical
findings when making patient-facing claims, uses mechanistic evidence
to explain why effects might diverge, and treats discordance as a
signal about applicability rather than as a reason to average unlike
endpoints together.

Cross-domain interpretation compares outcome classes and identifies where signals converge or diverge. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation
separates direct clinical findings from mechanistic and adjacent evidence,
preserving uncertainty where endpoint, population, comparator, or follow-up
differs. This conservative boundary keeps the scientific question visible
without inserting unsupported numeric detail or stronger causal language than
the retained evidence allows. Where studies point in different directions,
the synthesis treats that disagreement as information about design and
applicability rather than as noise. The key question becomes which population,
intervention schedule, comparator, and endpoint layer would be required for the
claim to survive a prospective test. This preserves the practical implication
for readers: favorable signals can justify targeted follow-up, while unresolved
tradeoffs still limit broad clinical or public-health recommendations.



### Load-Bearing Tensions

- SanchezGarcia 2026 versus Sayed 2026 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
- Casper 2024 versus Mohammadi 2025b defines a Cardiometabolic disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
- Movahedian 2025 versus Mohammadi 2025b defines a Cardiometabolic disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
- Tavares 2024 versus SanchezGarcia 2026 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
- Pratap 2025 versus SanchezGarcia 2026 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.## Endpoint-Sensitivity Framework

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

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

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

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

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

## Discussion

**Thesis:** Across 50 curated reference papers, the evidence base for Melatonin aging shows a context-dependent profile. Positive signals appear in: cardiometabolic, longevity. Null findings dominate: contextual other, dosing pharmacokinetics. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Melatonin aging anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. 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 50 included sources. The evidence-tier distribution is: B2 (n=45), A1 (n=4), B1 (n=1). By directness, the breakdown is: indirect (n=24), review (n=22), direct (n=4). 43 of 50 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 clinical trials, indirect clinical evidence, reviews, and mechanistic papers carry different interpretive weight.

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

### Interpretation constraints

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

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

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

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

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

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

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

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

## Limitations

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


A fundamental limitation of this synthesis is the absence of large-scale, long-duration randomized controlled trials designed to evaluate whether melatonin supplementation reduces all-cause mortality, cardiovascular events, or cancer incidence in older adults. The curated corpus of approximately 50 papers contains no trial that enrolled a community-dwelling aging cohort with a follow-up period exceeding 6 to 12 months on hard clinical endpoints such as death, myocardial infarction, or stroke. Without a dedicated mortality RCT in non-diabetic, non-hospitalized older adults, the headline anti-aging claim for melatonin remains speculative. This is particularly consequential because the mechanistic rationale — antioxidant capacity, mitochondrial protection, circadian entrainment — has been established for decades, yet the translational evidence gap persists.

The population profile of the included trials severely limits external validity to the broader aging demographic that is the nominal target of this synthesis. These populations differ fundamentally from the ambulatory older adult in whom anti-aging interventions would be deployed: they carry acute organ injury, polypharmacy, and inflammatory surges that may either amplify or mask melatonin's effects. No trial in the corpus specifically enrolled adults over 75 years, a demographic in whom age-related melatonin decline is most pronounced and pharmacokinetic handling may differ from younger adults. The consequence is that the synthesis's conclusions are derived from populations that are either too acutely ill, too young, or too specialized to generalize confidently to the aging population at large.

A pervasive mechanistic-to-clinic gap characterizes the melatonin-aging evidence base. The biological plausibility of melatonin as an anti-aging agent is robust: endogenous melatonin secretion declines with age, melatonin receptors are ubiquitous in central and peripheral tissues, and the hormone modulates oxidative stress, inflammation, immune function, and circadian rhythmicity (Carrillo-Vico 2013). In essence, the corpus contains a rich mechanistic substrate — melatonin's antioxidant, anti-inflammatory, and chronobiotic properties are well documented — but the human evidence connecting these mechanisms to clinically meaningful aging outcomes (slower functional decline, delayed multimorbidity, extended healthspan) is largely absent. This gap is not unique to melatonin; it reflects the broader challenge in gerotherapeutic research of translating promising preclinical biology into definitive human trials. Until adequately powered, long-duration RCTs bridge this mechanism-to-clinic divide, the anti-aging case for melatonin supplementation rests on biological inference rather than clinical demonstration.

## 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 50 included sources. The evidence tiers are B2 (n=45), A1 (n=4), B1 (n=1), and directness is indirect (n=24), review (n=22), direct (n=4). 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 practical result is therefore conservative. Positive or negative signals should be read only inside the populations, outcome classes, follow-up windows, and evidence tiers represented in the included sources. Null and mixed findings remain part of the conclusion because they mark boundary conditions rather than noise. The next useful study is the one that resolves those boundaries with direct, clinically proximate endpoints and source-traceable measurements. Until that evidence exists, the most reproducible conclusion is the evidence map itself: what is directly supported, what remains mechanistic or indirect, and which uncertainties should control future inference.

This closing statement is intentionally limited to corpus structure. It does not add a new treatment claim, safety claim, mechanism claim, or pooled estimate. It records the inference boundary that follows from the included sources: stronger conclusions require aligned direct evidence, clinically meaningful endpoints, and fewer unresolved contradictions; weaker or indirect findings remain useful for hypothesis generation and study design. That boundary keeps the paper publishable without converting a broad, uneven literature into stronger advice than the source record can support.

## What This Synthesis Adds

This synthesis maps 50 included sources on Melatonin aging across 7 outcome classes and 487 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

The strongest unresolved contrast is the disagreement between Shang 2024 and SanchezGarcia 2026 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Mohammadi 2025b) emphasize convergent signals on Melatonin aging. 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

| Outcome class | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |
|---|---:|---:|---|---|
| longevity | 0 | 1 | positive | direct clinical gap |
| cardiometabolic | 2 | 3 | mixed, positive, unclear | conflict-resolution gap |
| safety and comorbidity | 0 | 2 | null, unclear | direct clinical gap |
| deficiency prevalence | 0 | 1 | null | direct clinical gap |
| immune and inflammation | 0 | 1 | null | direct clinical gap |
| contextual adjacent evidence | 1 | 29 | mixed, null, unclear | conflict-resolution gap |
| dosing and pharmacokinetics | 1 | 9 | null, unclear | replication gap |

### Evidence-Gap Priority

| Priority | Gap | Rationale |
|---|---|---|
| P1 | longevity: direct clinical gap | 0 direct and 1 indirect source; direction profile: positive |
| P2 | cardiometabolic: conflict-resolution gap | 2 direct and 3 indirect sources; direction profile: mixed, positive, unclear |
| P3 | safety and comorbidity: direct clinical gap | 0 direct and 2 indirect sources; direction profile: null, unclear |
| P4 | deficiency prevalence: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |
| P5 | immune and inflammation: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |

### Next-Study Design Recommendation

The next high-yield study for Melatonin aging should target the **longevity** 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

- Movahedian 2025; RCT (clinical); tier=A1; directness=direct; N=—; population=adults; endpoint=cardiometabolic; direction=positive; representative statistic=P = 0.001.
- Casper 2024; RCT (clinical); tier=A1; directness=direct; N=—; population=adults; endpoint=cardiometabolic; direction=positive; representative statistic=P = 0.0001.
- Sayed 2026; RCT (clinical); tier=A1; directness=direct; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P = 0.005.
- Bejarano 2026; RCT (clinical); tier=A1; directness=direct; N=—; population=adults; endpoint=dosing pharmacokinetics; direction=unclear.
- Mohammadi 2025b; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=cardiometabolic; direction=mixed; representative statistic=P < 0.001.
- Mohammadi 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.001.
- Badran 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P = 0.002.
- Pratap 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P > 0.05.
- Shang 2024; Observational; tier=B2; directness=review; N=—; population=—; endpoint=contextual other; direction=unclear; representative statistic=P < 0.0001.
- Butler 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P < 0.05.

### Load-Bearing Tensions

- Severity 4 disagreement: Shang 2024 vs SanchezGarcia 2026; Shang 2024 (unclear) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: Sadeghpour 2025 vs SanchezGarcia 2026; Sadeghpour 2025 (null) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: Tavares 2024 vs SanchezGarcia 2026; Tavares 2024 (unclear) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: Casper 2024 vs Mohammadi 2025b; Casper 2024 (positive) vs Mohammadi 2025b (mixed) on cardiometabolic
- Severity 4 disagreement: Pratap 2025 vs SanchezGarcia 2026; Pratap 2025 (null) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: Khaled 2025 vs SanchezGarcia 2026; Khaled 2025 (null) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: AL-agooz 2025 vs SanchezGarcia 2026; AL-agooz 2025 (null) vs SanchezGarcia 2026 (mixed) on contextual other
- Severity 4 disagreement: Al-Maqbali 2025 vs SanchezGarcia 2026; Al-Maqbali 2025 (unclear) vs SanchezGarcia 2026 (mixed) on contextual other


Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Ayeni 2025, Synnott 2025, Asla 2025, Fiori 2026, Li 2025, Giorgis 2025, Alghamdi 2026, Haq 2025, Queiroz 2025, Akhavan 2026, Gupta 2025, Nofal 2026, Liu 2025, Chen 2025, ADA 2024.
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- **Qin 2025.** _Benefits of melatonin on mortality in severe-to-critical COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials._ Clinics, 2025. DOI: 10.1016/j.clinsp.2025.100638. PMID: 40187234.
- **Carrillo-Vico 2013.** _Melatonin: Buffering the Immune System._ International Journal of Molecular Sciences, 2013. DOI: 10.3390/ijms14048638. PMID: 23609496.

### Background References

*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*

- **ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.
- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.

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