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# Research Synthesis: Melatonin Aging — full paper ## Abstract This paper synthesizes melatonin aging as an aging-related intervention across 50 included source papers and 3008 high-confidence extracted claims. The evidence profile contains 4 direct clinical sources, 24 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 487 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the cardiometabolic and longevity outcome classes, null signals in the contextual adjacent evidence, dosing and pharmacokinetics, safety and comorbidity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that melatonin aging should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## Methods ### Review type and protocol This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-melatonin_aging-v06-DAILY-2026-06-02T02-05-10Z-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: 2026-06-02. ### 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 | This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 30 included sources were assigned to this outcome class. Directional coding: mixed=1, null=25, unclear=4. Directness coding: direct=1, indirect=17, review=12. ### Dosing Pharmacokinetics Outcomes 10 included sources were assigned to this outcome class. Directional coding: null=9, unclear=1. Directness coding: direct=1, indirect=2, review=7. ### Cardiometabolic Outcomes Cardiometabolic remains a separate Results slice (n=5; claims=753; unclear signal in 2/5 sources; 2 direct; 2 indirect; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. ### Safety Comorbidity Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: indirect=1, review=1. ### Deficiency Prevalence Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Immune Inflammation Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Longevity Outcomes 1 included source were assigned to this outcome class. Directional coding: positive=1. Directness coding: review=1. ## 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. 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. The strongest unresolved contrast is the disagreement between Shang 2024 and SanchezGarcia 2026 on contextual adjacent evidence (severity 4), 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 ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. The principal limitation is evidence-role imbalance. The retained corpus contains 4 direct clinical sources, 24 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, which means causal interpretation depends on how much weight is assigned to each evidence tier. A second limitation is endpoint heterogeneity. Study-level signals span the cardiometabolic and longevity outcome classes, the contextual adjacent evidence, dosing and pharmacokinetics, safety and comorbidity outcome classes, no dominant outcome class, and the cardiometabolic and contextual adjacent evidence outcome classes; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design. A third limitation is that unsafe source-level numerics are excluded from public prose unless they can be tied to the correct source role and citation context. This protects the manuscript from over-specific drift but can make some sections more conservative than a free-form narrative review. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another. The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty. The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct clinical signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support. No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record. ## Conclusion For melatonin aging, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support melatonin aging as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging. Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Ayeni 2025, Synnott 2025, Alawi 2026, Wu 2026, Guo 2026, Dessap 2025, Asla 2025, Fiori 2026, Leung 2025, Du 2026, Pang 2025, Kracht 2026, Li 2025, Giorgis 2025, Abuhassan 2026, Wu 2025, Oda 2025, Ginzac 2025, Saraiva 2026, Suram 2025, Alghamdi 2026, Bradfield 2025, Haq 2025, Queiroz 2025, Akhavan 2026, Gupta 2025, Esmaeilzadeh 2025, Lv 2025, Nofal 2026, Kilic 2025, Liu 2025, Chen 2025, Qin 2025, Carrillo-Vico 2013, Studenski 2011, ADA 2024, Cruz-Jentoft 2019, Ioannidis 2005. ## References - **Mohammadi 2025.** _Melatonin administered postoperatively lowers oxidative stress and inflammation and significantly recovers heart function in patients undergoing CABG surgery._ European Journal of Medical Research, 2025. DOI: 10.1186/s40001-025-02789-9. 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DOI: 10.3389/fnut.2026.1742464. PMID: 41769636. - **Dessap 2025.** _Melatonin for prevention of delirium in patients receiving mechanical ventilation in the intensive care unit: a multiarm multistage adaptive randomized controlled clinical trial (DEMEL)._ Intensive Care Medicine, 2025. DOI: 10.1007/s00134-025-08002-z. PMID: 40608082. - **Asla 2025.** _Melatonin as a Possible Stimulus to Unmask an Oxytocin-Deficient State in Hypopituitarism and Hypothalamic Damage._ The Journal of Clinical Endocrinology and Metabolism, 2025. DOI: 10.1210/clinem/dgaf201. PMID: 40166823. - **SanchezGarcia 2026.** _Oral Melatonin in Critically Ill Patients With COVID‐19: A Quasi‐Experimental Pragmatic Trial._ Journal of Medical Virology, 2026. DOI: 10.1002/jmv.70807. 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DOI: 10.3389/fnut.2026.1687221. PMID: 41693954. - **Pang 2025.** _Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study: a protocol for a multicentre phase 1 safety trial of melatonin to augment therapeutic hypothermia for moderate/severe hypoxic ischaemic encephalopathy._ BMJ Open, 2025. DOI: 10.1136/bmjopen-2025-107083. PMID: 40846329. - **Kracht 2026.** _Melatonin Use in Young Children._ JAMA Network Open, 2026. DOI: 10.1001/jamanetworkopen.2025.51958. PMID: 41481289. - **Li 2025.** _Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia with sleep disturbance via enhanced vagal activity: a randomized controlled trial._ International Journal of Surgery (London, England), 2025. DOI: 10.1097/JS9.0000000000003296. PMID: 40905853. - **Khaled 2025.** _Melatonin for preventing postoperative delirium in elderly patients: A multicenter randomized placebo-controlled pilot study._ Medicine, 2025. DOI: 10.1097/MD.0000000000041615. PMID: 39998812. - **Giorgis 2025.** _A prospective randomized crossover trial investigating melatonin versus sleep deprivation for sleep induction in nap electroencephalography._ Epilepsia Open, 2025. DOI: 10.1002/epi4.70169. PMID: 41208640. - **Abuhassan 2026.** _The effect of melatonin supplementation on lipid profile, oxidative stress, inflammatory marker, and sleep quality in patients with chronic kidney disease: a GRADE assessed meta-analysis._ Frontiers in Nutrition, 2026. DOI: 10.3389/fnut.2026.1772877. PMID: 41727206. - **Wu 2025.** _Melatonin improved the outcomes of women with ART: a systematic review and meta-analysis of randomized trials._ Frontiers in Reproductive Health, 2025. DOI: 10.3389/frph.2025.1680984. PMID: 41064014. - **Oda 2025.** _Exogenous melatonin boosts vaccine-induced immunity in individuals with high pre-existing influenza immunity._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1663763. PMID: 41208956. - **Ginzac 2025.** _Melatonin supplementation for quality of life in older patients with advanced cancer: a randomized controlled trial._ BMC Geriatrics, 2025. DOI: 10.1186/s12877-025-06899-1. PMID: 41421991. - **Sadeghpour 2025.** _The effects of melatonin on follicular oxidative stress and art outcomes in women with diminished ovarian reserve: a randomized controlled trial._ Journal of Ovarian Research, 2025. DOI: 10.1186/s13048-024-01584-0. PMID: 39780224. - **Saraiva 2026.** _Low‐Dose Melatonin, Climacteric Symptoms and Sleep in Female Shift Workers: A Randomized Controlled Trial._ Journal of Pineal Research, 2026. DOI: 10.1111/jpi.70140. PMID: 41841489. - **AL-agooz 2025.** _Clinical and radiographic evaluation of melatonin and chitosan loaded nanoparticles in the treatment of periodontal intra-bony defects: A Randomized controlled clinical trial._ Clinical Oral Investigations, 2025. DOI: 10.1007/s00784-025-06323-3. PMID: 40312586. - **Suram 2025.** _Dysregulation of melatonin rhythm in Parkinson’s and Huntington’s disease: a systematic review and meta-analysis._ Frontiers in Aging Neuroscience, 2025. DOI: 10.3389/fnagi.2025.1637881. PMID: 41143249. - **Alghamdi 2026.** _Effectiveness of melatonin supplementation for improving sleep quality and disease severity in children with atopic dermatitis: a systematic review and meta-analysis._ Frontiers in Medicine, 2026. DOI: 10.3389/fmed.2025.1718859. PMID: 41647028. - **Bradfield 2025.** _Double-blind, randomised, placebo-controlled trial to evaluate the effectiveness of late gestation oral melatonin supplementation in reducing induction of labour rates in nulliparous women: the MyTIME study protocol._ BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-090370. PMID: 39855663. - **Haq 2025.** _Melatonin for blood pressure control in adults._ The Cochrane Database of Systematic Reviews, 2025. DOI: 10.1002/14651858.CD016159. PMID: 40955729. - **Queiroz 2025.** _Effect of peri‐operative pharmacological interventions on postoperative delirium in patients having cardiac surgery: a systematic review and Bayesian network meta‐analysis._ Anaesthesia, 2025. DOI: 10.1111/anae.16757. PMID: 40888048. - **Akhavan 2026.** _Comparing Intranasal Midazolam, Oral Melatonin, and Distraction Cards for Pain and Stress Management in Pediatric Intravenous Line Insertion: A Randomized Controlled Trial._ Pain Research & Management, 2026. DOI: 10.1155/prm/9887917. PMID: 41696535. - **Gupta 2025.** _Relative Efficacy of Conventional Monotherapies and Select Nonconventional, Over‐the‐Counter Products for Male Androgenetic Alopecia: A Network Meta‐Analysis Study._ Journal of Cosmetic Dermatology, 2025. DOI: 10.1111/jocd.70483. 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"title": "Research Synthesis: Melatonin Aging \u2014 full paper"
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