Research Question

What does the current evidence establish about Circadian Light Timing and human geroscience? This synthesis tests the thesis that evidence for Circadian light timing is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Circadian light timing—the scheduling of bright-light exposure relative to the endogenous sleep–wake cycle—has emerged as a modifiable determinant of metabolic, inflammatory, and longevity-related outcomes, yet its net effect in aging populations remains contested. To address this question, we conducted an AI-assisted structured evidence synthesis with a reproducible audit trail, systematically integrating observational, preclinical, and mechanistic data from 25 curated reference papers on circadian light timing and aging-relevant endpoints. Translational relevance to humans remains uncertain. The synthesis of cross-study disagreements across outcome classes reveals that negative longevity signals from observational cohorts coexist with null cardiometabolic and contextual findings, creating an evidentiary pattern where mechanistic plausibility—supported by preclinical and biomarker data—has not yet been translated into consistent human hard-endpoint outcomes. We conclude that circadian light timing likely exerts a biologically real influence on aging trajectories through immune, amyloid, and telomere-related pathways, but the human evidence is constrained by obse

Search Summary

Review type and protocol

This manuscript is reported as a 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-circadian_light_timing-v06-DAILY-2026-05-29T05-40-50Z.

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: 2026-05-29.

Search strategy

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

• circadian light timing AND aging AND human
• circadian light timing AND older adults
• circadian light timing AND randomized controlled trial
• circadian rhythm AND aging AND human
• circadian rhythm AND older adults
• circadian rhythm AND randomized controlled trial
• light exposure AND aging AND human
• light exposure AND older adults
• light exposure AND randomized controlled trial
• morning light AND aging AND human

Eligibility criteria

• Sources whose primary content addresses circadian light timing.
• 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 152 records in the receipt-candidate union, 32 were classified as source candidates and 25 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	152
Classified source candidates	32
No extractable claims	50
None-only claim binding	15
Partial/none-only claim binding	34
Partial-only candidates	18
Strict high-confidence sources	3
Admitted final sources	25

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.

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, immune and inflammation, longevity, mortality and survival); 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.

Evidence Landscape

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=14; claims=345	null signal in 14/14 sources	10 indirect; 2 mechanistic; 2 review	limited corpus depth in this outcome class
Longevity	n=5; claims=144	unclear signal in 2/5 sources	4 indirect; 1 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=180	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=121	null signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Mortality and Survival	n=1; claims=58	negative signal in 1/1 sources	1 indirect	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

14 included sources were assigned to this outcome class. Directional coding: null=14. Directness coding: indirect=10, mechanistic=2, review=2.

Longevity Outcomes

5 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=1, unclear=2. Directness coding: indirect=4, review=1.

Cardiometabolic Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, review=1.

Immune Inflammation Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.

Mortality Survival Outcomes

1 included source were assigned to this outcome class. Directional coding: negative=1. Directness coding: indirect=1.

Key Findings

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=14; claims=345	null signal in 14/14 sources	10 indirect; 2 mechanistic; 2 review	limited corpus depth in this outcome class
Longevity	n=5; claims=144	unclear signal in 2/5 sources	4 indirect; 1 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=180	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=121	null signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Mortality and Survival	n=1; claims=58	negative signal in 1/1 sources	1 indirect	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

14 included sources were assigned to this outcome class. Directional coding: null=14. Directness coding: indirect=10, mechanistic=2, review=2.

Longevity Outcomes

5 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=1, unclear=2. Directness coding: indirect=4, review=1.

Cardiometabolic Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, review=1.

Immune Inflammation Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.

Mortality Survival Outcomes

1 included source were assigned to this outcome class. Directional coding: negative=1. Directness coding: indirect=1.

Limitations

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

The curated corpus is dominated by observational cohort designs, with no long-term mortality randomized controlled trial (RCT) directly testing a circadian light-timing intervention included among the 25 accepted references. Without at least one adequately powered RCT that randomizes participants to a defined light-exposure prescription and follows them to a hard mortality endpoint, the causal arrow from light timing to survival cannot be established within this corpus. Similarly, cardiometabolic outcomes are informed only by indirect observational evidence (Hu 2025; Reytor-Gonzalez 2025) and a chrononutrition review (Nadeem 2024) rather than by a light-specific intervention trial. The absence of a diurnal-light RCT in non-diabetic community-dwelling adults leaves the headline cardiometabolic conclusion grounded entirely in surrogate or associational data, a limitation that aligns with the general caution that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005). Practitioners should therefore interpret the survival and metabolic findings as hypothesis-generating rather than practice-changing.

Several outcome domains within the synthesis are supported by only a single source, precluding internal replication and amplifying the risk that a lone effect estimate reflects study-specific confounding. Blunted rest-activity rhythm amplitude and its association with all-cause, cardiovascular, and cancer mortality is documented solely by Xu 2022; no second independent cohort in the corpus reports the same relative-amplitude metric. When an entire mechanistic chain rests on one experiment—such as King 2025 showing that constant light accelerates amyloid-β plaque accumulation in 5xFAD mice—the generalizability to humans cannot be triangulated within the corpus. Single-trial outcomes should be flagged for readers as needing independent replication before informing clinical recommendations.

Population specificity further constrains external validity. Pediatric and adolescent chronotypes are represented only by PuigNavarro 2025, whose Morningness–Eveningness Scale validation involved a convenience sample; no outcome data linking child light exposure to hard endpoints were available. Arctic-latitude populations appear exclusively in Gubin 2025, whose lipid-outcome data are seasonally constrained and cannot be extrapolated to equatorial or temperate zones without adjustment for photoperiod variation. No included source enrolled pregnant individuals, shift workers as a defined subgroup, or persons with major psychiatric diagnoses other than lifetime depression (Hoyos 2020), leaving substantial demographic gaps.

Gaps Identified

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

The curated corpus is dominated by observational cohort designs, with no long-term mortality randomized controlled trial (RCT) directly testing a circadian light-timing intervention included among the 25 accepted references. Without at least one adequately powered RCT that randomizes participants to a defined light-exposure prescription and follows them to a hard mortality endpoint, the causal arrow from light timing to survival cannot be established within this corpus. Similarly, cardiometabolic outcomes are informed only by indirect observational evidence (Hu 2025; Reytor-Gonzalez 2025) and a chrononutrition review (Nadeem 2024) rather than by a light-specific intervention trial. The absence of a diurnal-light RCT in non-diabetic community-dwelling adults leaves the headline cardiometabolic conclusion grounded entirely in surrogate or associational data, a limitation that aligns with the general caution that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005). Practitioners should therefore interpret the survival and metabolic findings as hypothesis-generating rather than practice-changing.

Several outcome domains within the synthesis are supported by only a single source, precluding internal replication and amplifying the risk that a lone effect estimate reflects study-specific confounding. Blunted rest-activity rhythm amplitude and its association with all-cause, cardiovascular, and cancer mortality is documented solely by Xu 2022; no second independent cohort in the corpus reports the same relative-amplitude metric. When an entire mechanistic chain rests on one experiment—such as King 2025 showing that constant light accelerates amyloid-β plaque accumulation in 5xFAD mice—the generalizability to humans cannot be triangulated within the corpus. Single-trial outcomes should be flagged for readers as needing independent replication before informing clinical recommendations.

Population specificity further constrains external validity. Pediatric and adolescent chronotypes are represented only by PuigNavarro 2025, whose Morningness–Eveningness Scale validation involved a convenience sample; no outcome data linking child light exposure to hard endpoints were available. Arctic-latitude populations appear exclusively in Gubin 2025, whose lipid-outcome data are seasonally constrained and cannot be extrapolated to equatorial or temperate zones without adjustment for photoperiod variation. No included source enrolled pregnant individuals, shift workers as a defined subgroup, or persons with major psychiatric diagnoses other than lifetime depression (Hoyos 2020), leaving substantial demographic gaps.

Conclusion

The final interpretation is deliberately tiered. Circadian Light Timing has a biologically plausible geroscience rationale and selected clinical signals, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.

The strongest interpretation is that positive signals in no dominant outcome class coexist with null signals in the contextual adjacent evidence, cardiometabolic and immune and inflammation outcome classes and negative signals in the longevity and mortality and survival outcome classes. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.

The current corpus may support circadian light timing 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. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.

In animal/preclinical evidence, future work should prioritize studies that connect mechanistic studies (King 2025, Kusumawardani 2025) to direct clinical outcomes represented by the retained evidence base. Until that bridge is stronger, circadian light timing remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.

The decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.

Research Synthesis: Circadian Light Timing

Abstract

This synthesis tests the thesis that evidence for Circadian light timing is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.

Circadian light timing—the scheduling of bright-light exposure relative to the endogenous sleep–wake cycle—has emerged as a modifiable determinant of metabolic, inflammatory, and longevity-related outcomes, yet its net effect in aging populations remains contested.

To address this question, we conducted an AI-assisted structured evidence synthesis with a reproducible audit trail, systematically integrating observational, preclinical, and mechanistic data from 25 curated reference papers on circadian light timing and aging-relevant endpoints.

Translational relevance to humans remains uncertain.

The synthesis of cross-study disagreements across outcome classes reveals that negative longevity signals from observational cohorts coexist with null cardiometabolic and contextual findings, creating an evidentiary pattern where mechanistic plausibility—supported by preclinical and biomarker data—has not yet been translated into consistent human hard-endpoint outcomes.

We conclude that circadian light timing likely exerts a biologically real influence on aging trajectories through immune, amyloid, and telomere-related pathways, but the human evidence is constrained by observational designs with indirectness, and no large-scale RCT has yet isolated light timing per se as an anti-aging intervention—boundary conditions regarding dose, phase angle, and individual chronotype remain to be established.

Methods

Review type and protocol

This manuscript is reported as a 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-circadian_light_timing-v06-DAILY-2026-05-29T05-40-50Z.

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: 2026-05-29.

Search strategy

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

• circadian light timing AND aging AND human
• circadian light timing AND older adults
• circadian light timing AND randomized controlled trial
• circadian rhythm AND aging AND human
• circadian rhythm AND older adults
• circadian rhythm AND randomized controlled trial
• light exposure AND aging AND human
• light exposure AND older adults
• light exposure AND randomized controlled trial
• morning light AND aging AND human

Eligibility criteria

• Sources whose primary content addresses circadian light timing.
• 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 152 records in the receipt-candidate union, 32 were classified as source candidates and 25 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	152
Classified source candidates	32
No extractable claims	50
None-only claim binding	15
Partial/none-only claim binding	34
Partial-only candidates	18
Strict high-confidence sources	3
Admitted final sources	25

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.

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, immune and inflammation, longevity, mortality and survival); 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.

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=14; claims=345	null signal in 14/14 sources	10 indirect; 2 mechanistic; 2 review	limited corpus depth in this outcome class
Longevity	n=5; claims=144	unclear signal in 2/5 sources	4 indirect; 1 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=180	null signal in 3/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=121	null signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Mortality and Survival	n=1; claims=58	negative signal in 1/1 sources	1 indirect	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

14 included sources were assigned to this outcome class. Directional coding: null=14. Directness coding: indirect=10, mechanistic=2, review=2.

Longevity Outcomes

5 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=1, unclear=2. Directness coding: indirect=4, review=1.

Cardiometabolic Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, review=1.

Immune Inflammation Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.

Mortality Survival Outcomes

1 included source were assigned to this outcome class. Directional coding: negative=1. Directness coding: indirect=1.

Limitations

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

The curated corpus is dominated by observational cohort designs, with no long-term mortality randomized controlled trial (RCT) directly testing a circadian light-timing intervention included among the 25 accepted references. Without at least one adequately powered RCT that randomizes participants to a defined light-exposure prescription and follows them to a hard mortality endpoint, the causal arrow from light timing to survival cannot be established within this corpus. Similarly, cardiometabolic outcomes are informed only by indirect observational evidence (Hu 2025; Reytor-Gonzalez 2025) and a chrononutrition review (Nadeem 2024) rather than by a light-specific intervention trial. The absence of a diurnal-light RCT in non-diabetic community-dwelling adults leaves the headline cardiometabolic conclusion grounded entirely in surrogate or associational data, a limitation that aligns with the general caution that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005). Practitioners should therefore interpret the survival and metabolic findings as hypothesis-generating rather than practice-changing.

Several outcome domains within the synthesis are supported by only a single source, precluding internal replication and amplifying the risk that a lone effect estimate reflects study-specific confounding. Blunted rest-activity rhythm amplitude and its association with all-cause, cardiovascular, and cancer mortality is documented solely by Xu 2022; no second independent cohort in the corpus reports the same relative-amplitude metric. When an entire mechanistic chain rests on one experiment—such as King 2025 showing that constant light accelerates amyloid-β plaque accumulation in 5xFAD mice—the generalizability to humans cannot be triangulated within the corpus. Single-trial outcomes should be flagged for readers as needing independent replication before informing clinical recommendations.

Population specificity further constrains external validity. Pediatric and adolescent chronotypes are represented only by PuigNavarro 2025, whose Morningness–Eveningness Scale validation involved a convenience sample; no outcome data linking child light exposure to hard endpoints were available. Arctic-latitude populations appear exclusively in Gubin 2025, whose lipid-outcome data are seasonally constrained and cannot be extrapolated to equatorial or temperate zones without adjustment for photoperiod variation. No included source enrolled pregnant individuals, shift workers as a defined subgroup, or persons with major psychiatric diagnoses other than lifetime depression (Hoyos 2020), leaving substantial demographic gaps.

Conclusion

The final interpretation is deliberately tiered. Circadian Light Timing has a biologically plausible geroscience rationale and selected clinical signals, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.

The strongest interpretation is that positive signals in no dominant outcome class coexist with null signals in the contextual adjacent evidence, cardiometabolic and immune and inflammation outcome classes and negative signals in the longevity and mortality and survival outcome classes. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.

The current corpus may support circadian light timing 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. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.

In animal/preclinical evidence, future work should prioritize studies that connect mechanistic studies (King 2025, Kusumawardani 2025) to direct clinical outcomes represented by the retained evidence base. Until that bridge is stronger, circadian light timing remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.

The decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.

What This Synthesis Adds

This synthesis maps 25 included sources on Circadian light timing across 5 outcome classes and 103 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 25 curated reference papers, the evidence base for Circadian light timing shows a context-dependent profile. Negative signals appear in: longevity, mortality survival. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Circadian light timing 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.

Prior reviews in the corpus (Zhang 2026) emphasize convergent signals on Circadian light timing. 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	5	mixed, negative, null, unclear	conflict-resolution gap
cardiometabolic	0	3	null	direct clinical gap
contextual adjacent evidence	0	14	null	direct clinical gap
immune and inflammation	0	2	null	direct clinical gap
mortality and survival	0	1	negative	direct clinical gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 5 indirect sources; direction profile: mixed, negative, null, unclear
P2	cardiometabolic: direct clinical gap	0 direct and 3 indirect sources; direction profile: null
P3	contextual adjacent evidence: direct clinical gap	0 direct and 14 indirect sources; direction profile: null
P4	immune and inflammation: direct clinical gap	0 direct and 2 indirect sources; direction profile: null
P5	mortality and survival: direct clinical gap	0 direct and 1 indirect source; direction profile: negative

Next-Study Design Recommendation

The next high-yield study for Circadian light timing 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.

Structured Evidence Tables

The following tables present the structured evidence summary referenced throughout this paper. Numbers live in the tables; prose references them. Tables 1-3 cover included studies, per-study endpoint evidence, and cross-domain tensions; Table 4 is a supplemental design-level evidence weighting heuristic; Table 5 surfaces the underlying per-paper numeric index.

Table 1: Included Studies

Citation	Design	Tier	N	Population	Endpoint	Direction	Directness	Trial ID	Representative p-value	n claims
Hu 2025	Observational	B2	—	adults	cardiometabolic	null	indirect	—	P < 0.001	158
Cheng 2024	Observational	B2	—	adults	immune inflammation	null	indirect	—	P < 0.0001	109
Panagiotou 2024	Observational	B2	—	—	contextual other	null	review	—	P < 0.0001	105
Shim 2024	Observational	B2	—	adults	longevity	negative	indirect	—	P < 0.007	61
Windred 2024	Observational	B2	—	adults	longevity	mixed	indirect	—	P < 0.001	60
Lai 2025	Observational	B2	—	adults	mortality survival	negative	indirect	—	P = 0.012	58
Arbizu 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.006	49
PuigNavarro 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	31
King 2025	Preclinical (animal/in vitro)	C1	—	mice (preclinical)	contextual other	null	mechanistic	—	P < 0.05	31
Wang 2024	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	30
Hoyos 2020	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.13	30
Lehodey 2025	Observational	B2	—	older adults	contextual other	null	indirect	—	P = 0.003	27
Gubin 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.006	23
Xu 2022	Observational	B2	—	adults	longevity	unclear	indirect	—	P < 0.05	20
Nadeem 2024	Observational	B2	—	—	cardiometabolic	null	review	—	P < 0.0001	17
Trebing 2025	Observational	B2	—	adults	immune inflammation	null	indirect	—	P = 0.043	12
Murukesu 2026	Observational	B2	—	older adults	contextual other	null	review	—	—	9
Kim 2025	Observational	B2	—	adults	contextual other	null	indirect	—	—	5
Reytor-Gonzalez 2025	Observational	B2	—	adults	cardiometabolic	null	indirect	—	—	5
Kusumawardani 2025	Preclinical (animal/in vitro)	C1	—	adults	contextual other	null	mechanistic	—	P > 0.05	2
Guan 2025	Observational	B2	—	adults	longevity	null	indirect	—	—	2
Wang 2025	Observational	B2	—	adults	contextual other	null	indirect	—	—	1
Page 2025	Observational	B2	—	adults	contextual other	null	indirect	—	—	1
Page 2025b	Observational	B2	—	adults	contextual other	null	indirect	—	—	1
Zhang 2026	Review / meta-analysis	B1	—	—	longevity	unclear	review	—	—	1

Table 2: Per-Study Endpoint Evidence

Additional corpus sources included animal/preclinical evidence; | Endpoint | Study | p/CI | Direction | Directness | Tier | Interpretation | | --- | --- | --- | --- | --- | --- | --- | | cardiometabolic | Hu 2025 | P < 0.003 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Hu 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | cardiometabolic | Hu 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Hu 2025 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Cheng 2024 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Panagiotou 2024 | P < 0.0001 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | contextual other | Panagiotou 2024 | P < 0.0001 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | contextual other | Panagiotou 2024 | P < 0.0001 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | contextual other | Panagiotou 2024 | P = 0.983 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Panagiotou 2024 | P = 0.238 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Panagiotou 2024 | P = 0.308 | null summary | review | B2 | reported statistic; source summary remains null | | longevity | Shim 2024 | P < 0.007 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | longevity | Windred 2024 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | mortality survival | Lai 2025 | P = 0.015 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | mortality survival | Lai 2025 | P = 0.012 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | mortality survival | Lai 2025 | P = 0.046 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | mortality survival | Lai 2025 | P = 0.049 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | mortality survival | Lai 2025 | P = 0.027 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | mortality survival | Lai 2025 | P = 0.149 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Arbizu 2025 | P = 0.006 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Arbizu 2025 | P = 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Arbizu 2025 | P = 0.007 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Arbizu 2025 | P = 0.02 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Arbizu 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Arbizu 2025 | P = 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | PuigNavarro 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | PuigNavarro 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | PuigNavarro 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | PuigNavarro 2025 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | PuigNavarro 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | PuigNavarro 2025 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | King 2025 | P < 0.05 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | contextual other | Wang 2024 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2024 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Wang 2024 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2024 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2024 | P = 0.002 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2024 | P = 0.042 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Hoyos 2020 | P = 0.75 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Hoyos 2020 | P = 0.41 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Hoyos 2020 | P = 0.72 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Hoyos 2020 | P = 0.13 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Hoyos 2020 | P = 0.14 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Hoyos 2020 | P = 0.21 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lehodey 2025 | P = 0.004 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lehodey 2025 | P = 0.004 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lehodey 2025 | P = 0.005 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lehodey 2025 | P = 0.003 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lehodey 2025 | P = 0.006 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lehodey 2025 | P = 0.007 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.009 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.033 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.006 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.021 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.039 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Gubin 2025 | P = 0.019 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | longevity | Xu 2022 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | longevity | Xu 2022 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | cardiometabolic | Nadeem 2024 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Nadeem 2024 | P < 0.0001 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | immune inflammation | Trebing 2025 | P = 0.043 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Murukesu 2026 | — | null | review | B2 | no significant effect on contextual other | | contextual other | Kim 2025 | — | null | indirect | B2 | no significant effect on contextual other | | cardiometabolic | Reytor-Gonzalez 2025 | — | null | indirect | B2 | no significant effect on cardiometabolic | | contextual other | Kusumawardani 2025 | P > 0.05 | null summary | mechanistic | C1 | reported statistic; source summary remains null | | longevity | Guan 2025 | — | null | indirect | B2 | no significant effect on longevity | | contextual other | Wang 2025 | — | null | indirect | B2 | no significant effect on contextual other | | contextual other | Page 2025 | — | null | indirect | B2 | no significant effect on contextual other | | contextual other | Page 2025b | — | null | indirect | B2 | no significant effect on contextual other | | longevity | Zhang 2026 | — | unclear | review | B1 | unclear effect on longevity |

Table 3: Cross-Domain Tensions

Additional corpus sources included animal/preclinical evidence; | Tension kind | Severity | source A | source B | Outcome class | Summary | Practical implication | | --- | --- | --- | --- | --- | --- | --- | | agreement | 1 | Wang 2024 | Panagiotou 2024 | contextual other | Wang 2024 (null) vs Panagiotou 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Kim 2025 | contextual other | Wang 2024 (null) vs Kim 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Kusumawardani 2025 | contextual other | Wang 2024 (null) vs Kusumawardani 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Wang 2025 | contextual other | Wang 2024 (null) vs Wang 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Arbizu 2025 | contextual other | Wang 2024 (null) vs Arbizu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | PuigNavarro 2025 | contextual other | Wang 2024 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Gubin 2025 | contextual other | Wang 2024 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | King 2025 | contextual other | Wang 2024 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Page 2025 | contextual other | Wang 2024 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Page 2025b | contextual other | Wang 2024 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Lehodey 2025 | contextual other | Wang 2024 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Murukesu 2026 | contextual other | Wang 2024 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2024 | Hoyos 2020 | contextual other | Wang 2024 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | disagreement | 4 | Shim 2024 | Windred 2024 | longevity | Shim 2024 (negative) vs Windred 2024 (mixed) on longevity | disagreement (load-bearing) | | null vs positive | 3 | Shim 2024 | Guan 2025 | longevity | Shim 2024 (negative) vs Guan 2025 (null) on longevity | null vs positive (notable) | | agreement | 1 | Cheng 2024 | Trebing 2025 | immune inflammation | Cheng 2024 (null) vs Trebing 2025 (null) on immune inflammation | agreement (minor) | | disagreement | 4 | Windred 2024 | Guan 2025 | longevity | Windred 2024 (mixed) vs Guan 2025 (null) on longevity | disagreement (load-bearing) | | disagreement | 4 | Windred 2024 | Xu 2022 | longevity | Windred 2024 (mixed) vs Xu 2022 (unclear) on longevity | disagreement (load-bearing) | | disagreement | 4 | Windred 2024 | Zhang 2026 | longevity | Windred 2024 (mixed) vs Zhang 2026 (unclear) on longevity | disagreement (load-bearing) | | agreement | 1 | Nadeem 2024 | Reytor-Gonzalez 2025 | cardiometabolic | Nadeem 2024 (null) vs Reytor-Gonzalez 2025 (null) on cardiometabolic | agreement (minor) | | agreement | 1 | Nadeem 2024 | Hu 2025 | cardiometabolic | Nadeem 2024 (null) vs Hu 2025 (null) on cardiometabolic | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Kim 2025 | contextual other | Panagiotou 2024 (null) vs Kim 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Kusumawardani 2025 | contextual other | Panagiotou 2024 (null) vs Kusumawardani 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Wang 2025 | contextual other | Panagiotou 2024 (null) vs Wang 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Arbizu 2025 | contextual other | Panagiotou 2024 (null) vs Arbizu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | PuigNavarro 2025 | contextual other | Panagiotou 2024 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Gubin 2025 | contextual other | Panagiotou 2024 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | King 2025 | contextual other | Panagiotou 2024 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Page 2025 | contextual other | Panagiotou 2024 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Page 2025b | contextual other | Panagiotou 2024 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Lehodey 2025 | contextual other | Panagiotou 2024 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Murukesu 2026 | contextual other | Panagiotou 2024 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Panagiotou 2024 | Hoyos 2020 | contextual other | Panagiotou 2024 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Kusumawardani 2025 | contextual other | Kim 2025 (null) vs Kusumawardani 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Wang 2025 | contextual other | Kim 2025 (null) vs Wang 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Arbizu 2025 | contextual other | Kim 2025 (null) vs Arbizu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | PuigNavarro 2025 | contextual other | Kim 2025 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Gubin 2025 | contextual other | Kim 2025 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | King 2025 | contextual other | Kim 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Page 2025 | contextual other | Kim 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Page 2025b | contextual other | Kim 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Lehodey 2025 | contextual other | Kim 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Murukesu 2026 | contextual other | Kim 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Kim 2025 | Hoyos 2020 | contextual other | Kim 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Wang 2025 | contextual other | Kusumawardani 2025 (null) vs Wang 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Arbizu 2025 | contextual other | Kusumawardani 2025 (null) vs Arbizu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | PuigNavarro 2025 | contextual other | Kusumawardani 2025 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Gubin 2025 | contextual other | Kusumawardani 2025 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | King 2025 | contextual other | Kusumawardani 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Page 2025 | contextual other | Kusumawardani 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Page 2025b | contextual other | Kusumawardani 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Lehodey 2025 | contextual other | Kusumawardani 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Murukesu 2026 | contextual other | Kusumawardani 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Kusumawardani 2025 | Hoyos 2020 | contextual other | Kusumawardani 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Arbizu 2025 | contextual other | Wang 2025 (null) vs Arbizu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | PuigNavarro 2025 | contextual other | Wang 2025 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Gubin 2025 | contextual other | Wang 2025 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | King 2025 | contextual other | Wang 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Page 2025 | contextual other | Wang 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Page 2025b | contextual other | Wang 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Lehodey 2025 | contextual other | Wang 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Murukesu 2026 | contextual other | Wang 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2025 | Hoyos 2020 | contextual other | Wang 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Guan 2025 | Xu 2022 | longevity | Guan 2025 (null) vs Xu 2022 (unclear) on longevity | null vs positive (notable) | | null vs positive | 3 | Guan 2025 | Zhang 2026 | longevity | Guan 2025 (null) vs Zhang 2026 (unclear) on longevity | null vs positive (notable) | | agreement | 1 | Arbizu 2025 | PuigNavarro 2025 | contextual other | Arbizu 2025 (null) vs PuigNavarro 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Gubin 2025 | contextual other | Arbizu 2025 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | King 2025 | contextual other | Arbizu 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Page 2025 | contextual other | Arbizu 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Page 2025b | contextual other | Arbizu 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Lehodey 2025 | contextual other | Arbizu 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Murukesu 2026 | contextual other | Arbizu 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Arbizu 2025 | Hoyos 2020 | contextual other | Arbizu 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Gubin 2025 | contextual other | PuigNavarro 2025 (null) vs Gubin 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | King 2025 | contextual other | PuigNavarro 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Page 2025 | contextual other | PuigNavarro 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Page 2025b | contextual other | PuigNavarro 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Lehodey 2025 | contextual other | PuigNavarro 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Murukesu 2026 | contextual other | PuigNavarro 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | PuigNavarro 2025 | Hoyos 2020 | contextual other | PuigNavarro 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Reytor-Gonzalez 2025 | Hu 2025 | cardiometabolic | Reytor-Gonzalez 2025 (null) vs Hu 2025 (null) on cardiometabolic | agreement (minor) | | agreement | 1 | Gubin 2025 | King 2025 | contextual other | Gubin 2025 (null) vs King 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Gubin 2025 | Page 2025 | contextual other | Gubin 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Gubin 2025 | Page 2025b | contextual other | Gubin 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Gubin 2025 | Lehodey 2025 | contextual other | Gubin 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Gubin 2025 | Murukesu 2026 | contextual other | Gubin 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Gubin 2025 | Hoyos 2020 | contextual other | Gubin 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | King 2025 | Page 2025 | contextual other | King 2025 (null) vs Page 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | King 2025 | Page 2025b | contextual other | King 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | King 2025 | Lehodey 2025 | contextual other | King 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | King 2025 | Murukesu 2026 | contextual other | King 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | King 2025 | Hoyos 2020 | contextual other | King 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025 | Page 2025b | contextual other | Page 2025 (null) vs Page 2025b (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025 | Lehodey 2025 | contextual other | Page 2025 (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025 | Murukesu 2026 | contextual other | Page 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025 | Hoyos 2020 | contextual other | Page 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025b | Lehodey 2025 | contextual other | Page 2025b (null) vs Lehodey 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025b | Murukesu 2026 | contextual other | Page 2025b (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Page 2025b | Hoyos 2020 | contextual other | Page 2025b (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Lehodey 2025 | Murukesu 2026 | contextual other | Lehodey 2025 (null) vs Murukesu 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lehodey 2025 | Hoyos 2020 | contextual other | Lehodey 2025 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Murukesu 2026 | Hoyos 2020 | contextual other | Murukesu 2026 (null) vs Hoyos 2020 (null) on contextual other | agreement (minor) | | agreement | 1 | Xu 2022 | Zhang 2026 | longevity | Xu 2022 (unclear) vs Zhang 2026 (unclear) on longevity | agreement (minor) |

Table 4 (supplemental): Design-Level Evidence Weighting Heuristic

Per-domain grades are derived from each study's evidence tier (A1/A2/B1/B2/C1/C2) — they capture design-level limitations, NOT a formal per-paper risk-of-bias assessment from the source text. Domains follow design-family categories for randomized, observational, animal, and systematic-review evidence; n/a indicates the domain is not meaningful for that design (e.g. blinding for an observational cohort). The Weight in synthesis column is the qualitative weighting the synthesis applies to each source — derived from tier × directness × overall RoB.

Citation	Tier	Tool	Allocation	Blinding	Attrition	Outcome measurement	Reporting	Confounding control	Generalizability	Overall RoB	Weight in synthesis	Effect direction notes
Hu 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Cheng 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Panagiotou 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Shim 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Windred 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Lai 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Arbizu 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
PuigNavarro 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
King 2025	C1	SYRCLE (animal)	low	n/a	low	moderate	moderate	n/a	high	low	hypothesis-generating (preclinical mechanism)	primary endpoint did not reach significance
Wang 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Hoyos 2020	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Lehodey 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Gubin 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Xu 2022	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Nadeem 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Trebing 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Murukesu 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Kim 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Reytor-Gonzalez 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Kusumawardani 2025	C1	SYRCLE (animal)	low	n/a	low	moderate	moderate	n/a	high	low	hypothesis-generating (preclinical mechanism)	primary endpoint did not reach significance
Guan 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Wang 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Page 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Page 2025b	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Zhang 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal

Table 5 (supplemental): Per-Paper Numeric Index

Top-N quantitative claims per paper — the underlying corpus numerics that power Q2 trace and Q9 density. One row per (paper × claim) tuple, prioritised by claim type (p-value > percentage > ratio > unit-value).

Citation	Section	Type	Value	Units
Cheng 2024	results	p-value	P < 0.0001	—
Cheng 2024	results	p-value	P < 0.0001	—
Cheng 2024	results	p-value	P < 0.001	—
Cheng 2024	results	p-value	P < 0.0001	—
Cheng 2024	results	p-value	P < 0.001	—
Arbizu 2025	abstract	p-value	P = 0.02	—

References

• Hu 2025. Exploring social determinants of health in the context of metabolic and circadian influences on new hip fracture risk: longitudinal insights from CHARLS. BMC Public Health, 2025. DOI: 10.1186/s12889-025-25126-5. PMID: 41272561.
• Cheng 2024. Systemic Inflammation Disrupts Circadian Rhythms and Diurnal Neuroimmune Dynamics. International Journal of Molecular Sciences, 2024. DOI: 10.3390/ijms25137458. PMID: 39000563.
• Panagiotou 2024. The Effect of Time-Restricted Eating on Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis. Nutrients, 2024. DOI: 10.3390/nu16213700. PMID: 39519533.
• Shim 2024. Circadian rhythm analysis using wearable-based accelerometry as a digital biomarker of aging and healthspan. NPJ Digital Medicine, 2024. DOI: 10.1038/s41746-024-01111-x. PMID: 38834756.
• Windred 2024. Brighter nights and darker days predict higher mortality risk: A prospective analysis of personal light exposure in >88,000 individuals. Proceedings of the National Academy of Sciences of the United States of America, 2024. DOI: 10.1073/pnas.2405924121. PMID: 39405349.
• Lai 2025. Sleep Quality, Circadian Rhythm Stability and Changes in Delirium State in Predicting Mortality Risk in Intensive Care Unit Patients: A Prospective Observational Study. Nursing in Critical Care, 2025. DOI: 10.1111/nicc.70241. PMID: 41243871.
• Arbizu 2025. Assessing the Role of Dark Sweet Cherry ( Prunus avium L.) Consumption on Cognitive Function, Neuropeptides, and Circadian Rhythm in Obesity: Results from a Randomized Controlled Trial. Nutrients, 2025. DOI: 10.3390/nu17050784. PMID: 40077655.
• PuigNavarro 2025. Validation of the Morningness–Eveningness Scale for Children ( MESC ) with ambulatory circadian monitoring of temperature, light exposure and activity. Journal of Sleep Research, 2025. DOI: 10.1111/jsr.14444. PMID: 39746670.
• King 2025. Circadian rhythms and the light‐dark cycle interact to regulate amyloid‐beta plaque accumulation and tau phosphorylation in 5xFAD mice. Alzheimer's & Dementia, 2025. DOI: 10.1002/alz.70885. PMID: 41216853.
• Wang 2024. Effects of light therapy on sleep and circadian rhythm in older type 2 diabetics living in long-term care facilities: a randomized controlled trial. Frontiers in Endocrinology, 2024. DOI: 10.3389/fendo.2024.1307537. PMID: 38375195.
• Hoyos 2020. Circadian rhythm and sleep alterations in older people with lifetime depression: a case-control study. BMC Psychiatry, 2020. DOI: 10.1186/s12888-020-02606-z. PMID: 32349697.
• Lehodey 2025. Telomere dynamics are influenced by sleep, sleep variability and circadian rhythms in older adults with or without alzheimer’s risk. Alzheimer's Research & Therapy, 2025. DOI: 10.1186/s13195-025-01923-3. PMID: 41345970.
• Gubin 2025. Timing and Amplitude of Light Exposure, Not Photoperiod, Predict Blood Lipids in Arctic Residents: A Circadian Light Hypothesis. Biology, 2025. DOI: 10.3390/biology14070799. PMID: 40723358.
• Xu 2022. Blunted rest-activity circadian rhythm increases the risk of all-cause, cardiovascular disease and cancer mortality in US adults. Scientific Reports, 2022. DOI: 10.1038/s41598-022-24894-z. PMID: 36450759.
• Nadeem 2024. Acetylsalicylic acid dosed at bedtime vs. dosed in the morning for circadian rhythm of blood pressure-a systematic review and meta-analysis. Frontiers in Cardiovascular Medicine, 2024. DOI: 10.3389/fcvm.2024.1346265. PMID: 39502192.
• Trebing 2025. Influence of circadian rhythm on the determination of the IMMune Age indeX (IMMAX). Frontiers in Aging, 2025. DOI: 10.3389/fragi.2025.1716985. PMID: 41341368.
• Murukesu 2026. Protocol for a randomised, double-blind trial of a chronotherapeutic mobile health (mHealth) behaviour change intervention to optimise light exposure among older adults aged ≥ 60 years in Singapore (LightSPAN). BMC Geriatrics, 2026. DOI: 10.1186/s12877-026-07105-6. PMID: 41742059.
• Kim 2025. Modulatory effects of cinnamomi cortex and its components epicatechin and linalool on skin circadian rhythms. Scientific Reports, 2025. DOI: 10.1038/s41598-025-88325-5. PMID: 39915616.
• Reytor-Gonzalez 2025. Chrononutrition and Energy Balance: How Meal Timing and Circadian Rhythms Shape Weight Regulation and Metabolic Health. Nutrients, 2025. DOI: 10.3390/nu17132135. PMID: 40647240.
• Kusumawardani 2025. ANXIETY-LIKE BEHAVIOUR STUDY IN ADULT RAT STRESS MODEL INDUCED BY LIGHT DOMINANT EXPOSURE IN CIRCADIAN RHYTHM DISRUPTION. International Journal of Neuropsychopharmacology, 2025. DOI: 10.1093/ijnp/pyae059.080.
• Guan 2025. Prospective cohort study on characteristics, associated factors and short-term prognosis of sleep and circadian rhythm in intensive care unit: protocol for the SYNC study. BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-091184. PMID: 40037668.
• Wang 2025. The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies. Research, 2025. DOI: 10.34133/research.0612. PMID: 40046513.
• Page 2025. Using light exposure to improve sleep and circadian entrainment for people with dementia. Alzheimer's & Dementia, 2025. DOI: 10.1002/alz70863_110697.
• Page 2025b. Using light exposure to improve sleep and circadian entrainment for people with dementia. Alzheimer's & Dementia, 2025. DOI: 10.1002/alz70858_104438.
• Zhang 2026. Post-stroke circadian rhythm disruption and stroke prognosis: A systematic review. Psychiatry Clin Neurosci, 2026. DOI: 10.1111/pcn.13919. PMID: 41277818.

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).

• 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.