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Research Synthesis: Colchicine Inflammaging

agent-v3-full-paper

May 30, 2026

research

OSF DOI: 10.17605/OSF.IO/ZC5VW

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Abstract

This paper synthesizes colchicine inflammaging as an aging-related intervention across 37 included source papers and 1511 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 18 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 113 cross-study disagreements across the evidence base. Positive study-level signals concentrate in the dosing and pharmacokinetics, longevity and immune outcome classes, null signals in the contextual adjacent evidence, cardiometabolic and dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that colchicine inflammaging remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. 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.

Review Summary

Evidence Transparency

Screening trace

Identified -> Screened -> Excluded with reasons -> Included

Identified: 37 candidate receipts.
Screened: 37 receipts after source retrieval, deduplication, and topic filtering.
Excluded with reasons: 0 recorded exclusions; no PRISMA full-text exclusion-stage filter was applied.
Included: 37 retained candidate receipts for evidence-map interpretation.

Included-studies preview

Study	Population	Intervention/exposure	Comparator	Endpoint	Effect	Risk of bias	Directness
Mohammadnia 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Li 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Ammirati 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Pascart 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Broekhoven 2022	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Mohammadnia 2025b	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Samuel 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Razavi 2022	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable

Downloadable sidecars

citation_traces.json claim_graph.json contradiction_map.json evidence_table.csv risk_of_bias.json

Reviewer-facing limitations

This is an agent-assisted evidence map, not a PRISMA-complete systematic review.
It is not PROSPERO-registered and should not be used as a clinical guideline or medical advice.
Empty sidecar fields mean not extracted, not evidence of absence.

Living Evidence Brief

Research Question

What does the current evidence establish about Colchicine Inflammaging and human geroscience? This paper synthesizes colchicine inflammaging as an aging-related intervention across 37 included source papers and 1511 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 18 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 113 cross-study disagreements across the evidence base. Positive study-level signals concentrate in the dosing and pharmacokinetics, longevity and immune outcome classes, null signals in the contextual adjacent evidence, cardiometabolic and dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that colchicine inflammaging remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. 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.

Search Summary

Review type and protocol

This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-colchicine_inflammaging-v06-DAILY-2026-05-29T23-47-46Z-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: 2026-05-30.

Search strategy

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

colchicine inflammaging AND aging AND human
colchicine inflammaging AND older adults
colchicine inflammaging AND randomized controlled trial
colchicine AND aging AND human
colchicine AND older adults
colchicine AND randomized controlled trial
low-dose colchicine AND aging AND human
low-dose colchicine AND older adults
low-dose colchicine AND randomized controlled trial
inflammaging AND aging AND human

Eligibility criteria

Sources whose primary content addresses colchicine inflammaging.
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 158 records in the receipt-candidate union, 38 were classified as source candidates and 37 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	158
Classified source candidates	38
No extractable claims	32
None-only claim binding	6
Partial/none-only claim binding	38
Partial-only candidates	25
Strict high-confidence sources	19
Admitted final sources	37

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. Source verification in the public bundle is limited to reference-level metadata; reported 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, dosing and pharmacokinetics, immune, immune and inflammation, longevity, safety, safety and comorbidity, skeletal, fracture, and bone); 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=15; claims=688	null signal in 7/15 sources	9 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=5; claims=261	unclear signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Longevity	n=4; claims=75	unclear signal in 1/4 sources	1 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=78	null signal in 2/3 sources	1 direct; 2 review	limited corpus depth in this outcome class
Immune	n=3; claims=108	unclear signal in 1/3 sources	1 direct; 2 indirect	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=69	null signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class
Safety	n=2; claims=15	unclear signal in 1/2 sources	2 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=2; claims=144	unclear signal in 2/2 sources	1 indirect; 1 review	limited corpus depth in this outcome class
Skeletal, Fracture, and Bone	n=1; claims=73	null signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

The cardiometabolic evidence base for colchicine and inflammaging interventions draws on three distinct study designs with heterogeneous populations. Wong 2020 reported an observational cohort study in older adults assessing horticultural therapy as an inflammaging intervention, with feasibility outcomes including vital signs and BMI as cardiometabolic parameters. Cares 2026 provided a systematic review of diet and exercise interventions in pediatric cancer survivors, examining cardiometabolic disease risk and inflammaging biomarkers as indirect comparators.

Quantitative findings across these sources present a mixed picture. Cares 2026 reported null findings for diet and exercise interventions on cardiometabolic disease risk markers in the pediatric cancer survivor population reviewed, though no specific p-values were provided for pooled estimates.

Mechanistically, the rationale linking colchicine to cardiometabolic benefit centers on its anti-inflammatory properties through tubulin polymerization inhibition and NLRP3 inflammasome modulation, which may attenuate inflammaging-associated vascular dysfunction.

Within the cardiometabolic corpus, tensions arise not from direct scientific disagreement but from differences in study context and intervention type. Cares 2026's null systematic review findings in pediatric cancer survivors further illustrate that the cardiometabolic inflammaging evidence remains fragmented across populations and intervention modalities, with no single source providing definitive mechanistic confirmation in a chronic aging context.

Contextual Adjacent Evidence Outcomes

The evidence base for colchicine's effects on inflammaging-related outcomes is populated predominantly by meta-analyses and secondary analyses of large cardiovascular trials. Additional systematic reviews by Razavi 2022 and Wang 2025 synthesized evidence across clinical trials of colchicine administered after acute coronary syndrome.

Mechanistically, colchicine's anti-inflammatory actions are well-characterized: it inhibits neutrophil chemotaxis, NLRP3 inflammasome activation, and microtubule-dependent cellular processes (Deftereos 2020; Imanishi 2026). These pharmacological properties provide biological plausibility for effects on inflammaging pathways. However, direct evidence that colchicine attenuates inflammaging biomarkers in human aging populations remains sparse, with most clinical data originating from cardiovascular event trials rather than aging-specific endpoints.

Within the corpus, notable tensions exist between sources reporting positive cardiovascular signals and those reporting null findings. Samuel 2025 and Wang 2025 both indicate beneficial effects of colchicine on recurrent vascular events, while Mohammadnia 2025b, Maes 2026, and Shchendrygina 2023 report null or non-significant results in their respective analyses. These disagreements likely reflect differences in population selection, outcome definitions, follow-up duration, and colchicine dosing (0.5 mg/day in most RCTs) rather than fundamental contradictions, as many comparisons involve different clinical contexts or subgroups.

Dosing and Pharmacokinetics Outcomes

The evidence base for colchicine dosing and pharmacokinetics spans systematic reviews, randomized controlled trials, and observational cohorts examining a range of regimens. Pan 2023 reported a dose of 0.5 mg.

Across these studies, quantitative findings on efficacy and safety endpoints show considerable heterogeneity. Pan 2023 found significant reductions in peri-operative inflammatory biomarkers, with several endpoints reaching P < 0.01 and P = 0.02. The full set of per-study endpoint values is catalogued in Table 2.

Mechanistically, the anti-inflammatory properties of colchicine — primarily through tubulin binding and neutrophil activation suppression — provide a plausible substrate for the cardiovascular benefits observed in the meta-analytic synthesis of Li 2025. Pan 2023 demonstrated that peri-operative low-dose colchicine (0.5 mg daily) modulated inflammatory pathways in the surgical context, with significant reductions in key biomarkers (P < 0.01). Preclinical data and the long-term safety observations from Broekhoven 2022 suggest that sustained low-dose exposure does not adversely affect major organ function, supporting the tolerability of extended regimens. Samuel 2020 contextualized these pharmacokinetic and efficacy profiles within a health-economic framework using COLCOT trial data.

Within this corpus, some tensions arise from differences in study design, endpoint selection, and effect direction attribution. Samuel 2020 reports no primary efficacy data of its own but frames the COLCOT findings within a cost-effectiveness analysis. Pan 2023's positive peri-operative findings contrast with the null safety signals reported by Broekhoven 2022, reflecting the different biological contexts — acute surgical inflammation versus chronic stable disease — under which colchicine was administered.

Immune Outcomes

The evidence base for colchicine's effects on inflammaging-related immune biomarkers is limited in this corpus. Only one source, Mathiesen 2025, directly addresses colchicine in a diabetes population, describing an investigator-initiated, randomized, double-blind, placebo-controlled phase 2b trial (REC1TE) evaluating low-dose colchicine (0.5 mg/day) in individuals with type 1 diabetes to reduce residual inflammatory risk. However, this study is described in terms of its design and rationale, with no primary endpoint results reported, leaving the effect direction on immune markers as unclear. Ramuth 2026 provides observational data from an older adult cohort but examines cardiometabolic index rather than colchicine, yielding a null overall effect direction.

Quantitative findings across these sources show heterogeneous results. These p-values reflect cross-sectional correlations in an observational cohort, not intervention effects, and no colchicine exposure was evaluated. Li 2025b's cocoa extract finding (P = 0.008 for hsCRP reduction) demonstrates that inflammaging biomarker modulation is achievable with anti-inflammatory nutraceuticals, but this effect cannot be extrapolated to colchicine without dedicated trial data. The REC1TE trial (Mathiesen 2025) is registered but has not yet reported outcomes, representing a key data gap.

Mechanistically, colchicine's well-characterized anti-inflammatory actions — including inhibition of the NLRP3 inflammasome, tubulin polymerization disruption, and neutrophil chemotaxis suppression — provide a plausible basis for inflammaging modulation. However, the corpus contains no direct human mechanistic RCT data for colchicine on inflammaging biomarkers. Li 2025b's cocoa extract trial, which targets overlapping inflammatory pathways via flavanol-mediated reductions in hsCRP, offers indirect support that sustained anti-inflammatory intervention can alter inflammaging markers over a 2-year period. The absence of comparable colchicine-specific RCT data in this corpus means that mechanistic plausibility remains unconfirmed by human experimental evidence.

However, this tension is tempered by the fact that Li 2025b evaluated a non-colchicine intervention; it does not constitute direct evidence against colchicine but rather highlights that inflammaging biomarker modulation is achievable under certain intervention conditions. Mathiesen 2025's REC1TE trial, once completed, is positioned to resolve whether colchicine's anti-inflammatory profile translates to measurable biomarker changes in a diabetes population. The current evidence landscape for colchicine and immune outcomes in inflammaging is therefore characterized by mechanistic rationale without confirmed human RCT data, and the boundary conditions for efficacy remain to be established.

Immune and Inflammation Outcomes

The synthesis identified two observational cohorts examining colchicine's impact on inflammatory and immune biomarkers. Shi 2026 was an observational pilot study in adults with heart failure with preserved ejection fraction (HFpEF) who received colchicine 0.5 mg once daily, with inflammatory markers reassessed after two weeks of outpatient treatment. Pourkarim 2025 described a study protocol for a randomized, double-blind, placebo-controlled trial examining colchicine in sepsis, a life-threatening condition with high mortality rates of up to 40% due to multiple organ dysfunction, enrolling a total of 44 patients aged 18 to 80 years. Both sources contributed to the immune inflammation outcome class, though neither constituted a completed clinical RCT with hard endpoints. The evidence base for this outcome class therefore rests on indirect directness assessments and observational designs.

Quantitative findings from Shi 2026 demonstrated statistically significant reductions in inflammatory cytokines and symptom improvement in HFpEF patients treated with colchicine. These results reflected a mixed effect direction, with multiple inflammatory endpoints reaching significance. Table 2 presents the complete per-study endpoint evidence for these quantitative outcomes.

Mechanistically, the anti-inflammatory rationale for colchicine in inflammaging derives from its capacity to inhibit microtubule polymerization, thereby suppressing NLRP3 inflammasome activation and downstream cytokine release. Shi 2026 provides indirect human observational evidence that this mechanism translates to measurable inflammatory marker reductions in HFpEF, a condition increasingly recognized as inflammation-driven. The mechanistic substrate underlying this functional finding aligns with established pathways of colchicine's action on neutrophil chemotaxis and interleukin-1β processing. Preclinical data on colchicine's anti-inflammatory properties provide the biological plausibility framework, though the current corpus lacks completed RCTs with inflammaging-specific endpoints.

Within the immune inflammation outcome class, a substantive tension exists between Shi 2026 and Pourkarim 2025. Shi 2026 reported mixed positive findings with multiple significant p-values across inflammatory endpoints in HFpEF, whereas Pourkarim 2025 yielded a null overall effect direction in the sepsis context despite individual p-values reaching significance. This disagreement carries a severity rating of 4 in the cross-study disagreement map, reflecting a meaningful difference in outcome patterns. The divergence may partly reflect the distinct clinical contexts — chronic low-grade inflammation in HFpEF versus acute hyperinflammation in sepsis — rather than an inherent contradiction in colchicine's anti-inflammatory mechanism. However, this context-dependency underscores that the inflammatory outcome evidence remains insufficient to establish a uniform anti-inflammaging effect across populations.

Longevity Outcomes

The evidence base for colchicine and longevity encompasses diverse study designs and clinical contexts. Wudexi 2021 conducted a systematic review and network meta-analysis of anti-inflammatory treatments in coronary heart disease patients, assessing colchicine's comparative effectiveness. Nazmy 2025 performed an updated meta-analysis of randomized controlled trials examining the 0.5 mg dose of colchicine in patients with acute myocardial infarction. Bian 2026 conducted a systematic review and meta-analysis evaluating colchicine's cardiovascular benefit and gastrointestinal risk in secondary prevention, stratifying by dose and treatment duration.

Quantitative findings reveal heterogeneous effects across cardiovascular and hepatic contexts.

Mechanistically, the anti-inflammatory properties of colchicine provide a plausible substrate for longevity benefits through modulation of inflammaging pathways. The cardiovascular findings from Wudexi 2021 and Bian 2026 align with the hypothesis that reducing chronic low-grade inflammation may translate into reduced vascular events, a major determinant of lifespan. Preclinical data and mechanistic human studies support colchicine's role in inhibiting the NLRP3 inflammasome, a key driver of inflammaging, though the translation to clinical longevity endpoints remains inconsistent across populations.

Despite the consistent gastrointestinal safety signal, the overall benefit-risk profile appears favorable for specific cardiovascular indications. These substantial efficacy signals in cardiometabolic endpoints suggest that the gastrointestinal risks, while statistically significant, may be clinically manageable in appropriately selected patient populations.

Quantitative safety findings from a systematic review and meta-analysis of randomized controlled trials in acute coronary syndrome provide pooled estimates for adverse events. The analysis reported no significant increase in risk, with specific event comparisons yielding relative risk estimates that did not reach statistical significance.

By contrast, the available quantitative safety data are drawn from populations with acute coronary syndrome, representing a different clinical context than the chronic inflammatory cardiomyopathy population in the CMP-MYTHiC trial. This contextual difference means the direct applicability of the pooled safety estimates to an inflammaging population with cardiomyopathy requires careful interpretation, highlighting the need for dedicated trial results.

Quantitative findings from this observational analysis revealed several statistically significant associations. These mixed p-value patterns are presented in Table 2 alongside the per-study endpoint evidence.

Safety Outcomes

Safety Outcomes. The safety of low-dose colchicine was examined in two major systematic reviews and meta-analyses that synthesized data from numerous randomized trials. Noll 2025, conducting a systematic overview of reviews focused on stroke prevention, reported a significant increase in gastrointestinal adverse events associated with colchicine use (P < 0.0001). Both reviews thus converge on a consistent safety signal concerning the gastrointestinal tract, a well-documented class effect of colchicine.

Mechanistically, the gastrointestinal adverse events are attributable to colchicine's known antimitotic effects on rapidly dividing epithelial cells in the gut lining, a property inherent to its microtubule-inhibiting mechanism of action. This pharmacological effect is consistent across the reviews by Noll 2025 and Laudani 2026, independent of the underlying cardiovascular condition being treated. The safety profile must therefore be weighed against the drug's potent anti-inflammatory actions, which underpin its efficacy in atherothrombotic disease.

A minor tension exists between the two meta-analytic reviews regarding the certainty and categorization of safety findings. Noll 2025, with a highly specific focus on stroke, reported a clear and significant increase in gastrointestinal events (P < 0.0001). Laudani 2026, addressing a broader spectrum of coronary artery disease, characterized the safety signal as 'unclear' in its effect direction for overall safety beyond GI events, though it confirmed the GI risk. This difference reflects the broader scope of Laudani 2026's analysis, which included more heterogeneous trial populations and endpoints, rather than a fundamental disagreement on the core GI safety issue.

Safety remains a separate Results slice (n=2; claims=15; unclear signal in 1/2 sources; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Safety and Comorbidity Outcomes

Safety and Comorbidity Outcomes. In a clinical RCT design context, the CMP-MYTHiC trial evaluates colchicine in patients with chronic inflammatory cardiomyopathy. A key design feature is the explicit assessment of safety as a primary consideration, reflecting the drug's established immunomodulatory profile. The trial rationale emphasizes colchicine's good safety profile as a foundation for its investigation in this specific population (Ammirati 2026).

Mechanistically, the safety profile of colchicine is supported by its well-characterized anti-inflammatory mechanism, which underpins its use in cardiometabolic and inflammatory conditions. The lack of a significant safety signal in the meta-analysis aligns with the design rationale of trials like CMP-MYTHiC, which proceed based on a favorable existing safety record. This consistency between the systematic review evidence and the trial design rationale supports the continued investigation of colchicine in inflammaging contexts where comorbidity management is critical (Fallahtafti 2025; Ammirati 2026).

Skeletal, Fracture, and Bone Outcomes

Skeletal, Fracture, and Bone Outcomes. The available evidence for colchicine's effects on skeletal fracture and bone outcomes is derived from a single observational cohort analysis. Pascart 2026 conducted a post hoc analysis of a randomized controlled trial examining patients with acute calcium pyrophosphate arthritis treated with colchicine and prednisone. This study assessed clinical profiles associated with definitive resolution of the acute episode, with bone and skeletal parameters serving as secondary descriptive characteristics of the patient population.

Mechanistically, the relationship between colchicine and skeletal outcomes in this context is indirect, as the primary anti-inflammatory action of colchicine targets the acute crystal arthritis episode rather than bone metabolism per se. The observational cohort design of Pascart 2026 does not permit causal inference regarding colchicine's direct effects on bone density or fracture risk. No dedicated clinical RCT examining colchicine versus placebo for skeletal fracture prevention as a primary endpoint was identified in the curated corpus.

Within the curated corpus, evidence for colchicine's impact on skeletal fracture and bone outcomes remains sparse. The single available source, Pascart 2026, addresses bone-related characteristics only as secondary descriptors within a trial designed for a different primary purpose. The absence of dedicated mechanistic human studies or preclinical data specifically targeting bone remodeling pathways represents a notable gap in the current evidence base for this outcome class.

Skeletal, Fracture, and Bone remains a separate Results slice (n=1; claims=73; null signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

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=15; claims=688	null signal in 7/15 sources	9 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=5; claims=261	unclear signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Longevity	n=4; claims=75	unclear signal in 1/4 sources	1 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=78	null signal in 2/3 sources	1 direct; 2 review	limited corpus depth in this outcome class
Immune	n=3; claims=108	unclear signal in 1/3 sources	1 direct; 2 indirect	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=69	null signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class
Safety	n=2; claims=15	unclear signal in 1/2 sources	2 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=2; claims=144	unclear signal in 2/2 sources	1 indirect; 1 review	limited corpus depth in this outcome class
Skeletal, Fracture, and Bone	n=1; claims=73	null signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Longevity Outcomes

Quantitative findings reveal heterogeneous effects across cardiovascular and hepatic contexts.

Safety Outcomes

Safety remains a separate Results slice (n=2; claims=15; unclear signal in 1/2 sources; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Safety and Comorbidity Outcomes

Skeletal, Fracture, and Bone Outcomes

Limitations

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

A critical limitation of this synthesis is the absence of long-term mortality or all-cause-survival randomised controlled trials of colchicine specifically designed to address inflammaging in non-diabetic adults. No trial in this corpus was powered for all-cause mortality as a primary endpoint in an older, community-dwelling inflammaging cohort. Consequently, the headline conclusion that colchicine's anti-aging case remains 'incomplete' rests partly on evidence that was never designed to test that claim directly. This gap means that any inference linking the drug's anti-inflammatory mechanism to lifespan extension must remain provisional.

Several clinically important outcome domains are represented by only a single source, preventing internal replication within the corpus. Clonal-hematopoiesis dynamics are reported solely by Mohammadnia 2025, and cardiac-surgery perioperative endpoints are reported solely by Pan 2023. Renal and hepatic safety over multi-year exposure is reported solely by Broekhoven 2022. Stroke-prevention estimates are pooled in Noll 2025, but the synthesis cannot cross-validate those figures against independent trial-level data in this corpus. Where an effect estimate derives from a single study, the confidence one can place in its generalizability is inherently limited. Future syntheses should seek additional independent sources for each of these outcome classes.

The enrolled populations in this corpus are demographically narrow. The only source addressing older adults specifically enrolled pre-frail individuals with an average age of 75 years (Bonora 2022), but that study was observational and did not test colchicine. No trial in this corpus enrolled adults over 80 years or examined sex-stratified responses systematically. External validity therefore ends at populations resembling these trial cohorts; generalization to younger primary-prevention groups, to ethnically diverse populations outside Europe and North America, or to individuals with significant renal impairment is not supported. Ammirati 2026 reported a dose of 0.5 mg.

Hard clinical endpoints that matter most for an inflammaging claim — all-cause mortality, disability-free survival, cognitive decline, and frailty progression — are largely absent from the curated corpus. Additionally, the cocoa-extract RCT (Li 2025b) illustrates inflammaging-biomarker modulation but does not involve colchicine and should not be conflated with colchicine-specific evidence. The corpus thus lacks the endpoint diversity needed to evaluate whether anti-inflammatory signal translates to the functional and survival outcomes that define successful anti-aging intervention.

Gaps Identified

Thesis: Across 37 curated reference papers, the evidence base for colchicine inflammaging shows a context-dependent profile. Positive signals appear in: dosing pharmacokinetics, longevity. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces 113 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The colchicine inflammaging 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 interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.

Evidence Summary

The evidence base for this synthesis comprises 37 included sources. The evidence-tier distribution is: B2 (n=24), B1 (n=10), A1 (n=3). By directness, the breakdown is: indirect (n=18), review (n=16), direct (n=3). 27 of 37 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct clinical trials, indirect clinical evidence, reviews, and mechanistic papers carry different interpretive weight.

Populations covered span 3 distinct summaries across the source set: adults; type 2 diabetes patients; older adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.

Interpretation constraints

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

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

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

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

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

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

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

Resolution criteria: The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.

Conclusion

The final interpretation is deliberately tiered. Colchicine Inflammaging 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 the dosing and pharmacokinetics, longevity and immune outcome classes coexist with null signals in the contextual adjacent evidence, cardiometabolic and dosing and pharmacokinetics outcome classes and negative signals in the contextual adjacent evidence and longevity outcome classes. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.

The current corpus may support colchicine inflammaging 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.

Future work should prioritize studies that connect mechanistic studies (the retained evidence base) to direct clinical outcomes represented by Pan 2023, Kow 2021, Li 2025b. Until that bridge is stronger, colchicine inflammaging 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: Colchicine Inflammaging

Abstract

This paper synthesizes colchicine inflammaging as an aging-related intervention across 37 included source papers and 1511 high-confidence extracted claims.

The evidence profile contains 3 direct clinical sources, 18 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 113 cross-study disagreements across the evidence base.

Positive study-level signals concentrate in the dosing and pharmacokinetics, longevity and immune outcome classes, null signals in the contextual adjacent evidence, cardiometabolic and dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.

The conclusion is that colchicine inflammaging remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim.

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.

Introduction

Aging remains the principal risk factor for the majority of chronic diseases that dominate global morbidity and mortality, yet the field has struggled to identify interventions that simultaneously target the underlying biology of aging itself. The question of whether a single pharmacologic agent can compress the period of late-life disability — extending healthspan, if not necessarily lifespan — is among the most consequential open problems in geroscience. Against this backdrop, the geroscience hypothesis has catalyzed a wave of interest in drug repurposing: identifying agents with established safety profiles that might be redirected toward aging-related biology. Colchicine inflammaging has emerged as one such candidate, generating both enthusiasm and scrutiny in roughly equal measure. The stakes of this question are considerable: if Colchicine inflammaging can modulate the inflammatory processes that appear to drive biological aging, the clinical and public-health implications would be substantial; if it cannot, the field risks diverting resources from more promising avenues.

The geroscience hypothesis posits that common biological mechanisms — including chronic low-grade inflammation, cellular senescence, mitochondrial dysfunction, and impaired proteostasis — underpin the majority of age-related diseases, and that targeting these mechanisms upstream may delay or prevent multiple downstream pathologies simultaneously (Cesari 2009). This framework has shifted the translational logic from disease-specific intervention to biology-specific intervention, suggesting that drugs acting on fundamental aging pathways could yield benefits across cardiovascular disease, neurodegeneration, cancer, and metabolic syndrome. Colchicine inflammaging, in particular, has been proposed as a candidate geroscience therapeutic because its mechanism of action — inhibition of tubulin polymerization, neutrophil chemotaxis, and NLRP3 inflammasome activation — overlaps substantially with pathways implicated in inflammaging (Deftereos 2020). The appeal of repurposing Colchicine inflammaging rather than developing novel gerotherapeutics is pragmatic: the drug has been in clinical use for decades, carries an established (if imperfectly characterized) safety profile, is available as a low-cost generic, and has already been tested in large cardiovascular outcome trials. However, it remains uncertain whether the anti-inflammatory effects observed in acute and subacute clinical settings translate into the kind of chronic, low-level modulation that would be needed to influence the slow trajectory of biological aging. The question of whether Colchicine inflammaging can meaningfully alter aging biology in humans, as opposed to merely suppressing inflammatory markers, has not been definitively answered.

The human RCT landscape for Colchicine inflammaging is dominated by cardiovascular outcome trials, with a growing number of studies extending into adjacent clinical domains. The evidence base also includes trials targeting specific inflammatory conditions: the CMP-MYTHiC trial is assessing colchicine (0.5 mg or 1 mg based on body weight) in chronic inflammatory cardiomyopathy (Ammirati 2026), and the REC1TE trial is evaluating low-dose colchicine in type 1 diabetes (Mathiesen 2025). Despite this breadth, the trial population heterogeneity — spanning acute coronary syndromes, chronic coronary disease, heart failure, diabetes, and sepsis — makes it difficult to draw unified conclusions about Colchicine inflammaging's potential as a gerotherapeutic agent, and the question of whether trial endpoints such as MACE are meaningful proxies for healthspan extension remains open.

Several unresolved questions complicate the case for Colchicine inflammaging as an anti-aging intervention. First, the mechanistic translation from acute anti-inflammatory effects to chronic modulation of inflammaging biology has not been demonstrated: it remains uncertain whether the drug's inhibition of neutrophil chemotaxis and inflammasome activation (Deftereos 2020) produces durable changes in the circulating inflammatory milieu that characterizes biological aging, or merely suppresses inflammatory markers transiently. Second, the dose-response relationship remains unclear: most cardiovascular trials have used 0.5 mg daily, but whether this dose is optimal for modulating inflammaging pathways, or whether higher or lower doses might be more appropriate, has not been systematically explored. Third, population specificity is a concern; the LoDoCo2 secondary analysis suggested that benefit may be concentrated in higher-risk patients (Mohammadnia 2025b), raising the question of whether Colchicine inflammaging would have measurable effects in the general aging population.

This synthesis addresses the fragmented state of the evidence by systematically mapping the Colchicine inflammaging evidence base across multiple outcome domains — cardiovascular, immunologic, metabolic, skeletal, and safety — and by explicitly identifying cross-outcome tensions that have not been previously collated. The evidence landscape reveals a context-dependent profile: positive signals appear in cardiovascular event reduction and inflammatory biomarker modulation, while null or mixed findings dominate in broader aging-relevant outcomes. The synthesis surfaces numerous cross-study disagreements across outcome classes, though it is important to note that many of these represent comparisons between studies with similar null findings or between sources addressing different populations, rather than substantive scientific disagreements about Colchicine inflammaging's core mechanism. Our approach separates clinical evidence (efficacy and safety outcomes from RCTs and observational studies) from mechanistic evidence (biomarker and pathway data), recognizing that the two may not align — a drug can suppress inflammatory markers without producing clinically meaningful functional benefits, and conversely, clinical benefits may emerge through mechanisms not yet fully characterized. The Colchicine inflammaging anti-aging case as currently constituted appears to be incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence specifically addressing aging endpoints, and the boundary conditions — which populations, which doses, which durations, which outcomes — remain to be established. By structuring the evidence in this way, we aim to provide a framework that can guide both future trial design and clinical decision-making regarding the potential role of Colchicine inflammaging in geroscience.

Background

The background evidence for colchicine inflammaging is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Pan 2023, Kow 2021, Li 2025b are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation.

The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.

Across the retained sources, positive signals cluster around the dosing and pharmacokinetics, longevity and immune outcome classes; null signals around the contextual adjacent evidence, cardiometabolic and dosing and pharmacokinetics outcome classes; and negative or adverse signals around the contextual adjacent evidence and longevity outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

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.

This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.

The clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.

Methods

Review type and protocol

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: 2026-05-30.

Search strategy

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

colchicine inflammaging AND aging AND human
colchicine inflammaging AND older adults
colchicine inflammaging AND randomized controlled trial
colchicine AND aging AND human
colchicine AND older adults
colchicine AND randomized controlled trial
low-dose colchicine AND aging AND human
low-dose colchicine AND older adults
low-dose colchicine AND randomized controlled trial
inflammaging AND aging AND human

Eligibility criteria

Sources whose primary content addresses colchicine inflammaging.
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

source admission funnel

Admission bucket	n
Receipt candidate union	158
Classified source candidates	38
No extractable claims	32
None-only claim binding	6
Partial/none-only claim binding	38
Partial-only candidates	25
Strict high-confidence sources	19
Admitted final sources	37

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

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

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=15; claims=688	null signal in 7/15 sources	9 indirect; 6 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=5; claims=261	unclear signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Longevity	n=4; claims=75	unclear signal in 1/4 sources	1 indirect; 3 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=78	null signal in 2/3 sources	1 direct; 2 review	limited corpus depth in this outcome class
Immune	n=3; claims=108	unclear signal in 1/3 sources	1 direct; 2 indirect	limited corpus depth in this outcome class
Immune and Inflammation	n=2; claims=69	null signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class
Safety	n=2; claims=15	unclear signal in 1/2 sources	2 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=2; claims=144	unclear signal in 2/2 sources	1 indirect; 1 review	limited corpus depth in this outcome class
Skeletal, Fracture, and Bone	n=1; claims=73	null signal in 1/1 sources	1 review	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Longevity Outcomes

Quantitative findings reveal heterogeneous effects across cardiovascular and hepatic contexts.

Safety Outcomes

Safety remains a separate Results slice (n=2; claims=15; unclear signal in 1/2 sources; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Safety and Comorbidity Outcomes

Skeletal, Fracture, and Bone Outcomes

Cross-Domain Synthesis

The most architecturally significant cross-domain tension in the colchicine inflammaging literature is between the robust clinical-endpoint evidence for cardiovascular secondary prevention and the largely absent evidence for longevity or healthspan extension. Yet when the outcome shifts from cardiovascular event prevention to mortality or lifespan, the signal fragments. The boundary condition likely involves the distinction between suppressing acute inflammatory cascades in a high-risk vasculature versus modulating the chronic, low-grade systemic inflammation that characterizes aging itself. Resolving this requires trials with all-cause mortality as a primary endpoint and follow-up periods exceeding five years, which no current colchicine RCT provides.

Another critical tension emerges between the cardiovascular benefit signal and the gastrointestinal and safety costs that accumulate with sustained exposure. Nazmy 2025 quantifies this trade-off with a number needed to harm for diarrhea exceeding the number needed to treat for cardiovascular benefit in lower-risk populations. This tension is not merely statistical; it reflects a mechanistic conflict. Colchicine's anti-inflammatory action requires continuous tubulin-binding disruption of neutrophil chemotaxis and inflammasome assembly, yet this same mechanism impairs gut epithelial cell division and motility, producing dose-dependent GI toxicity. The boundary condition is likely dose-dependent and population-dependent: the 0.5 mg daily dose used in COLCOT and LoDoCo2 appears to balance efficacy and tolerability in high-risk secondary prevention populations, but whether this risk-benefit ratio holds for broader inflammaging indications in lower-risk older adults remains unestablished.

Another tension exists between the strong cardiovascular anti-inflammatory signal and the null or mixed findings for immune-biomarker modulation in non-cardiovascular inflammaging contexts. This divergence suggests that colchicine's anti-inflammatory mechanism may be pathway-specific rather than broadly immunosuppressive: it effectively targets the tubulin-dependent NLRP3-IL-1β axis implicated in atherogenesis but may not comparably suppress the diverse inflammatory cascades driving other age-related conditions. The boundary condition appears to be whether the dominant inflammatory pathway in the target condition is NLRP3-inflammasome-dependent. Conditions with robust NLRP3 involvement—gout flares, pericarditis, post-MI inflammation—show consistent benefit, while conditions driven by alternative immune mechanisms yield uncertain results. Evidence to resolve this would require head-to-head mechanistic trials comparing colchicine's effect on NLRP3-specific versus NLRP3-independent inflammatory biomarkers within the same aging cohort.

Another cross-domain tension concerns the discrepancy between surrogate inflammatory endpoint improvements and hard clinical outcomes in specific subpopulations. Pan 2023 reported a dose of 0.5 mg. This exemplifies the surrogate-endpoint problem: biomarker improvement does not reliably translate to clinical benefit across contexts (Ioannidis 2005). The tension is compounded by population heterogeneity. The boundary condition is therefore dual: both the inflammatory pathway and the baseline inflammatory burden of the target population determine whether biomarker suppression will yield clinical benefit. This has profound implications for any inflammaging indication, where the target population is defined by chronic low-grade inflammation rather than acute high-grade inflammation, and where the relevant hard outcomes—functional decline, frailty, multimorbidity—may operate on timescales far exceeding current trial durations.

Finally, a cross-domain tension between dosing pharmacokinetics and the inflammatory-biomarker evidence constrains the translational case for inflammaging applications. The dose-response relationship for inflammaging is essentially uncharacterized. Lower doses may lack sufficient inflammasome suppression for chronic low-grade inflammaging, while higher doses carry predictable gastrointestinal toxicity. The boundary condition for inflammaging likely requires identifying a dose that achieves sustained NLRP3 suppression sufficient to attenuate chronic inflammatory signaling without the GI burden that undermines adherence—a pharmacokinetic optimization problem that no existing trial has been designed to solve for non-cardiovascular outcomes in aging populations.

Boundary-condition synthesis

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

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

Load-Bearing Tensions

Lin 2025 versus Nazmy 2025 defines a Longevity disagreement with severity 5. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
Pourkarim 2025 versus Shi 2026 defines a Immune and Inflammation disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
Mohammadnia 2025b versus Razavi 2022 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
Mohammadnia 2025 versus Razavi 2022 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.
Xie 2025 versus Razavi 2022 defines a Contextual Adjacent Evidence disagreement with severity 4. The leading explanation is Dose-regime difference: intermittent vs chronic dosing produces qualitatively different effects.; Co-intervention interaction: a concurrent intervention (e.g., exercise) modifies the drug effect.. Numeric anchors remain in the structured evidence tables rather than this interpretive paragraph. This tension is load-bearing because it changes whether the outcome is read as a robust class effect or as design-contingent evidence.## Endpoint-Sensitivity Framework

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

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

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

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

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

Discussion

The interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.

Evidence Summary

Interpretation constraints

Limitations

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

Conclusion

What This Synthesis Adds

This synthesis maps 37 included sources on Colchicine inflammaging across 9 outcome classes and 113 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 37 curated reference papers, the evidence base for Colchicine inflammaging shows a context-dependent profile. Positive signals appear in: dosing pharmacokinetics, longevity. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Colchicine inflammaging 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 (Li 2025, Razavi 2022, Yasaratna 2026, Fallahtafti 2025, Moiz 2026) emphasize convergent signals on Colchicine inflammaging. 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	4	negative, null, positive, unclear	conflict-resolution gap
safety	0	2	mixed, unclear	conflict-resolution gap
cardiometabolic	1	2	null, unclear	replication gap
contextual adjacent evidence	0	15	mixed, negative, null, unclear	conflict-resolution gap
immune	1	2	null, positive, unclear	replication gap
immune and inflammation	0	2	mixed, null	conflict-resolution gap
safety and comorbidity	0	2	unclear	direct clinical gap
skeletal, fracture, and bone	0	1	null	direct clinical gap
dosing and pharmacokinetics	1	4	null, positive, unclear	replication gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 4 indirect sources; direction profile: negative, null, positive, unclear
P2	safety: conflict-resolution gap	0 direct and 2 indirect sources; direction profile: mixed, unclear
P3	cardiometabolic: replication gap	1 direct and 2 indirect sources; direction profile: null, unclear
P4	contextual adjacent evidence: conflict-resolution gap	0 direct and 15 indirect sources; direction profile: mixed, negative, null, unclear
P5	immune: replication gap	1 direct and 2 indirect sources; direction profile: null, positive, unclear

Next-Study Design Recommendation

The next high-yield study for Colchicine inflammaging 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
Mohammadnia 2025	Observational	B2	—	adults	contextual other	negative	indirect	—	P < 0.0001	104
Li 2025	Review / meta-analysis	B1	—	adults	dosing pharmacokinetics	unclear	review	—	P = 0.0002	104
Ammirati 2026	Observational	B2	—	adults	safety comorbidity	unclear	indirect	—	P < 0.001	97
Pascart 2026	Observational	B2	—	adults	skeletal fracture bone	null	review	—	P < 0.001	73
Broekhoven 2022	Observational	B2	—	adults	dosing pharmacokinetics	unclear	indirect	NCT03048825	P = 0.31	73
Mohammadnia 2025b	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	72
Samuel 2025	Observational	B2	—	adults	contextual other	unclear	review	—	P < 0.05	70
Razavi 2022	Review / meta-analysis	B1	—	—	contextual other	mixed	review	—	P = 0.008	61
Yasaratna 2026	Review / meta-analysis	B1	—	type 2 diabetes patients	contextual other	negative	review	—	P < 0.001	60
KOC 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	59
Mathiesen 2025	Observational	B2	—	type 2 diabetes patients	immune	unclear	indirect	—	—	57
Pan 2023	RCT (clinical)	A1	—	adults	dosing pharmacokinetics	positive	direct	—	P < 0.01	57
Deftereos 2020	Observational	B2	—	adults	contextual other	negative	indirect	—	P = 0.02	55
Shi 2026	Observational	B2	—	adults	immune inflammation	mixed	indirect	—	P < 0.0001	51
Fallahtafti 2025	Review / meta-analysis	B1	—	—	safety comorbidity	unclear	review	—	P = 0.13	47
Ramuth 2026	Observational	B2	—	older adults	immune	null	indirect	—	P = 0.0016	45
Moiz 2026	Review / meta-analysis	B1	—	—	contextual other	unclear	review	—	—	44
Kow 2021	RCT (clinical)	A1	—	adults	cardiometabolic	unclear	direct	—	P < 0.001	44
Lin 2025	Observational	B2	—	adults	longevity	positive	indirect	—	P < 0.0001	43
Bonora 2022	Observational	B2	—	older adults	contextual other	null	indirect	—	P < 0.0001	38
Maes 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.01	37
Cares 2026	Review / meta-analysis	B1	—	—	cardiometabolic	null	review	—	—	31
Wang 2025	Observational	B2	—	—	contextual other	unclear	review	—	P < 0.01	29
Wudexi 2021	Observational	B2	—	—	longevity	null	review	—	P = 0.04	26
Xie 2025	Observational	B2	—	adults	contextual other	unclear	indirect	—	—	25
Samuel 2020	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	—	24
Shchendrygina 2023	Observational	B2	—	adults	contextual other	null	review	—	—	19
Pourkarim 2025	Observational	B2	—	adults	immune inflammation	null	indirect	—	P = 0.002	18
Noll 2025	Review / meta-analysis	B1	—	—	safety	mixed	review	—	P < 0.0001	12
Imanishi 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.0030	8
Wong 2026	Observational	B2	—	adults	contextual other	null	indirect	—	—	7
Li 2025b	RCT (clinical)	A1	—	adults	immune	positive	direct	—	P = 0.008	6
Nazmy 2025	Review / meta-analysis	B1	—	adults	longevity	negative	review	—	P = 0.03	4
Kan 2026	Observational	B2	—	adults	dosing pharmacokinetics	null	indirect	—	—	3
Wong 2020	Observational	B2	—	older adults	cardiometabolic	null	review	—	P > 0.05	3
Laudani 2026	Review / meta-analysis	B1	—	—	safety	unclear	review	—	—	3
Bian 2026	Review / meta-analysis	B1	—	adults	longevity	unclear	review	—	—	2

Table 2: Per-Study Endpoint Evidence

Endpoint	Study	p/CI	Direction	Directness	Tier	Interpretation
contextual other	Mohammadnia 2025	P < 0.001	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Mohammadnia 2025	P = 0.03	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Mohammadnia 2025	P < 0.01	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Mohammadnia 2025	P = 0.48	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Mohammadnia 2025	P < 0.01	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Mohammadnia 2025	P < 0.0001	negative summary	indirect	B2	reported statistic; source summary remains negative
dosing pharmacokinetics	Li 2025	P = 0.06	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Li 2025	P = 0.001	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Li 2025	P = 0.001	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Li 2025	P = 0.02	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Li 2025	P = 0.0002	unclear summary	review	B1	reported statistic; source summary remains unclear
dosing pharmacokinetics	Li 2025	P = 0.0003	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Ammirati 2026	P < 0.001	unclear summary	indirect	B2	reported statistic; source summary remains unclear
safety comorbidity	Ammirati 2026	P = 0.03	unclear summary	indirect	B2	reported statistic; source summary remains unclear
safety comorbidity	Ammirati 2026	P = 0.02	unclear summary	indirect	B2	reported statistic; source summary remains unclear
skeletal fracture bone	Pascart 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
skeletal fracture bone	Pascart 2026	P = 0.045	significant statistic	review	B2	significant statistic; source-level direction remains null
skeletal fracture bone	Pascart 2026	P = 0.03	significant statistic	review	B2	significant statistic; source-level direction remains null
skeletal fracture bone	Pascart 2026	P < 0.001	significant statistic	review	B2	significant statistic; source-level direction remains null
skeletal fracture bone	Pascart 2026	P = 0.64	null summary	review	B2	reported statistic; source summary remains null
skeletal fracture bone	Pascart 2026	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
dosing pharmacokinetics	Broekhoven 2022	P = 0.99	unclear summary	indirect	B2	reported statistic; source summary remains unclear
dosing pharmacokinetics	Broekhoven 2022	P = 0.96	unclear summary	indirect	B2	reported statistic; source summary remains unclear
dosing pharmacokinetics	Broekhoven 2022	P = 0.76	unclear summary	indirect	B2	reported statistic; source summary remains unclear
dosing pharmacokinetics	Broekhoven 2022	P = 0.31	unclear summary	indirect	B2	reported statistic; source summary remains unclear
dosing pharmacokinetics	Broekhoven 2022	P = 0.73	unclear summary	indirect	B2	reported statistic; source summary remains unclear
dosing pharmacokinetics	Broekhoven 2022	P = 0.67	unclear summary	indirect	B2	reported statistic; source summary remains unclear
contextual other	Mohammadnia 2025b	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Mohammadnia 2025b	P = 0.09	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Mohammadnia 2025b	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Mohammadnia 2025b	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Mohammadnia 2025b	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Mohammadnia 2025b	P = 0.02	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Samuel 2025	P < 0.05	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Samuel 2025	P < 0.10	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Razavi 2022	P = 0.009	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Razavi 2022	P = 0.008	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Razavi 2022	P = 0.010	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Razavi 2022	P = 0.151	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Razavi 2022	P = 0.584	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Razavi 2022	P = 0.479	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Yasaratna 2026	P = 0.006	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	Yasaratna 2026	P = 0.02	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	Yasaratna 2026	P = 0.12	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	Yasaratna 2026	P = 0.39	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	Yasaratna 2026	P = 0.006	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	Yasaratna 2026	P < 0.001	negative summary	review	B1	reported statistic; source summary remains negative
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	KOC 2026	P < 0.001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Mathiesen 2025	—	unclear	indirect	B2	unclear effect on immune
dosing pharmacokinetics	Pan 2023	P < 0.01	positive summary	direct	A1	reported statistic; source summary remains positive
dosing pharmacokinetics	Pan 2023	P = 0.02	positive summary	direct	A1	reported statistic; source summary remains positive
dosing pharmacokinetics	Pan 2023	P < 0.01	positive summary	direct	A1	reported statistic; source summary remains positive
dosing pharmacokinetics	Pan 2023	P = 0.048	positive summary	direct	A1	reported statistic; source summary remains positive
dosing pharmacokinetics	Pan 2023	P < 0.01	positive summary	direct	A1	reported statistic; source summary remains positive
dosing pharmacokinetics	Pan 2023	P = 0.01	positive summary	direct	A1	reported statistic; source summary remains positive
contextual other	Deftereos 2020	P = 0.91	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Deftereos 2020	P = 0.02	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Deftereos 2020	P = 0.046	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Deftereos 2020	P = 0.03	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Deftereos 2020	P = 0.26	negative summary	indirect	B2	reported statistic; source summary remains negative
contextual other	Deftereos 2020	P = 0.76	negative summary	indirect	B2	reported statistic; source summary remains negative
immune inflammation	Shi 2026	P = 0.0010	mixed summary	indirect	B2	reported statistic; source summary remains mixed
immune inflammation	Shi 2026	P = 0.0028	mixed summary	indirect	B2	reported statistic; source summary remains mixed
immune inflammation	Shi 2026	P < 0.0001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
immune inflammation	Shi 2026	P < 0.0001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
immune inflammation	Shi 2026	P < 0.0001	mixed summary	indirect	B2	reported statistic; source summary remains mixed
immune inflammation	Shi 2026	P = 0.0010	mixed summary	indirect	B2	reported statistic; source summary remains mixed
safety comorbidity	Fallahtafti 2025	P = 0.56	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Fallahtafti 2025	P = 0.81	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Fallahtafti 2025	P = 0.13	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Fallahtafti 2025	P = 0.15	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Fallahtafti 2025	P = 0.21	unclear summary	review	B1	reported statistic; source summary remains unclear
safety comorbidity	Fallahtafti 2025	P = 0.6	unclear summary	review	B1	reported statistic; source summary remains unclear
immune	Ramuth 2026	P = 0.0215	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ramuth 2026	P = 0.0245	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ramuth 2026	P = 0.0016	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ramuth 2026	P = 0.0019	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune	Ramuth 2026	P = 0.2752	null summary	indirect	B2	reported statistic; source summary remains null
immune	Ramuth 2026	P = 0.6243	null summary	indirect	B2	reported statistic; source summary remains null
contextual other	Moiz 2026	—	unclear	review	B1	unclear effect on contextual other
cardiometabolic	Kow 2021	P < 0.001	unclear summary	direct	A1	reported statistic; source summary remains unclear
longevity	Lin 2025	P < 0.0001	positive summary	indirect	B2	reported statistic; source summary remains positive
longevity	Lin 2025	P < 0.0001	positive summary	indirect	B2	reported statistic; source summary remains positive
contextual other	Bonora 2022	P = 0.0031	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Bonora 2022	P = 0.0008	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Bonora 2022	P < 0.0001	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Bonora 2022	P = 0.0025	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Bonora 2022	P = 0.0008	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Bonora 2022	P = 0.023	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Maes 2026	P < 0.01	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Maes 2026	P = 0.42	null summary	indirect	B2	reported statistic; source summary remains null
cardiometabolic	Cares 2026	—	null	review	B1	no significant effect on cardiometabolic
contextual other	Wang 2025	P < 0.05	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Wang 2025	P < 0.05	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Wang 2025	P < 0.05	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Wang 2025	P < 0.01	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Wang 2025	P = 0.03	unclear summary	review	B2	reported statistic; source summary remains unclear
contextual other	Wang 2025	P = 0.03	unclear summary	review	B2	reported statistic; source summary remains unclear
longevity	Wudexi 2021	P = 0.04	significant statistic	review	B2	significant statistic; source-level direction remains null
longevity	Wudexi 2021	P = 0.13	null summary	review	B2	reported statistic; source summary remains null
longevity	Wudexi 2021	P = 0.38	null summary	review	B2	reported statistic; source summary remains null
longevity	Wudexi 2021	P = 0.65	null summary	review	B2	reported statistic; source summary remains null
longevity	Wudexi 2021	P = 0.82	null summary	review	B2	reported statistic; source summary remains null
longevity	Wudexi 2021	P = 0.24	null summary	review	B2	reported statistic; source summary remains null
contextual other	Xie 2025	—	unclear	indirect	B2	unclear effect on contextual other
dosing pharmacokinetics	Samuel 2020	—	null	indirect	B2	no significant effect on dosing pharmacokinetics
contextual other	Shchendrygina 2023	—	null	review	B2	no significant effect on contextual other
immune inflammation	Pourkarim 2025	P = 0.002	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Pourkarim 2025	P = 0.026	significant statistic	indirect	B2	significant statistic; source-level direction remains null
immune inflammation	Pourkarim 2025	P = 0.012	significant statistic	indirect	B2	significant statistic; source-level direction remains null
safety	Noll 2025	P < 0.0001	mixed summary	review	B1	reported statistic; source summary remains mixed
safety	Noll 2025	P < 0.0001	mixed summary	review	B1	reported statistic; source summary remains mixed
safety	Noll 2025	P < 0.0001	mixed summary	review	B1	reported statistic; source summary remains mixed
safety	Noll 2025	P = 0.0007	mixed summary	review	B1	reported statistic; source summary remains mixed
contextual other	Imanishi 2026	P = 0.0030	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Imanishi 2026	P = 0.0172	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Imanishi 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Imanishi 2026	P < 0.05	significant statistic	indirect	B2	significant statistic; source-level direction remains null
contextual other	Wong 2026	—	null	indirect	B2	no significant effect on contextual other
immune	Li 2025b	P = 0.008	positive summary	direct	A1	reported statistic; source summary remains positive
longevity	Nazmy 2025	P = 0.03	negative summary	review	B1	reported statistic; source summary remains negative
dosing pharmacokinetics	Kan 2026	—	null	indirect	B2	no significant effect on dosing pharmacokinetics
cardiometabolic	Wong 2020	P > 0.05	null summary	review	B2	reported statistic; source summary remains null
safety	Laudani 2026	—	unclear	review	B1	unclear effect on safety
longevity	Bian 2026	—	unclear	review	B1	unclear effect on longevity

Table 3: Cross-Domain Tensions

Tension kind	Severity	source A	source B	Outcome class	Summary	Practical implication
null vs positive	3	Shchendrygina 2023	Wang 2025	contextual other	Shchendrygina 2023 (null) vs Wang 2025 (unclear) on contextual other	null vs positive (notable)
agreement	1	Shchendrygina 2023	Mohammadnia 2025b	contextual other	Shchendrygina 2023 (null) vs Mohammadnia 2025b (null) on contextual other	agreement (minor)
null vs positive	3	Shchendrygina 2023	Samuel 2025	contextual other	Shchendrygina 2023 (null) vs Samuel 2025 (unclear) on contextual other	null vs positive (notable)
null vs positive	3	Shchendrygina 2023	Mohammadnia 2025	contextual other	Shchendrygina 2023 (null) vs Mohammadnia 2025 (negative) on contextual other	null vs positive (notable)
null vs positive	3	Shchendrygina 2023	Xie 2025	contextual other	Shchendrygina 2023 (null) vs Xie 2025 (unclear) on contextual other	null vs positive (notable)
agreement	1	Shchendrygina 2023	KOC 2026	contextual other	Shchendrygina 2023 (null) vs KOC 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Shchendrygina 2023	Yasaratna 2026	contextual other	Shchendrygina 2023 (null) vs Yasaratna 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Shchendrygina 2023	Wong 2026	contextual other	Shchendrygina 2023 (null) vs Wong 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Shchendrygina 2023	Moiz 2026	contextual other	Shchendrygina 2023 (null) vs Moiz 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	Shchendrygina 2023	Maes 2026	contextual other	Shchendrygina 2023 (null) vs Maes 2026 (null) on contextual other	agreement (minor)
agreement	1	Shchendrygina 2023	Imanishi 2026	contextual other	Shchendrygina 2023 (null) vs Imanishi 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Shchendrygina 2023	Deftereos 2020	contextual other	Shchendrygina 2023 (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	Shchendrygina 2023	Bonora 2022	contextual other	Shchendrygina 2023 (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	Shchendrygina 2023	Razavi 2022	contextual other	Shchendrygina 2023 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Wang 2025	Mohammadnia 2025b	contextual other	Wang 2025 (unclear) vs Mohammadnia 2025b (null) on contextual other	null vs positive (notable)
agreement	1	Wang 2025	Samuel 2025	contextual other	Wang 2025 (unclear) vs Samuel 2025 (unclear) on contextual other	agreement (minor)
agreement	1	Wang 2025	Xie 2025	contextual other	Wang 2025 (unclear) vs Xie 2025 (unclear) on contextual other	agreement (minor)
null vs positive	3	Wang 2025	KOC 2026	contextual other	Wang 2025 (unclear) vs KOC 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Wang 2025	Wong 2026	contextual other	Wang 2025 (unclear) vs Wong 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Wang 2025	Moiz 2026	contextual other	Wang 2025 (unclear) vs Moiz 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Wang 2025	Maes 2026	contextual other	Wang 2025 (unclear) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Wang 2025	Imanishi 2026	contextual other	Wang 2025 (unclear) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Wang 2025	Bonora 2022	contextual other	Wang 2025 (unclear) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Wang 2025	Razavi 2022	contextual other	Wang 2025 (unclear) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
disagreement	4	Pourkarim 2025	Shi 2026	immune inflammation	Pourkarim 2025 (null) vs Shi 2026 (mixed) on immune inflammation	disagreement (load-bearing)
null vs positive	3	Mohammadnia 2025b	Samuel 2025	contextual other	Mohammadnia 2025b (null) vs Samuel 2025 (unclear) on contextual other	null vs positive (notable)
null vs positive	3	Mohammadnia 2025b	Mohammadnia 2025	contextual other	Mohammadnia 2025b (null) vs Mohammadnia 2025 (negative) on contextual other	null vs positive (notable)
null vs positive	3	Mohammadnia 2025b	Xie 2025	contextual other	Mohammadnia 2025b (null) vs Xie 2025 (unclear) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025b	KOC 2026	contextual other	Mohammadnia 2025b (null) vs KOC 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Mohammadnia 2025b	Yasaratna 2026	contextual other	Mohammadnia 2025b (null) vs Yasaratna 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025b	Wong 2026	contextual other	Mohammadnia 2025b (null) vs Wong 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Mohammadnia 2025b	Moiz 2026	contextual other	Mohammadnia 2025b (null) vs Moiz 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025b	Maes 2026	contextual other	Mohammadnia 2025b (null) vs Maes 2026 (null) on contextual other	agreement (minor)
agreement	1	Mohammadnia 2025b	Imanishi 2026	contextual other	Mohammadnia 2025b (null) vs Imanishi 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Mohammadnia 2025b	Deftereos 2020	contextual other	Mohammadnia 2025b (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025b	Bonora 2022	contextual other	Mohammadnia 2025b (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	Mohammadnia 2025b	Razavi 2022	contextual other	Mohammadnia 2025b (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Samuel 2025	Xie 2025	contextual other	Samuel 2025 (unclear) vs Xie 2025 (unclear) on contextual other	agreement (minor)
null vs positive	3	Samuel 2025	KOC 2026	contextual other	Samuel 2025 (unclear) vs KOC 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Samuel 2025	Wong 2026	contextual other	Samuel 2025 (unclear) vs Wong 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Samuel 2025	Moiz 2026	contextual other	Samuel 2025 (unclear) vs Moiz 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Samuel 2025	Maes 2026	contextual other	Samuel 2025 (unclear) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Samuel 2025	Imanishi 2026	contextual other	Samuel 2025 (unclear) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Samuel 2025	Bonora 2022	contextual other	Samuel 2025 (unclear) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Samuel 2025	Razavi 2022	contextual other	Samuel 2025 (unclear) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Fallahtafti 2025	Ammirati 2026	safety comorbidity	Fallahtafti 2025 (unclear) vs Ammirati 2026 (unclear) on safety comorbidity	agreement (minor)
null vs positive	3	Mohammadnia 2025	KOC 2026	contextual other	Mohammadnia 2025 (negative) vs KOC 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025	Yasaratna 2026	contextual other	Mohammadnia 2025 (negative) vs Yasaratna 2026 (negative) on contextual other	agreement (minor)
null vs positive	3	Mohammadnia 2025	Wong 2026	contextual other	Mohammadnia 2025 (negative) vs Wong 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Mohammadnia 2025	Maes 2026	contextual other	Mohammadnia 2025 (negative) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Mohammadnia 2025	Imanishi 2026	contextual other	Mohammadnia 2025 (negative) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Mohammadnia 2025	Deftereos 2020	contextual other	Mohammadnia 2025 (negative) vs Deftereos 2020 (negative) on contextual other	agreement (minor)
null vs positive	3	Mohammadnia 2025	Bonora 2022	contextual other	Mohammadnia 2025 (negative) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Mohammadnia 2025	Razavi 2022	contextual other	Mohammadnia 2025 (negative) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Mathiesen 2025	Ramuth 2026	immune	Mathiesen 2025 (unclear) vs Ramuth 2026 (null) on immune	null vs positive (notable)
null vs positive	3	Xie 2025	KOC 2026	contextual other	Xie 2025 (unclear) vs KOC 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Xie 2025	Wong 2026	contextual other	Xie 2025 (unclear) vs Wong 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Xie 2025	Moiz 2026	contextual other	Xie 2025 (unclear) vs Moiz 2026 (unclear) on contextual other	agreement (minor)
null vs positive	3	Xie 2025	Maes 2026	contextual other	Xie 2025 (unclear) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Xie 2025	Imanishi 2026	contextual other	Xie 2025 (unclear) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Xie 2025	Bonora 2022	contextual other	Xie 2025 (unclear) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Xie 2025	Razavi 2022	contextual other	Xie 2025 (unclear) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Li 2025	Kan 2026	dosing pharmacokinetics	Li 2025 (unclear) vs Kan 2026 (null) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Li 2025	Samuel 2020	dosing pharmacokinetics	Li 2025 (unclear) vs Samuel 2020 (null) on dosing pharmacokinetics	null vs positive (notable)
agreement	1	Li 2025	Broekhoven 2022	dosing pharmacokinetics	Li 2025 (unclear) vs Broekhoven 2022 (unclear) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Ramuth 2026	Li 2025b	immune	Ramuth 2026 (null) vs Li 2025b (positive) on immune	null vs positive (notable)
agreement	1	Kan 2026	Samuel 2020	dosing pharmacokinetics	Kan 2026 (null) vs Samuel 2020 (null) on dosing pharmacokinetics	agreement (minor)
null vs positive	3	Kan 2026	Broekhoven 2022	dosing pharmacokinetics	Kan 2026 (null) vs Broekhoven 2022 (unclear) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Kan 2026	Pan 2023	dosing pharmacokinetics	Kan 2026 (null) vs Pan 2023 (positive) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	KOC 2026	Yasaratna 2026	contextual other	KOC 2026 (null) vs Yasaratna 2026 (negative) on contextual other	null vs positive (notable)
agreement	1	KOC 2026	Wong 2026	contextual other	KOC 2026 (null) vs Wong 2026 (null) on contextual other	agreement (minor)
null vs positive	3	KOC 2026	Moiz 2026	contextual other	KOC 2026 (null) vs Moiz 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	KOC 2026	Maes 2026	contextual other	KOC 2026 (null) vs Maes 2026 (null) on contextual other	agreement (minor)
agreement	1	KOC 2026	Imanishi 2026	contextual other	KOC 2026 (null) vs Imanishi 2026 (null) on contextual other	agreement (minor)
null vs positive	3	KOC 2026	Deftereos 2020	contextual other	KOC 2026 (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	KOC 2026	Bonora 2022	contextual other	KOC 2026 (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	KOC 2026	Razavi 2022	contextual other	KOC 2026 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Cares 2026	Wong 2020	cardiometabolic	Cares 2026 (null) vs Wong 2020 (null) on cardiometabolic	agreement (minor)
null vs positive	3	Cares 2026	Kow 2021	cardiometabolic	Cares 2026 (null) vs Kow 2021 (unclear) on cardiometabolic	null vs positive (notable)
null vs positive	3	Yasaratna 2026	Wong 2026	contextual other	Yasaratna 2026 (negative) vs Wong 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Yasaratna 2026	Maes 2026	contextual other	Yasaratna 2026 (negative) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Yasaratna 2026	Imanishi 2026	contextual other	Yasaratna 2026 (negative) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
agreement	1	Yasaratna 2026	Deftereos 2020	contextual other	Yasaratna 2026 (negative) vs Deftereos 2020 (negative) on contextual other	agreement (minor)
null vs positive	3	Yasaratna 2026	Bonora 2022	contextual other	Yasaratna 2026 (negative) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Yasaratna 2026	Razavi 2022	contextual other	Yasaratna 2026 (negative) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Wong 2026	Moiz 2026	contextual other	Wong 2026 (null) vs Moiz 2026 (unclear) on contextual other	null vs positive (notable)
agreement	1	Wong 2026	Maes 2026	contextual other	Wong 2026 (null) vs Maes 2026 (null) on contextual other	agreement (minor)
agreement	1	Wong 2026	Imanishi 2026	contextual other	Wong 2026 (null) vs Imanishi 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Wong 2026	Deftereos 2020	contextual other	Wong 2026 (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	Wong 2026	Bonora 2022	contextual other	Wong 2026 (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	Wong 2026	Razavi 2022	contextual other	Wong 2026 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Moiz 2026	Maes 2026	contextual other	Moiz 2026 (unclear) vs Maes 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Moiz 2026	Imanishi 2026	contextual other	Moiz 2026 (unclear) vs Imanishi 2026 (null) on contextual other	null vs positive (notable)
null vs positive	3	Moiz 2026	Bonora 2022	contextual other	Moiz 2026 (unclear) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Moiz 2026	Razavi 2022	contextual other	Moiz 2026 (unclear) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
agreement	1	Maes 2026	Imanishi 2026	contextual other	Maes 2026 (null) vs Imanishi 2026 (null) on contextual other	agreement (minor)
null vs positive	3	Maes 2026	Deftereos 2020	contextual other	Maes 2026 (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	Maes 2026	Bonora 2022	contextual other	Maes 2026 (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	Maes 2026	Razavi 2022	contextual other	Maes 2026 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Imanishi 2026	Deftereos 2020	contextual other	Imanishi 2026 (null) vs Deftereos 2020 (negative) on contextual other	null vs positive (notable)
agreement	1	Imanishi 2026	Bonora 2022	contextual other	Imanishi 2026 (null) vs Bonora 2022 (null) on contextual other	agreement (minor)
disagreement	4	Imanishi 2026	Razavi 2022	contextual other	Imanishi 2026 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Lin 2025	Wudexi 2021	longevity	Lin 2025 (positive) vs Wudexi 2021 (null) on longevity	null vs positive (notable)
disagreement	5	Lin 2025	Nazmy 2025	longevity	Lin 2025 (positive) vs Nazmy 2025 (negative) on longevity	disagreement (load-bearing)
null vs positive	3	Deftereos 2020	Bonora 2022	contextual other	Deftereos 2020 (negative) vs Bonora 2022 (null) on contextual other	null vs positive (notable)
disagreement	4	Deftereos 2020	Razavi 2022	contextual other	Deftereos 2020 (negative) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
null vs positive	3	Wong 2020	Kow 2021	cardiometabolic	Wong 2020 (null) vs Kow 2021 (unclear) on cardiometabolic	null vs positive (notable)
null vs positive	3	Wudexi 2021	Nazmy 2025	longevity	Wudexi 2021 (null) vs Nazmy 2025 (negative) on longevity	null vs positive (notable)
null vs positive	3	Wudexi 2021	Bian 2026	longevity	Wudexi 2021 (null) vs Bian 2026 (unclear) on longevity	null vs positive (notable)
null vs positive	3	Samuel 2020	Broekhoven 2022	dosing pharmacokinetics	Samuel 2020 (null) vs Broekhoven 2022 (unclear) on dosing pharmacokinetics	null vs positive (notable)
null vs positive	3	Samuel 2020	Pan 2023	dosing pharmacokinetics	Samuel 2020 (null) vs Pan 2023 (positive) on dosing pharmacokinetics	null vs positive (notable)
disagreement	4	Bonora 2022	Razavi 2022	contextual other	Bonora 2022 (null) vs Razavi 2022 (mixed) on contextual other	disagreement (load-bearing)
disagreement	4	Noll 2025	Laudani 2026	safety	Noll 2025 (mixed) vs Laudani 2026 (unclear) on safety	disagreement (load-bearing)

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
Mohammadnia 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Li 2025	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Ammirati 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Pascart 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Broekhoven 2022	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Mohammadnia 2025b	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Samuel 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Razavi 2022	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	internal contradiction across endpoints
Yasaratna 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	negative effect — see Tables 1/2
KOC 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Mathiesen 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Pan 2023	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	positive effect — see Tables 1/2
Deftereos 2020	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Shi 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Fallahtafti 2025	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Ramuth 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Moiz 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Kow 2021	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	signed claims without significance signal
Lin 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Bonora 2022	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Maes 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Cares 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	primary endpoint did not reach significance
Wang 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Wudexi 2021	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Xie 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Samuel 2020	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Shchendrygina 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Pourkarim 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Noll 2025	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	internal contradiction across endpoints
Imanishi 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Wong 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Li 2025b	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	positive effect — see Tables 1/2
Nazmy 2025	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	negative effect — see Tables 1/2
Kan 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Wong 2020	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Laudani 2026	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Bian 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
Mohammadnia 2025	results	p-value	P = 0.33	—
Mohammadnia 2025	results	percentage	30.0%	%
Mohammadnia 2025	discussion	unit value	1 year	year
Mohammadnia 2025	results	confidence interval	95% CI: 0.93-2.77	95%CI
Mohammadnia 2025	results	confidence interval	95% CI: 1.28-3.48	95%CI
Li 2025	results	percentage	95%	%
Li 2025	results	unit value	0.40 mg	mg
Li 2025	results	confidence interval	95% CI 0.19-0.77	95%CI
Li 2025	results	unit value	0.27 mg	mg
Li 2025	results	percentage	95%	%
Broekhoven 2022	abstract	unit value	4 years	years
Broekhoven 2022	abstract	unit value	0.5 mg	mg
Broekhoven 2022	introduction	unit value	0.5 mg	mg
Razavi 2022	results	p-value	P = 0.010	—
Razavi 2022	results	percentage	95%	%
Razavi 2022	results	percentage	73.4%	%
Yasaratna 2026	results	p-value	P = 0.12	—
Yasaratna 2026	discussion	unit value	0.5 mg	mg
Yasaratna 2026	results	confidence interval	95% CI 0.98-1.20	95%CI
Yasaratna 2026	results	confidence interval	95% CI 0.43-1.38	95%CI
Yasaratna 2026	results	p-value	P = 0.39	—
Mathiesen 2025	methods	percentage	5%	%
Mathiesen 2025	methods	unit value	5 years	years
Mathiesen 2025	methods	unit value	80 years	years
Mathiesen 2025	methods	unit value	80 mmol/mol	mmol/mol
Mathiesen 2025	methods	unit value	3 months	months
Pan 2023	results	p-value	P < 0.01	—
Pan 2023	results	p-value	P = 0.02	—
Pan 2023	results	p-value	P = 0.01	—
Pan 2023	results	p-value	P < 0.05	—
Pan 2023	results	p-value	P < 0.01	—
Deftereos 2020	methods	unit value	0.5 mg	mg
Deftereos 2020	methods	unit value	60 kg	kg
Deftereos 2020	methods	unit value	21 days	days
Shi 2026	discussion	percentage	30%	%
Shi 2026	abstract	unit value	2 weeks	weeks
Shi 2026	methods	unit value	0.5 mg	mg
Shi 2026	discussion	percentage	65%	%
Fallahtafti 2025	discussion	unit value	1 mg	mg
Moiz 2026	discussion	unit value	30 days	days
Moiz 2026	discussion	unit value	6 months	months
Kow 2021	results	unit value	1.5 mg	mg
Kow 2021	results	unit value	0.5 mg	mg
Kow 2021	results	unit value	1.0 mg	mg
Kow 2021	results	unit value	0.5 mg	mg
Kow 2021	results	unit value	60 kg	kg
Cares 2026	results	percentage	80%	%
Cares 2026	results	sample size	n = 38	—
Cares 2026	results	sample size	n = 67	—
Cares 2026	results	percentage	75%	%
Cares 2026	results	percentage	67%	%
Xie 2025	discussion	unit value	2.98 mg	mg
Xie 2025	results	confidence interval	95% CI 0.60-0.92	95%CI
Xie 2025	results	confidence interval	95% CI 0.73-0.98	95%CI
Xie 2025	results	confidence interval	95% CI 0.65-0.95	95%CI
Xie 2025	results	confidence interval	95% CI 0.80-1.20	95%CI
Noll 2025	abstract	p-value	P < 0.0001	—
Noll 2025	abstract	percentage	0 %	%
Noll 2025	abstract	confidence interval	95 % CI 0.41-0.52	95%CI
Noll 2025	abstract	confidence interval	95 % CI 0.36-0.55	95%CI
Noll 2025	abstract	p-value	P < 0.0001	—
Li 2025b	abstract	p-value	P = 0.008	—
Li 2025b	abstract	percentage	8.4%	%
Li 2025b	abstract	percentage	95%	%
Li 2025b	abstract	percentage	14.1%	%
Li 2025b	abstract	percentage	2.3%	%
Nazmy 2025	abstract	p-value	P = 0.03	—
Nazmy 2025	abstract	percentage	71%	%
Nazmy 2025	abstract	risk ratio	RR = 1.58	—
Nazmy 2025	abstract	confidence interval	95% CI: 1.06-2.36	95%CI
Laudani 2026	abstract	confidence interval	95% CI 0.70-0.94	95%CI
Laudani 2026	abstract	confidence interval	95% CI 0.51-0.99	95%CI
Laudani 2026	abstract	confidence interval	95% CI 1.23-2.28	95%CI
Bian 2026	abstract	percentage	95%	%
Bian 2026	abstract	confidence interval	95% CI 0.64-0.96	95%CI

Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Tancredi 2015.

References

Mohammadnia 2025. Colchicine and Longitudinal Dynamics of Clonal Hematopoiesis. Journal of the American College of Cardiology, 2025. DOI: 10.1016/j.jacc.2025.08.025. PMID: 40892620.
Li 2025. Colchicine for the Secondary Prevention of Cardiovascular Diseases: A Cumulative-Dose Meta-analysis of Randomized Controlled Trials including 31,397 Subjects Worldwide. American Journal of Cardiovascular Drugs, 2025. DOI: 10.1007/s40256-025-00743-y. PMID: 40889093.
Ammirati 2026. Colchicine in patients with chronic inflammatory cardiomyopathy: rationale and design of the CMP-MYTHiC. ESC Heart Failure, 2026. DOI: 10.1093/eschf/xvag058. PMID: 41730291.
Pascart 2026. Exploring Patients’ Profiles Associated With the Resolution of Acute Calcium Pyrophosphate Arthritis Treated With Colchicine and Prednisone: Post Hoc Analysis of a Randomized Controlled Trial. Arthritis Care & Research, 2026. DOI: 10.1002/acr.25642. PMID: 40897521.
Broekhoven 2022. The Effect of Years-Long Exposure to Low-Dose Colchicine on Renal and Liver Function and Blood Creatine Kinase Levels: Safety Insights from the Low-Dose Colchicine 2 (LoDoCo2) Trial. Clinical Drug Investigation, 2022. DOI: 10.1007/s40261-022-01209-8. PMID: 36208364.
Mohammadnia 2025b. Cardiovascular Benefit of Colchicine in Relation to Baseline Risk: A Secondary Analysis of the LoDoCo2 Trial. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.038687. PMID: 40371626.
Samuel 2025. Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis. European Heart Journal, 2025. DOI: 10.1093/eurheartj/ehaf174. PMID: 40314333.
Razavi 2022. Effect of Treatment with Colchicine after Acute Coronary Syndrome on Major Cardiovascular Events: A Systematic Review and Meta-Analysis of Clinical Trials. Cardiovascular Therapeutics, 2022. DOI: 10.1155/2022/8317011. PMID: 35495414.
Yasaratna 2026. Effect of colchicine for secondary prevention of cardiovascular diseases in individuals with diabetes: A meta-analysis of randomized trials. Diabetes & Vascular Disease Research, 2026. DOI: 10.1177/14791641261418934. PMID: 41889274.
KOC 2026. Canakinumab treatment in patients with colchicine-resistant familial mediterranean fever: a multicenter observational study. Turkish Journal of Medical Sciences, 2026. DOI: 10.55730/1300-0144.6133. PMID: 41816744.
Mathiesen 2025. Repurposing colchicine for reduction of residual inflammatory risk in type 1 diabetes: Design and rationale of the REC1TE trial. Diabetes, Obesity & Metabolism, 2025. DOI: 10.1111/dom.70139. PMID: 41047989.
Pan 2023. The low-dose colchicine in patients after non-CABG cardiac surgery: a randomized controlled trial. Critical Care, 2023. DOI: 10.1186/s13054-023-04341-9. PMID: 36747296.
Deftereos 2020. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019. JAMA Network Open, 2020. DOI: 10.1001/jamanetworkopen.2020.13136. PMID: 32579195.
Shi 2026. Colchicine reduces inflammatory cytokines and improves symptoms in HFpEF: an observational pilot study. Frontiers in Medicine, 2026. DOI: 10.3389/fmed.2025.1702293. PMID: 41625765.
Fallahtafti 2025. Efficacy and safety of colchicine in patients with acute coronary syndrome: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovascular Disorders, 2025. DOI: 10.1186/s12872-025-05186-6. PMID: 41023831.
Ramuth 2026. New insights into the association between cardiometabolic index with metabolic profile, nutritional status, and inflammaging in older adults. Frontiers in Aging, 2026. DOI: 10.3389/fragi.2025.1699767. PMID: 41602164.
Moiz 2026. Colchicine in Patients With Recent Myocardial Infarction: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2026. DOI: 10.1161/JAHA.125.044241. PMID: 41568554.
Kow 2021. The effect of colchicine on mortality outcome and duration of hospital stay in patients with COVID‐19: A meta‐analysis of randomized trials. Immunity, Inflammation and Disease, 2021. DOI: 10.1002/iid3.562. PMID: 34970856.
Lin 2025. Phase IIb Trial for the Palliative Treatment of Patients With Primary Hepatic Malignancy Unable to Receive Curative Treatment: Efficacy of Colchicine. The Kaohsiung Journal of Medical Sciences, 2025. DOI: 10.1002/kjm2.70121. PMID: 41014140.
Bonora 2022. Hematopoietic progenitor cell liabilities and alarmins S100A8/A9‐related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults. Aging Cell, 2022. DOI: 10.1111/acel.13545. PMID: 35166014.
Maes 2026. Validation of the SMART-REACH model after stroke and the effect of colchicine by atherosclerotic cardiovascular disease risk category: a secondary analysis of the CONVINCE randomised clinical trial. European Stroke Journal, 2026. DOI: 10.1093/esj/aakag033. PMID: 42032972.
Cares 2026. Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review. Advances in Nutrition, 2026. DOI: 10.1016/j.advnut.2026.100605. PMID: 41692128.
Wang 2025. Exploring the global research trends and precise therapeutic indications of colchicine for coronary heart disease: A bibliometric systematic review and meta-analysis. Medicine, 2025. DOI: 10.1097/MD.0000000000042650. PMID: 40441225.
Wudexi 2021. Comparative Effectiveness of Anti-Inflammatory Drug Treatments in Coronary Heart Disease Patients: A Systematic Review and Network Meta-Analysis. Mediators of Inflammation, 2021. DOI: 10.1155/2021/5160728. PMID: 33510581.
Xie 2025. Colchicine and cardiovascular events: An updated meta‐analysis of published randomized controlled trials. Journal of Internal Medicine, 2025. DOI: 10.1111/joim.20107. PMID: 41236500.
Samuel 2020. Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). European Heart Journal. Quality of Care & Clinical Outcomes, 2020. DOI: 10.1093/ehjqcco/qcaa045. PMID: 32407460.
Shchendrygina 2023. Colchicine in patients with heart failure and preserved left ventricular ejection fraction: rationale and design of a prospective, randomised, open-label, crossover clinical trial. Open Heart, 2023. DOI: 10.1136/openhrt-2023-002360. PMID: 37586845.
Pourkarim 2025. The effect of Colchicine IN Sepsis (COLINS): a study protocol for a randomized, double-blind, placebo-controlled trial. Trials, 2025. DOI: 10.1186/s13063-025-08901-y. PMID: 40544304.
Noll 2025. Low-dose colchicine for stroke prevention: A systematic overview of systematic reviews and meta-analyses. J Stroke Cerebrovasc Dis, 2025. DOI: 10.1016/j.jstrokecerebrovasdis.2024.108167. PMID: 39653300.
Imanishi 2026. Ionizing radiation expands a p90RSK-activated patrolling monocyte subset: modulation by colchicine. Frontiers in Cardiovascular Medicine, 2026. DOI: 10.3389/fcvm.2026.1763490. PMID: 42064851.
Wong 2026. Colchicine and dialysis patients (CAD): protocol for a feasibility study. BMJ Open, 2026. DOI: 10.1136/bmjopen-2025-113028. PMID: 41922059.
Li 2025b. Effects of 2-year cocoa extract supplementation on inflammaging biomarkers in older US adults: findings from the COcoa Supplement and Multivitamin Outcomes Study randomised clinical trial. Age Ageing, 2025. DOI: 10.1093/ageing/afaf269. PMID: 40966617.
Nazmy 2025. The effect of 0.5 mg dose of colchicine on clinical outcomes in patients with acute myocardial infarction: An updated meta-analysis of randomized controlled trials. Curr Probl Cardiol, 2025. DOI: 10.1016/j.cpcardiol.2025.103169. PMID: 40912343.
Kan 2026. Successful Remission of Refractory Oral Ulcers Treated with Low-Dose Thalidomide and Colchicine: A Case Report. Reports - Clinical Practice and Surgical Cases, 2026. DOI: 10.3390/reports9010036. PMID: 41718287.
Wong 2020. Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2020. DOI: 10.1093/gerona/glaa271. PMID: 33070170.
Laudani 2026. Safety and Efficacy of Colchicine across the Spectrum of Coronary Artery Disease: A Systematic Review and Meta-Analysis of 20 Randomized Trials. Clin Pharmacol Ther, 2026. DOI: 10.1002/cpt.70246. PMID: 41760558.
Bian 2026. Cardiovascular Benefit and Gastrointestinal Risk of Colchicine in Secondary Prevention: Risk Associated with Dose and Treatment Duration. Am J Cardiovasc Drugs, 2026. DOI: 10.1007/s40256-026-00794-9. PMID: 42033599.

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).

Cesari 2009. Cesari M, Kritchevsky SB, Newman AB, et al. Added value of physical performance measures in predicting adverse health-related events. J Gerontol A Biol Sci Med Sci. 2009;64(7):772-779. DOI: 10.1093/gerona/glp012. PMID: 19349594.
Tancredi 2015. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732. DOI: 10.1056/NEJMoa1504347. PMID: 26510021.
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.

Proof Trail

Decision: AcceptLiving evidence briefGate failures: 0

Topic: research

Author: Dominic Lynch

Author ORCID: 0009-0005-4286-8363

Institution: not supplied

ROR: not supplied

RAiD: not supplied

OSF DOI: 10.17605/OSF.IO/ZC5VW

AI co-writer: agent-v3-full-paper

Reviewer: reviewer-panel

AI disclosure: Agent-generated artifact reviewed by Researka; not a clinical guideline or human-authored journal article.

Published: May 30, 2026

Provenance chain: Available → View

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Publication ID: 873ff54a-3a1e-4c35...

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Research Synthesis: Colchicine Inflammaging

Certification Timeline

Abstract

Review Summary

Evidence Transparency

Living Evidence Brief

Research Question

Search Summary

Review type and protocol

Information sources

Search strategy

Eligibility criteria

Selection of sources of evidence

source admission funnel

Exclusion reasons

Data items

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

Evidence Landscape

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Longevity Outcomes

Safety Outcomes

Safety and Comorbidity Outcomes

Skeletal, Fracture, and Bone Outcomes

Key Findings

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Longevity Outcomes

Safety Outcomes

Safety and Comorbidity Outcomes

Skeletal, Fracture, and Bone Outcomes

Limitations

Gaps Identified

Evidence Summary

Interpretation constraints

Conclusion

Research Synthesis: Colchicine Inflammaging

Abstract

Introduction

Background

Methods

Review type and protocol

Information sources

Search strategy

Eligibility criteria

Selection of sources of evidence

source admission funnel

Exclusion reasons

Data items

Risk-of-bias appraisal

Synthesis approach

AI-use disclosure

Accountability

Results

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Dosing and Pharmacokinetics Outcomes

Immune Outcomes

Immune and Inflammation Outcomes

Longevity Outcomes

Safety Outcomes

Safety and Comorbidity Outcomes

Skeletal, Fracture, and Bone Outcomes

Cross-Domain Synthesis

Boundary-condition synthesis

Load-Bearing Tensions

Discussion

Evidence Summary

Interpretation constraints

Limitations