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Research Synthesis: Ace Inhibitors Aging

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May 28, 2026

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OSF DOI: 10.17605/OSF.IO/X34VM

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Abstract

This synthesis tests the thesis that evidence for ACE inhibitors aging is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed for hypertension, yet whether they confer direct anti-aging benefits—attenuating frailty, preserving muscle function, or extending lifespan beyond blood-pressure control—remains debated. This synthesis applied a structured, AI-assisted evidence-synthesis approach with an auditable trail to integrate 47 curated reference papers spanning randomized trials, observational cohorts, and preclinical mechanistic studies on ACE inhibitors and aging-related outcomes. Functional aging endpoints were similarly ambiguous: ACE inhibitor therapy did not improve gait-speed reserve beyond statin effects in older adults (Spiegeleer 2025), and in the LACE trial ACE I/D genotype associated with grip and quadriceps strength in sarcopenic men but ACE inhibitor treatment itself did not produce a significant strength response (Rossios 2023). Importantly, no direct human trial with aging-specific primary endpoints—such as frailty incidence, sarcopenia progression, or all-cause longevity in non-diseased older adults—was identified in this synthesis. The mechanistic plausibility that ACE inhibition modulates inflammation, e

Review Summary

Evidence Transparency

Screening trace

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

Identified: 47 candidate receipts.
Screened: 47 receipts after source retrieval, deduplication, and topic filtering.
Excluded with reasons: 0 recorded exclusions; no PRISMA full-text exclusion-stage filter was applied.
Included: 47 retained candidate receipts for evidence-map interpretation.

Included-studies preview

Study	Population	Intervention/exposure	Comparator	Endpoint	Effect	Risk of bias	Directness
Lin 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Din 2026	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Spiegeleer 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Shen 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Bene 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Meattini 2025	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
Mostaza 2022	not extracted	not extracted	not extracted	not extracted	not extracted	not appraised in public preview	source-traceable
AmatSantos 2024	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 Ace Inhibitors Aging and human geroscience? This synthesis tests the thesis that evidence for ACE inhibitors aging is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed for hypertension, yet whether they confer direct anti-aging benefits—attenuating frailty, preserving muscle function, or extending lifespan beyond blood-pressure control—remains debated. This synthesis applied a structured, AI-assisted evidence-synthesis approach with an auditable trail to integrate 47 curated reference papers spanning randomized trials, observational cohorts, and preclinical mechanistic studies on ACE inhibitors and aging-related outcomes. Functional aging endpoints were similarly ambiguous: ACE inhibitor therapy did not improve gait-speed reserve beyond statin effects in older adults (Spiegeleer 2025), and in the LACE trial ACE I/D genotype associated with grip and quadriceps strength in sarcopenic men but ACE inhibitor treatment itself did not produce a significant strength response (Rossios 2023). Importantly, no direct human trial with aging-specific primary endpoints—such as frailty incidence, sarcopenia progression, or all-cause longevity in non-diseased older adults—was identified in this synthesis. The mechanistic plausibility that ACE inhibition modulates inflammation, e

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-ace_inhibitors_aging-v06-DAILY-2026-05-27T23-52-28Z-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: 2026-05-28.

Search strategy

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

ACE inhibitors aging AND aging AND human
ACE inhibitors aging AND older adults
ACE inhibitors aging AND randomized controlled trial
ACE inhibitor AND aging AND human
ACE inhibitor AND older adults
ACE inhibitor AND randomized controlled trial
enalapril AND aging AND human
enalapril AND older adults
enalapril AND randomized controlled trial
lisinopril AND aging AND human

Eligibility criteria

Sources whose primary content addresses ace inhibitors aging.
Sources with extractable quantitative or qualitative findings.
Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 175 records in the receipt-candidate union, 55 were classified as source candidates and 47 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	175
Classified source candidates	55
No extractable claims	20
None-only claim binding	10
Partial/none-only claim binding	61
Partial-only candidates	16
Strict high-confidence sources	13
Admitted final sources	47

Exclusion reasons

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

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating.

Risk-of-bias appraisal

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

Synthesis approach

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

AI-use disclosure

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

Accountability

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

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=26; claims=1346	null signal in 17/26 sources	1 direct; 21 indirect; 1 mechanistic; 3 review	limited corpus depth in this outcome class
Longevity	n=6; claims=158	unclear signal in 4/6 sources	4 indirect; 2 review	limited corpus depth in this outcome class
Cardiometabolic	n=5; claims=634	null signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=4; claims=145	null signal in 3/4 sources	3 indirect; 1 review	limited corpus depth in this outcome class
Immune	n=2; claims=197	null signal in 2/2 sources	1 indirect; 1 mechanistic	limited corpus depth in this outcome class
Frailty	n=1; claims=1	unclear signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Immune and Inflammation	n=1; claims=49	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Mortality and Survival	n=1; claims=24	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Muscle Function	n=1; claims=49	null signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

The evidence base for ACE inhibitors in the context of aging-related cardiometabolic outcomes comprises five studies, predominantly observational in design. Lin 2026 conducted an observational cohort emulating a target trial, examining mean weight change associated with initiation of and adherence to antihypertensive medications, including lisinopril, relative to comparators like amlodipine over a 24-month period in adults. Din 2026 performed a prospective randomized controlled study evaluating sexual function among hypertensive females receiving ramipril 2.5 mg daily for one month. Spiegeleer 2025 focused on older adults in an observational cohort, analyzing the association between statins and gait speed reserve (GSR) while considering concomitant medications, including ACE inhibitors. Azizzadeh 2026 conducted an observational cohort study, the LEAD study, examining the prevalence and determinants of vascular aging in Austrian adults, which included pharmacological treatments for diabetes and hypertension. The single clinical RCT, Zhang 2025, compared nifedipine-GITS and ramipril in Chinese and European patients with hypertension, providing direct evidence on blood pressure reduction.

Quantitative findings across these studies present a mixed profile, with no consistent cardiometabolic benefit or harm linked specifically to ACE inhibitors in aging contexts. Din 2026 reported a mixture of significant (P < 0.05, P < 0.05) and non-significant (P > 0.05) findings across different functional and cardiometabolic endpoints. The clinical RCT by Zhang 2025 demonstrated that both nifedipine-GITS and ramipril similarly reduced blood pressure, reporting a P = 0.02 for a comparative endpoint. By contrast, Azizzadeh 2026 reported no p-values in the provided excerpts, indicating a null or unreported effect for ACE inhibitor use on vascular aging determinants.

Mechanistically, the rationale for ACE inhibitors influencing aging-related cardiometabolic pathways centers on modulation of the renin-angiotensin system, which can affect vascular health, insulin sensitivity, and adiposity. Preclinical data and theoretical frameworks suggest potential benefits on endothelial function and oxidative stress. However, the human evidence from this corpus does not provide clear support. The clinical RCT by Zhang 2025 supports efficacy for blood pressure control, a key cardiometabolic risk factor, but its design does not assess aging-specific endpoints. Observational studies like Azizzadeh 2026, which explicitly examine vascular aging, report null findings, suggesting that in real-world populations, the benefit of ACE inhibitors may not extend beyond hypertension management to modify core aging trajectories.

Within the corpus, tensions are evident. Azizzadeh 2026, reporting null findings on vascular aging determinants, stands in disagreement with Spiegeleer 2025, which found mixed and significant associations between concomitant medications (potentially including ACE inhibitors) and gait speed reserve in older adults. Similarly, the null findings reported in Din 2026 for certain functional outcomes contrast with the unclear or negative signals reported in Lin 2026 and Zhang 2025, respectively, regarding weight change and blood pressure outcomes. The primary tension, therefore, is between studies suggesting potential functional or vascular impacts and those reporting no independent association with aging metrics, underscoring that the current evidence does not establish ACE inhibitors as standalone geroprotective agents for cardiometabolic health.

Contextual Adjacent Evidence Outcomes

The SAFE trial, a randomized, phase 3, double-blind, placebo-controlled trial, provided the most direct human RCT evidence within the corpus. This 2x2 factorial design evaluated the cardioprotective effects of ramipril, bisoprolol, or their combination in breast cancer patients receiving anthracycline chemotherapy.

Observational data from a cohort study following transcatheter aortic valve implantation (TAVI) provided more mixed evidence. The RASTAVI trial, a prospective randomized open, blinded endpoint (PROBE) design, compared ramipril with standard care in patients without reduced ejection fraction.

Mechanistically, the protective effects observed in the SAFE trial may be mediated through the attenuation of chemotherapy-induced oxidative stress, fibrosis, and cardiomyocyte injury, pathways implicated in age-related cardiac decline. Furthermore, a review of ramipril following TAVI notes the theoretical basis for ACE inhibition in modifying post-procedural cardiac remodeling, even though the clinical trial outcome was not uniformly positive (AmatSantos 2024).

The evidence base reveals notable tensions regarding context-dependency. By contrast, the positive cardioprotective signal from the anthracycline-exposed SAFE cohort (Meattini 2025; Bene 2025) stands in disagreement with the null or mixed findings from the TAVI (AmatSantos 2024) and post-myocardial infarction (Wang 2023) populations. These disagreements suggest that any potential geroprotective or cardioprotective benefit of ACE inhibitors is highly specific to the clinical context and underlying pathophysiology, rather than a generalizable effect.

A dedicated clinical trial examined the neurocognitive effects of ACE inhibition in older adults, a population central to aging research. This study enrolled participants aged 55 years or older with mild cognitive impairment (MCI) of the executive or mixed type and a history of hypertension, comparing candesartan to lisinopril.

A related mechanistic human study investigated the cerebrovascular substrate for cognitive effects. The CEDAR trial found that candesartan was associated with improved whole-brain cerebrovascular reactivity (CVR) compared to placebo in patients with MCI, with an adjusted within-group mean difference of 0.27 (95% CI not provided in excerpt).

Mechanistically, the substrate for these cognitive findings may involve ACE inhibitor effects on cerebral microvascular function and endothelial health, processes that deteriorate with vascular aging. This theoretical basis is further supported by a systematic review linking methylarginine levels, modulators of nitric oxide synthesis, to vascular aging, although direct evidence for ACE inhibitor modulation of this pathway in humans remains sparse (Carmo 2025).

Within this outcome class, a significant tension exists between the null primary cognitive findings in the MCI trial (Hajjar 2020) and the positive cerebrovascular reactivity finding from the CEDAR study (Henley 2023). This disagreement highlights a disconnect between a potential mechanistic effect on cerebral perfusion and a lack of demonstrable benefit on standardized cognitive batteries. Furthermore, the severity of the disagreement is amplified when considering that the positive CEDAR finding contrasts with numerous null effects on other vascular aging markers across the corpus, suggesting that any cerebrovascular benefit may be narrow and not broadly anti-aging.

The corpus included several studies examining systemic or safety outcomes pertinent to aging, such as renal function, treatment adherence, and adverse events. A secondary analysis of a stroke prevention trial in Ghana evaluated a polypill containing ramipril 5 mg. An evaluation of preoperative ACE inhibitor use for renal protection in cardiac surgery found that ACE inhibitors attenuated post-operative declines in renal function, with several comparisons reaching P < 0.05, though not all metrics differed (P > 0.05) (Kilic 2026).

Regarding treatment persistence, a real-world cohort study from Singapore reported that prescription rates for ACEi/ARB/ARNI declined by 16% within 6 months of initiation in patients with heart failure with reduced ejection fraction (HFrEF) (Senanayake 2026). These findings underscore the practical challenges of maintaining long-term therapy and the potential for central nervous system side effects in the elderly population.

Mechanistically, the renal protective effects observed in cardiac surgery may be mediated through modulation of intra-renal hemodynamics and reduction of inflammation, pathways relevant to age-related nephron loss (Kilic 2026). The high attrition rate observed in the Singapore cohort (Senanayake 2026) points to a mechanistic tension between the theoretical long-term benefits of ACE inhibition and the practical reality of patient tolerance and persistence. Furthermore, the case of lisinopril-induced hallucinations (Golder 2026) suggests a potential, if rare, effect on central neurotransmitter systems, a consideration for geriatric prescribing.

A notable tension emerges between the positive renal protection signal from a surgical context (Kilic 2026) and the broader pattern of null or mixed findings for ACE inhibitors in other aging-related domains across the corpus. The pragmatic finding of high treatment discontinuation (Senanayake 2026) stands in disagreement with any assumption of straightforward long-term geroprotective use. Collectively, these systemic and safety outcomes reinforce that the risk-benefit profile of ACE inhibitors in older adults is complex, with specific benefits in certain procedural contexts coexisting with practical adherence barriers and potential adverse effects.

Frailty Outcomes

The evidence for ACE inhibitor effects on frailty is derived exclusively from a preclinical model. Translational relevance to humans remains uncertain. The intervention involved a dose of 30 mg/kg/day administered via feed. The primary outcome assessed was the attenuation of frailty development in middle-aged animals.

Preclinical data from Keller 2019 suggest that enalapril treatment attenuated the development of frailty in aging mice. The study also reported differential modification of pro- and anti-inflammatory cytokines between male and female animals. However, no p-values or effect sizes were provided in the available excerpts to quantify these changes. The effect direction for the overall frailty outcome was classified as unclear due to the limited mechanistic focus.

Mechanistically, the attenuation of frailty in the mouse model is proposed to involve modulation of the renin-angiotensin system and associated inflammatory pathways. Keller 2019 specifically noted differential cytokine responses, suggesting a biological basis for the observed functional changes. This provides theoretical plausibility for a role of ACE inhibitors in age-related frailty, but the pathway has not been validated in human clinical populations.

A fundamental tension exists within this evidence base: the sole available study is a preclinical investigation in mice, and no direct human trials with aging-specific endpoints such as frailty were identified in the corpus. While mechanistic plausibility is suggested by the animal data, this does not equate to proven clinical benefit in humans. The translation from rodent models to human geriatric outcomes remains an unresolved challenge.

Immune Outcomes

The evidence base for ACE inhibitor effects on immune outcomes is derived from two distinct study types with no direct human trials on aging-specific endpoints. An observational cohort study by Shen and colleagues examined the association between food allergen sensitization and early vascular aging (EVA) in adults. This study identified that sensitization to at least one common food allergen was associated with an increased risk of EVA, with an odds ratio (OR) of 1.91 (95% confidence interval [CI], 1.1 to 3.3). The population studied were adults, and the study did not directly assess ACE inhibitor use, providing only contextual, indirect evidence.

Preclinical data provide the primary mechanistic foundation for investigating immune modulation. A study in spontaneously hypertensive rats (SHR) by Diego and colleagues evaluated the modulation of pro-inflammatory cytokines by nebivolol-based polytherapies with valsartan or lisinopril. Translational relevance to humans remains uncertain. These preclinical results suggest a mechanistic basis for ACE inhibitors influencing inflammatory pathways relevant to aging, though this effect was observed in a polypharmacy context in hypertensive animals.

Mechanistically, the preclinical observation of cytokine modulation by an ACE inhibitor-containing regimen provides theoretical plausibility for a role in age-related inflammation. By contrast, the human observational data link immune-mediated sensitization to vascular aging phenotypes but do not establish a causal pathway involving ACE inhibition. This juxtaposition highlights a key tension: while animal models demonstrate direct immunomodulatory effects, the human data connect immune dysregulation to aging outcomes without implicating a specific pharmacological intervention. Consequently, the boundary conditions for any potential geroprotective immune effect of ACE inhibitors remain to be established in humans.

Within the curated corpus, there is a tension in the directness of evidence. The preclinical study by Diego 2024 offers strong mechanistic data on cytokine modulation, while the observational study by Shen 2025 provides only indirect, contextual evidence linking immune factors to vascular aging. Both studies report null or context-dependent overall findings regarding ACE inhibitors as standalone agents for immune aging outcomes. This divergence underscores the current incomplete state of the evidence, where mechanistic plausibility coexists with a lack of direct human trial data on aging-specific immune endpoints.

Immune and Inflammation Outcomes. The sole identified study investigating ACE inhibitor effects on immune and inflammatory pathways in the context of viral infection was an observational cohort using a transgenic mouse model. Animals were treated with lisinopril at a dose of 10 mg/kg per day for 21 days prior to intranasal inoculation with 10⁵ PFU of SARS-CoV-2 (Wuhan strain). The experimental design assessed viral load, ACE2 receptor expression in lung tissue, and markers of inflammatory response following infection. This preclinical model is relevant to the aging context because ACE2 expression changes with age and because the RAS axis is implicated in inflammaging. However, it is important to note that no direct human trials with aging-specific endpoints such as frailty, muscle function, or longevity were identified in the corpus. The study thus provides only indirect, mechanistic evidence regarding immune and inflammatory modulation by ACE inhibitors.

Longevity Outcomes

The corpus includes multiple observational cohorts and systematic reviews examining the association between ACE inhibitor use and mortality, though no direct trials with aging-specific endpoints such as frailty or muscle function were identified. Jin 2025 examined guideline-directed medical therapy—including ACE inhibitors—and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction across two nationwide retrospective cohorts, though specific effect sizes and p-values were not reported in the available excerpts.

Kakaletsis 2024, a systematic review and meta-analysis, found that acute ischemic stroke patients with arterial stiffness and vascular aging—as measured by higher pulse wave velocity—had approximately 46.2% increased risk of poor functional outcome, 12.7% higher risk of mortality, and 13.9% greater risk of hemorrhagic transformation, underscoring the prognostic relevance of vascular aging parameters. Secondary 2023 described the PARALLEL-HF study, a multicenter, randomized, double-blind, double-dummy, parallel-group trial assessing sacubitril/valsartan (200 mg) in heart failure, which is relevant context for understanding renin-angiotensin-aldosterone system modulation in cardiovascular populations. The tension between the mixed findings of Yamal 2023 and the null direction reported by Li 2023 highlights the heterogeneity in the evidence base regarding ACE inhibitors and mortality outcomes.

Mechanistically, the theoretical basis for ACE inhibitor effects on longevity rests on modulation of the renin-angiotensin-aldosterone system, which is implicated in vascular aging, endothelial dysfunction, and arterial stiffness. The vascular aging data from Kakaletsis 2024 suggest that targeting arterial stiffness pathways could plausibly affect mortality trajectories, though this link remains indirect. Preclinical data and human mechanistic studies support the concept that angiotensin-converting enzyme inhibition may attenuate age-related vascular remodeling, yet the clinical RCT evidence does not consistently translate this mechanistic plausibility into proven longevity benefits. This synthesis does not support marketing ACE inhibitors as standalone geroprotective interventions, even where otherwise indicated for hypertension or heart failure.

Within the corpus, significant tensions exist regarding the longevity effects of ACE inhibitors. The unclear effect directions from Jin 2025 and Murray-Thomas 2025 add further ambiguity, as both studies examined populations where ACE inhibitors are guideline-recommended but did not isolate a clear longevity signal. Secondary 2023, describing the PARALLEL-HF trial of sacubitril/valsartan, represents a related but mechanistically distinct intervention that complicates direct comparison with traditional ACE inhibitors. These disagreements, particularly between studies reporting mixed findings and those reporting null results, underscore that the ACE inhibitors aging evidence base remains incomplete, with boundary conditions for any potential geroprotective effect yet to be established.

Mortality and Survival Outcomes. The evidence base for mortality and survival outcomes related to ACE inhibitors in aging populations is sparse, with no direct randomized controlled trials identified. The sole available study is an observational retrospective cohort from Tsunan Town, Japan, which examined population-level trends in antihypertensive therapy. The research investigated combined ACE inhibitor and β-blocker therapy, but specific effect sizes, hazard ratios, or p-values for mortality endpoints were not reported in the available excerpts. Consequently, this evidence is classified as indirect, with an unclear effect direction on age-related mortality outcomes.

Mechanistically, ACE inhibitors may theoretically influence survival through effects on cardiovascular remodeling, fibrosis, and cellular senescence pathways. However, the current corpus lacks human mechanistic studies or clinical RCTs that directly link these pathways to measurable longevity outcomes in aging populations. The observational data from Tsunan Town does not establish a causal or even correlative link between ACE inhibitor use and reduced mortality in older adults. Therefore, while biological pathways may suggest a theoretical basis for geroprotection, the clinical translation of this mechanism is unsupported by the available human evidence. Future research must bridge this gap by incorporating survival analyses with extended follow-up periods in older adult cohorts.

Safety and Comorbidity Outcomes

The included studies examined safety and comorbidity outcomes in adult populations, though none were designed with aging-specific primary endpoints. Mostaza 2022 assessed a cardiovascular polypill containing an ACE inhibitor in adults at high and very high cardiovascular risk without a previous event, with outcomes measured after 16 weeks (Mostaza 2022). Gross 2012 described the EARLY PRO-TECT Alport trial (NCT01485978), a double-blind, randomized, placebo-controlled, multicenter phase III trial evaluating ramipril safety and efficacy in pediatric patients with Alport syndrome, an indication with indirect relevance to aging cohorts (Gross 2012). Sun 2016 compared the efficacy and safety of different ACE inhibitors in patients with chronic heart failure, a condition that imposes significant healthcare resource utilization through repeated hospitalization (Sun 2016).

Quantitative findings from the observational cohort studies yielded predominantly null results for safety and comorbidity outcomes. Per-study endpoint details are presented in Table 2 (Per-Study Endpoint Evidence). These findings are consistent with a null effect direction reported across the safety and comorbidity outcome class in this corpus.

Mechanistically, the theoretical basis for ACE inhibitor benefit in aging-related comorbidities rests on the modulation of the renin-angiotensin-aldosterone system (RAAS), which influences vascular stiffness, renal perfusion, and cardiac remodeling. Tanriover 2023 highlighted that pulse wave velocity of the aorta and systolic blood pressure independently predicted kidney function decline in chronic kidney disease, providing a mechanistic substrate linking vascular aging to renal outcomes (Tanriover 2023). However, no source in this corpus provides direct evidence from randomized controlled trials with geriatric-specific endpoints such as frailty incidence, muscle function, or survival. The mechanistic plausibility thus remains theoretical rather than clinically demonstrated in the context of aging.

Within-corpus tensions are evident in the comparison of study conclusions on safety and comorbidity. Gross 2012, reporting on the EARLY PRO-TECT Alport trial of ramipril, found a null safety signal in a controlled setting (Gross 2012), while Sun 2016 reported unclear effect directions when comparing different ACE inhibitors in heart failure, suggesting that drug-specific heterogeneity may modulate outcomes (Sun 2016). These discrepancies may reflect differences in population, formulation, or outcome ascertainment rather than true pharmacological disagreement. The synthesis does not support marketing ACE inhibitors as standalone geroprotective interventions based on the available safety and comorbidity evidence.

Immune and Inflammation Outcomes

Quantitative findings from Silva-Santos 2024 revealed a complex and partially paradoxical profile. Lisinopril treatment significantly increased lung ACE2 expression, which served as the primary receptor for SARS-CoV-2 cell entry. Consistent with increased receptor availability, viral load in lung tissue was elevated in lisinopril-treated animals compared to controls. Critically, however, this reduction in inflammatory signaling did not translate into improved clinical disease severity. The dissociation between the suppression of measurable inflammation and the absence of clinical benefit underscores the complexity of RAS modulation in acute infection settings. These findings suggest that ACE inhibitor-mediated anti-inflammatory effects may be context-dependent and insufficient to overcome the competing risk of enhanced viral replication driven by ACE2 upregulation.

Mechanistically, the findings from Silva-Santos 2024 are interpretable through the dual role of ACE2 in the renin-angiotensin system. ACE2 degrades angiotensin II to angiotensin 1-7, a peptide with anti-inflammatory and vasodilatory properties, which is the basis for the theoretical anti-inflammatory benefit of ACE inhibition. However, ACE2 simultaneously functions as the obligate entry receptor for SARS-CoV-2, creating a mechanistic trade-off: interventions that upregulate ACE2 to reduce inflammation may concurrently facilitate viral pathogenesis. This duality illustrates a key boundary condition for the geroprotective hypothesis — mechanistic plausibility for anti-inflammatory benefit does not equate to proven clinical benefit, particularly when the intervention modulates a pathway with pleiotropic and context-dependent effects. The mechanistic substrate underlying this functional finding, the ACE2–angiotensin 1-7 axis, remains a promising theoretical basis for attenuating inflammaging but awaits validation in aging-specific human models.

Within the corpus, the evidence for ACE inhibitor effects on immune and inflammatory outcomes is limited to a single preclinical study, which constrains the ability to identify within-corpus tensions through divergent findings. No directly contradictory human data were available to set against the Silva-Santos 2024 results. The primary tension identified is internal to the study itself: the coexistence of suppressed inflammation with worsened viral outcomes represents a mechanistic paradox that complicates straightforward translation to aging populations. Furthermore, because the model used an acute viral infection rather than chronic low-grade inflammation characteristic of aging, the applicability of these findings to the inflammaging phenotype remains theoretical. The absence of corroborating human data means that the observed anti-inflammatory signal, while statistically supported, cannot be generalized with confidence. Future research would need to disentangle the ACE2-mediated trade-off between anti-inflammatory benefit and infection susceptibility in aged, non-transgenic human cohorts before clinical relevance can be established.

Immune and Inflammation remains a separate Results slice (n=1; claims=49; unclear signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Mortality and Survival Outcomes

The absence of source-traced quantitative data on mortality outcomes precludes a definitive synthesis of ACE inhibitor effects on longevity or survival in older adults. The Ishikawa 2025 observational cohort, while noting demographic shifts and the use of antihypertensive regimens, does not provide comparative risk estimates or survival analyses between treated and untreated groups. This represents a critical gap in the evidence base, as mechanistic plausibility from preclinical models cannot be extrapolated to proven clinical benefit without supporting human trial data. The lack of robust mortality data underscores the need for dedicated randomized controlled trials with aging-specific endpoints. Without such evidence, any claims regarding ACE inhibitors as geroprotective interventions remain speculative and should be rigorously hedged.

A central tension within the mortality evidence is the disconnect between the indirect, population-level ecological data and the need for individual-level clinical outcomes. The Ishikawa 2025 study provides demographic context but no direct measure of treatment effect on survival, limiting its utility for assessing geroprotective efficacy. This contrasts sharply with the requirement for randomized controlled trials that isolate the effect of ACE inhibitors from confounding variables such as comorbidities, polypharmacy, and baseline health status. The synthesis highlights that no source in the corpus resolves this tension, leaving the mortality-survival outcome class reliant on a single, non-direct study. Consequently, the evidence base for ACE inhibitors impacting age-related mortality is currently incomplete and insufficient to inform clinical recommendations for geroprotection.

Mortality and Survival remains a separate Results slice (n=1; claims=24; unclear signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Muscle Function Outcomes

Muscle Function Outcomes. The evidence for ACE inhibitor effects on muscle function in older adults is primarily derived from the LACE trial, an observational cohort study. This investigation specifically examined whether ACE I/D genotype associates with muscle strength and body composition in older adults with sarcopenia, and whether genotype predicts response to ACE inhibitor therapy. The study population comprised older adults with sarcopenia, with outcomes including hand grip and quadriceps strength measured before and after an intervention period. The study design represents a clinical investigation context rather than a direct anti-aging intervention trial (Rossios 2023).

Quantitative findings from the LACE trial revealed several statistically significant associations between ACE I/D genotype and muscle-related parameters. These significant associations were observed specifically in sarcopenic men, indicating a sex-specific genetic influence on muscle strength. However, the critical finding was that ACE I/D genotype was not associated with response to ACE inhibitor therapy in this older adult population (Rossios 2023).

Mechanistically, the biological plausibility for ACE inhibitors affecting muscle function operates through angiotensin II modulation. Angiotensin II promotes skeletal muscle wasting through ubiquitin-proteasome pathway activation and satellite cell inhibition, providing a theoretical basis for ACE inhibitor-mediated muscle protection. The LACE trial's finding that genotype associates with strength parameters supports the mechanistic substrate involving the renin-angiotensin system in muscle biology. However, the absence of genotype-treatment interaction for ACE inhibitor response suggests that the theoretical mechanism may not translate directly to therapeutic benefit in sarcopenia management (Rossios 2023).

A notable tension within the corpus emerges from the LACE trial's dual findings. By contrast, the null finding for genotype-treatment interaction indicates that ACE inhibitor therapy does not differentially benefit patients based on their ACE genotype profile. This divergence between genetic association and therapeutic response underscores that mechanistic plausibility does not equate to proven clinical benefit for ACE inhibitors as geroprotective interventions in sarcopenia (Rossios 2023).

Muscle Function remains a separate Results slice (n=1; claims=49; null signal in 1/1 sources; 1 indirect; 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=26; claims=1346	null signal in 17/26 sources	1 direct; 21 indirect; 1 mechanistic; 3 review	limited corpus depth in this outcome class
Longevity	n=6; claims=158	unclear signal in 4/6 sources	4 indirect; 2 review	limited corpus depth in this outcome class
Cardiometabolic	n=5; claims=634	null signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=4; claims=145	null signal in 3/4 sources	3 indirect; 1 review	limited corpus depth in this outcome class
Immune	n=2; claims=197	null signal in 2/2 sources	1 indirect; 1 mechanistic	limited corpus depth in this outcome class
Frailty	n=1; claims=1	unclear signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Immune and Inflammation	n=1; claims=49	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Mortality and Survival	n=1; claims=24	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Muscle Function	n=1; claims=49	null signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Frailty Outcomes

Immune Outcomes

Longevity Outcomes

Safety and Comorbidity Outcomes

Immune and Inflammation Outcomes

Mortality and Survival Outcomes

Muscle Function Outcomes

Muscle Function remains a separate Results slice (n=1; claims=49; null signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Limitations

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

The curated corpus is dominated by observational cohort designs and secondary analyses, with no dedicated long-term mortality or longevity RCT among the 47 reference papers. Consequently, the headline claim that ACE inhibitors may modulate aging trajectories rests on an evidence base in which the highest-quality human data address cardiometabolic or oncologic endpoints rather than geriatric outcomes, limiting direct inference about anti-aging efficacy.

Several outcome domains in the cross-study disagreement map are represented by only a single source, precluding within-corpus replication. Similarly, gait-speed reserve findings depend on Spiegeleer 2025 alone, which measured statin-ACE inhibitor interactions in a Belgian cohort of older adults rather than ACE-inhibitor monotherapy. Single-source outcomes cannot be cross-validated within the current evidence set and remain vulnerable to idiosyncratic methodological features.

Population specificity further constrains external validity. Community-dwelling older adults without overt cardiometabolic disease, who represent the principal target population for any geroprotective indication, were essentially absent from the corpus. The sole study explicitly enrolling older adults with mild cognitive impairment, Hajjar 2020, compared candesartan to lisinopril and yielded mixed neurocognitive results rather than definitive aging-outcome data. Generalization to healthy aging populations therefore remains unsupported.

Critical aging endpoints were not measured across the corpus. No source reported validated frailty scales (e.g., Fried phenotype), sarcopenia incidence, disability-free survival, or healthspan as a primary endpoint. The LACE trial informed by Rossios 2023 assessed hand-grip and quadriceps strength as secondary outcomes in sarcopenic adults but found no significant response to ACE-inhibitor therapy, and the study did not track incident frailty transitions over time. Endpoint scope is therefore limited to surrogate markers such as blood pressure change, inflammatory biomarkers, and echocardiographic parameters, which carry the general limitation that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005). Without trials designed to capture clinical aging phenotypes, the mechanistic plausibility drawn from preclinical and biomarker data cannot be translated into evidence-based geroprotective recommendations.

Gaps Identified

Thesis: Across 47 curated reference papers, the evidence base for ACE inhibitors aging shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: contextual other, cardiometabolic. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces 346 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The ACE inhibitors aging anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The 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 47 included sources. The evidence-tier distribution is: B2 (n=40), C1 (n=3), A1 (n=2), B1 (n=2). By directness, the breakdown is: indirect (n=35), review (n=7), mechanistic (n=3), direct (n=2). 31 of 47 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; frail / sarcopenic adults; 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. Ace Inhibitors Aging 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 contextual adjacent evidence coexist with null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic and negative signals in contextual adjacent evidence, cardiometabolic. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.

The current corpus may support ace inhibitors aging as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. 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.

Additional corpus sources included animal/preclinical evidence; future work should prioritize studies that connect mechanistic studies (Diego 2024, Alanis 2025, Keller 2019) to direct clinical outcomes represented by Meattini 2025, Zhang 2025. Until that bridge is stronger, ace inhibitors aging 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: Ace Inhibitors Aging

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed for hypertension, yet whether they confer direct anti-aging benefits—attenuating frailty, preserving muscle function, or extending lifespan beyond blood-pressure control—remains debated.

This synthesis applied a structured, AI-assisted evidence-synthesis approach with an auditable trail to integrate 47 curated reference papers spanning randomized trials, observational cohorts, and preclinical mechanistic studies on ACE inhibitors and aging-related outcomes.

Functional aging endpoints were similarly ambiguous: ACE inhibitor therapy did not improve gait-speed reserve beyond statin effects in older adults (Spiegeleer 2025), and in the LACE trial ACE I/D genotype associated with grip and quadriceps strength in sarcopenic men but ACE inhibitor treatment itself did not produce a significant strength response (Rossios 2023).

Importantly, no direct human trial with aging-specific primary endpoints—such as frailty incidence, sarcopenia progression, or all-cause longevity in non-diseased older adults—was identified in this synthesis.

The mechanistic plausibility that ACE inhibition modulates inflammation, endothelial function, and tissue fibrosis in ways theoretically relevant to aging biology is supported by preclinical and biomarker-level evidence (Keller 2019; Diego 2024), yet this theoretical basis does not equate to proven geroprotective efficacy.

The evidence profile indicates that the current evidence does not support marketing ACE inhibitors as standalone anti-aging or geroprotective interventions even where they are otherwise indicated for hypertension or heart failure; mechanistic promise exists, but the boundary conditions under which any class member might slow biological aging in humans remain to be established through trials designed with aging-specific endpoints.

Introduction

The geroscience hypothesis proposes that targeting fundamental aging biology could delay or prevent multiple age-related diseases simultaneously, rather than addressing each condition in isolation. This framework has catalyzed interest in drug repurposing, where medications approved for specific indications are evaluated for broader geroprotective potential. The appeal of repurposing lies in the availability of established safety data, regulatory precedent, and global manufacturing infrastructure. ACE inhibitors aging occupies a distinctive position in this landscape because the renin-angiotensin-aldosterone system appears to intersect with several biological processes implicated in aging. This mechanistic finding has been proposed as the theoretical basis for investigating whether similar effects might translate to human populations. However, it remains uncertain whether preclinical frailty attenuation observed in rodent models corresponds to clinically meaningful outcomes in older adults. The distinction between mechanistic plausibility and proven clinical efficacy represents a critical boundary condition for the ACE inhibitors aging hypothesis.

Angiotensin-converting enzyme inhibitors constitute one of the most prescribed drug classes globally, with agents such as ramipril, lisinopril, and enalapril serving as first-line therapies for hypertension and heart failure. The extensive clinical history of ACE inhibitors aging provides both advantages and limitations for geroprotective investigation. On one hand, decades of post-marketing surveillance have established well-characterized safety profiles and dosing regimens. On the other hand, the primary indications for these medications—blood pressure reduction and cardioprotection—have dominated clinical research priorities. sources from the curated evidence base illustrate this pattern: ramipril has been evaluated in the RASTAVI trial for post-TAVI outcomes (AmatSantos 2024), in the SAFE trial for cardioprotection during anthracycline therapy (Meattini 2025), and in the EARLY PRO-TECT trial for Alport syndrome (Gross 2012). These trials demonstrate regulatory and clinical accessibility but address disease-specific endpoints rather than aging biology. The question of whether ACE inhibitors aging can be investigated within existing trial infrastructure remains open, particularly given the absence of aging-specific regulatory pathways. Evidence suggests that repurposing existing agents may accelerate translational timelines, yet the endpoints required for geroprotective claims differ fundamentally from those used in cardiovascular trials.

Several unresolved questions constrain the interpretation of ACE inhibitors aging evidence and define the boundary conditions for future research. Mechanism-to-function translation remains problematic: preclinical findings such as Keller 2019's frailty attenuation in mice have not been replicated in human trials with aging-specific endpoints. Population specificity poses additional challenges, as the SAFE trial demonstrated sex-based differences in cardiac outcomes during anthracycline therapy (Meattini 2025). Duration of exposure remains uncertain; the LACE trial examining ACE inhibitor therapy in older adults with sarcopenia found that ACE I/D genotype associated with strength in sarcopenic men but not with response to therapy (Rossios 2023). Dose-response relationships for geroprotective effects have not been established, and the question of whether standard cardiovascular dosing would suffice for aging modification is open. Evidence suggests that ACE inhibitors aging may have differential effects across outcome classes, with positive signals in contextual outcomes but null or negative findings in cardiometabolic domains. The tension between mechanistic plausibility and clinical evidence remains the central unresolved question.

This synthesis contributes to the ACE inhibitors aging literature by systematically mapping cross-outcome tensions and structuring evidence weighting across mechanistic and clinical domains. The curated evidence base reveals cross-study disagreements across outcome classes, reflecting fundamental disagreements about whether ACE inhibitors modify aging biology or merely treat age-associated disease. The separation of mechanistic plausibility from clinical efficacy is essential: preclinical findings such as enalapril's effects on pro- and anti-inflammatory cytokines in aging mice (Keller 2019) establish theoretical basis but cannot substitute for human trial evidence. Positive signals appear in contextual outcomes, including the RASTAVI trial's findings on ramipril after TAVI (AmatSantos 2024), while negative signals emerge in cardiometabolic domains such as Zhang 2025's comparison of nifedipine-GITS and ramipril in hypertensive patients. Null findings dominate safety and comorbidity outcomes across multiple trials. The synthesis surfaces the question of whether ACE inhibitors aging can be substantiated from available evidence, and the answer appears to be that mechanistic plausibility coexists with mixed or sparse human-RCT evidence. The boundary conditions for geroprotective claims remain to be established through trials specifically designed with aging endpoints. This work does not support marketing ACE inhibitors as standalone geroprotective interventions, even where otherwise indicated for hypertension.

Background

Additional corpus sources included animal/preclinical evidence; the background evidence for ace inhibitors aging is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Meattini 2025, Zhang 2025 are interpreted separately from mechanistic studies such as Diego 2024, Alanis 2025, Keller 2019, 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 contextual adjacent evidence; null signals around contextual adjacent evidence, safety and comorbidity, cardiometabolic; and negative or adverse signals around contextual adjacent evidence, cardiometabolic. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.

The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct clinical signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

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: 2026-05-28.

Search strategy

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

ACE inhibitors aging AND aging AND human
ACE inhibitors aging AND older adults
ACE inhibitors aging AND randomized controlled trial
ACE inhibitor AND aging AND human
ACE inhibitor AND older adults
ACE inhibitor AND randomized controlled trial
enalapril AND aging AND human
enalapril AND older adults
enalapril AND randomized controlled trial
lisinopril AND aging AND human

Eligibility criteria

Sources whose primary content addresses ace inhibitors aging.
Sources with extractable quantitative or qualitative findings.
Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

source admission funnel

Admission bucket	n
Receipt candidate union	175
Classified source candidates	55
No extractable claims	20
None-only claim binding	10
Partial/none-only claim binding	61
Partial-only candidates	16
Strict high-confidence sources	13
Admitted final sources	47

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=26; claims=1346	null signal in 17/26 sources	1 direct; 21 indirect; 1 mechanistic; 3 review	limited corpus depth in this outcome class
Longevity	n=6; claims=158	unclear signal in 4/6 sources	4 indirect; 2 review	limited corpus depth in this outcome class
Cardiometabolic	n=5; claims=634	null signal in 2/5 sources	1 direct; 3 indirect; 1 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=4; claims=145	null signal in 3/4 sources	3 indirect; 1 review	limited corpus depth in this outcome class
Immune	n=2; claims=197	null signal in 2/2 sources	1 indirect; 1 mechanistic	limited corpus depth in this outcome class
Frailty	n=1; claims=1	unclear signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Immune and Inflammation	n=1; claims=49	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Mortality and Survival	n=1; claims=24	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Muscle Function	n=1; claims=49	null signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Frailty Outcomes

Immune Outcomes

Longevity Outcomes

Safety and Comorbidity Outcomes

Immune and Inflammation Outcomes

Mortality and Survival Outcomes

Muscle Function Outcomes

Muscle Function remains a separate Results slice (n=1; claims=49; null signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Cross-Domain Synthesis

A central tension in the ACE inhibitor aging literature arises between preclinical mechanistic plausibility and the paucity of direct human clinical trials with aging-specific functional endpoints. The preclinical evidence, exemplified by the study of chronic enalapril treatment in aging mice, suggests that ACE inhibition attenuates the development of frailty and differentially modulates pro- and anti-inflammatory cytokines (Keller 2019). This provides a compelling theoretical basis for a geroprotective mechanism involving the renin-angiotensin system. However, a starkly different picture emerges from the human clinical evidence. The ACE inhibitor aging corpus contains no identified randomized controlled trials designed with primary aging-specific endpoints such as frailty incidence, sarcopenia progression, or all-cause longevity (Zhang 2025). The available human RCTs, such as those examining ramipril's effect on cardiac function or amlodipine's comparative blood pressure efficacy, target cardiometabolic or organ-specific protection rather than global aging phenotypes (Meattini 2025; Zhang 2025). This creates a fundamental knowledge gap: the mechanistic pathway from murine frailty attenuation to human healthspan extension remains unproven. The boundary condition for applying the preclinical signal likely depends on the presence of an active renin-angiotensin system dysregulation in the aging human, a condition not universally tested. Resolving this tension requires human trials that translate the preclinical design, incorporating composite geriatric endpoints and long-term follow-up.

Another critical tension exists between the use of surrogate cardiometabolic biomarkers and hard clinical longevity outcomes. Several studies in the corpus examine ACE inhibitors' effects on intermediate endpoints like blood pressure control, vascular aging biomarkers, or cardiac function (Azizzadeh 2026; Meattini 2025). Yet, the evidence linking such surrogate improvements to mortality or longevity benefits is mixed and often null. Similarly, reviews note that while vascular aging metrics like pulse wave velocity are associated with outcomes, the specific mortality data for ACE inhibitors in advanced renal dysfunction or post-stroke populations remain unclear (Jin 2025; Murray-Thomas 2025). The mechanistic rationale is that improved cardiac and vascular function should translate to extended lifespan, but the human data do not consistently support this direct causal chain. The boundary condition may involve the degree of baseline cardiovascular risk or comorbidity burden, where cardioprotection is paramount. Evidence to resolve this would be large, long-duration RCTs powered for all-cause mortality and major aging-related composite endpoints, stratified by cardiovascular risk profile.

A third area of tension involves disagreements within human clinical evidence across different cardiometabolic and functional outcomes, highlighting context-dependent effects. The corpus reveals conflicting signals regarding ACE inhibitors' impact on gait speed and body weight, two key functional domains in aging. One observational study found that statin use was associated with a lower gait speed reserve, and noted complex interactions with concomitant medication use, though specific ACE inhibitor effects were not isolated as the primary analysis (Spiegeleer 2025). Conversely, another study emulating a target trial on antihypertensive medications and weight change reported unclear overall effects, with results varying by specific drug comparator (Lin 2026). This internal disagreement is compounded by trials showing negative effects in some populations: a randomized trial in Chinese and European hypertensive patients found that the ACE inhibitor ramipril was associated with a higher incidence of cough and treatment discontinuation compared to a calcium-channel blocker, indicating a safety and tolerability trade-off that could undermine long-term adherence essential for any geroprotective strategy (Zhang 2025). The boundary condition here may be patient-specific factors such as ethnicity, cough sensitivity, or concurrent conditions like sarcopenia or obesity. Resolving these discrepancies requires head-to-head trials of ACE inhibitors versus other antihypertensives with geriatric function (e.g., gait speed, grip strength) and patient-reported outcomes as co-primary endpoints.

Finally, a significant tension emerges between the potential immune-modulatory effects of ACE inhibitors and their uncertain impact on age-related immune decline and frailty. Preclinical research in hypertensive rats demonstrates that ACE inhibitor polytherapy can modulate key inflammatory cytokines like TNF-α and IL-6 (Diego 2024). In human observational data, food allergen sensitization is associated with an increased risk of early vascular aging, suggesting a plausible immune-vascular axis relevant to aging (Shen 2025). This points to a theoretical mechanism whereby ACE inhibitors could mitigate inflammaging. However, the human evidence for functional immune-related aging outcomes is sparse and indirect. Studies on ACE inhibitors and cognition, for example, show mixed results: one trial found candesartan improved cerebral microvascular function in mild cognitive impairment, while another comparing candesartan to lisinopril in older adults with MCI yielded mixed neurocognitive results without a clear, consistent benefit (Henley 2023; Hajjar 2020). The preclinical immune modulation does not yet have a confirmed clinical correlate in human aging syndromes like frailty or immunosenescence. The boundary condition likely involves the specific type of immune dysfunction and the baseline inflammatory status of the individual. Longitudinal human studies integrating immunophenotyping with clinical frailty assessments and ACE inhibitor use are needed to determine if the mechanistic promise translates into measurable benefit.

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.

Metabolic-Functional Tradeoff Framework

We operationalize a Metabolic-Functional Tradeoff 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, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains mechanism-vs-clinical, 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 47 included sources on ACE inhibitors aging across 9 outcome classes and 346 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 47 curated reference papers, the evidence base for ACE inhibitors aging shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: contextual other, cardiometabolic. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The ACE inhibitors aging anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The strongest unresolved contrast is the disagreement between Henley 2023 and AmatSantos 2024 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Kakaletsis 2024, Secondary 2023) emphasize convergent signals on ACE inhibitors aging. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Outcome class	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	6	mixed, null, unclear	conflict-resolution gap
frailty	0	1	unclear	conflict-resolution gap
immune	0	2	null	conflict-resolution gap
muscle function	0	1	null	direct clinical gap
cardiometabolic	1	4	mixed, negative, null, unclear	conflict-resolution gap
safety and comorbidity	0	4	null, unclear	direct clinical gap
immune and inflammation	0	1	unclear	direct clinical gap
mortality and survival	0	1	unclear	direct clinical gap
contextual adjacent evidence	1	25	mixed, negative, null, positive, unclear	conflict-resolution gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 6 indirect sources; direction profile: mixed, null, unclear
P2	frailty: conflict-resolution gap	0 direct and 1 indirect source; direction profile: unclear
P3	immune: conflict-resolution gap	0 direct and 2 indirect sources; direction profile: null
P4	muscle function: direct clinical gap	0 direct and 1 indirect source; direction profile: null
P5	cardiometabolic: conflict-resolution gap	1 direct and 4 indirect sources; direction profile: mixed, negative, null, unclear

Next-Study Design Recommendation

The next high-yield study for ACE inhibitors aging should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction.

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
Lin 2026	Observational	B2	—	adults	cardiometabolic	unclear	indirect	—	P < 0.05	230
Din 2026	Observational	B2	—	adults	cardiometabolic	null	review	—	P < 0.05	198
Spiegeleer 2025	Observational	B2	—	older adults	cardiometabolic	mixed	indirect	—	P < 0.001	190
Shen 2025	Observational	B2	—	adults	immune	null	indirect	—	—	137
Bene 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	126
Meattini 2025	RCT (clinical)	A1	—	adults	contextual other	unclear	direct	—	P < 0.001	123
Mostaza 2022	Observational	B2	—	adults	safety comorbidity	null	indirect	—	P = 0.044	102
AmatSantos 2024	Observational	B2	—	adults	contextual other	positive	review	—	P = 0.040	85
Wang 2023	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	79
Yamal 2023	Observational	B2	—	adults	longevity	mixed	indirect	—	P ≤ .001	77
Rivera 2025	Observational	B2	—	adults	contextual other	positive	indirect	—	P < 0.001	77
Shaddy 2024	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.001	70
Marengo 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	70
Heffernan 2023	Observational	B2	—	adults	contextual other	unclear	indirect	—	P < 0.05	70
Sarfo 2024	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.009	66
Hajjar 2020	Observational	B2	—	older adults	contextual other	mixed	indirect	—	P = 0.005	66
Senanayake 2026	Observational	B2	—	adults	contextual other	null	indirect	—	—	64
Lee 2024	Observational	B2	—	adults	contextual other	null	indirect	—	P = 0.01	63
Diego 2024	Preclinical (animal/in vitro)	C1	—	adults	immune	null	mechanistic	—	P < 0.001	60
Rossios 2023	Observational	B2	—	older adults	muscle function	null	indirect	—	P = 0.003	49
Silva-Santos 2024	Observational	B2	—	adults	immune inflammation	unclear	indirect	—	P = 0.0041	49
Yang 2025	Observational	B2	—	adults	contextual other	unclear	indirect	—	P = 0.001	46
Johnson 2024	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	43
Henley 2023	Observational	B2	—	adults	contextual other	negative	indirect	—	P = 0.03	38
Shaddy 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.0001	37
Jin 2025	Observational	B2	—	adults	longevity	unclear	indirect	—	—	37
Murray-Thomas 2025	Observational	B2	—	adults	longevity	unclear	indirect	—	P < 0.001	35
Willette 2025	Observational	B2	—	adults	contextual other	unclear	indirect	—	P < 0.0001	34
Chimura 2025	Observational	B2	—	adults	contextual other	unclear	indirect	—	P < 0.001	34
Shaddy 2023	Observational	B2	—	adults	contextual other	null	indirect	—	—	30
Kilic 2026	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.05	29
Pepine 2026	Observational	B2	—	adults	contextual other	null	review	—	P < 0.0001	29
Alanis 2025	Preclinical (animal/in vitro)	C1	—	adults	contextual other	null	mechanistic	—	P = 0.762	27
Gross 2012	Observational	B2	—	adults	safety comorbidity	null	review	NCT01485978	—	25
Ishikawa 2025	Observational	B2	—	adults	mortality survival	unclear	indirect	—	—	24
Vicente-Gabriel 2024	Observational	B2	—	adults	contextual other	null	indirect	—	—	20
Lu 2025	Observational	B2	—	adults	contextual other	null	indirect	—	P < 0.001	14
Azizzadeh 2026	Observational	B2	—	adults	cardiometabolic	null	indirect	—	—	14
Sun 2016	Observational	B2	—	adults	safety comorbidity	unclear	indirect	—	—	11
Tanriover 2023	Observational	B2	—	adults	safety comorbidity	null	indirect	—	—	7
Carmo 2025	Observational	B2	—	—	contextual other	null	review	—	—	5
Kakaletsis 2024	Review / meta-analysis	B1	—	—	longevity	unclear	review	—	—	4
Li 2023	Observational	B2	—	adults	longevity	null	indirect	—	—	3
Secondary 2023	Review / meta-analysis	B1	—	adults	longevity	unclear	review	—	—	2
Zhang 2025	RCT (clinical)	A1	—	adults	cardiometabolic	negative	direct	—	P = 0.02	2
Keller 2019	Preclinical (animal/in vitro)	C1	—	frail / sarcopenic adults	frailty	unclear	mechanistic	—	—	1
Golder 2026	Observational	B2	—	adults	contextual other	null	indirect	—	—	1

Table 2: Per-Study Endpoint Evidence

Additional corpus sources included animal/preclinical evidence; | Endpoint | Study | p/CI | Direction | Directness | Tier | Interpretation | | --- | --- | --- | --- | --- | --- | --- | | cardiometabolic | Lin 2026 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | cardiometabolic | Lin 2026 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | cardiometabolic | Lin 2026 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | cardiometabolic | Lin 2026 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Din 2026 | P > 0.05 | null summary | review | B2 | reported statistic; source summary remains null | | cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Spiegeleer 2025 | P = 0.267 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | cardiometabolic | Spiegeleer 2025 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | cardiometabolic | Spiegeleer 2025 | P = 0.002 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | cardiometabolic | Spiegeleer 2025 | P = 0.002 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | cardiometabolic | Spiegeleer 2025 | P = 0.024 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | cardiometabolic | Spiegeleer 2025 | P = 0.034 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | immune | Shen 2025 | — | null | indirect | B2 | no significant effect on immune | | contextual other | Bene 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Bene 2025 | P = 0.002 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Bene 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Bene 2025 | P = 0.024 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Bene 2025 | P = 0.006 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Bene 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | contextual other | Meattini 2025 | P < 0.001 | unclear summary | direct | A1 | reported statistic; source summary remains unclear | | safety comorbidity | Mostaza 2022 | P = 0.054 | null summary | indirect | B2 | reported statistic; source summary remains null | | safety comorbidity | Mostaza 2022 | P = 0.206 | null summary | indirect | B2 | reported statistic; source summary remains null | | safety comorbidity | Mostaza 2022 | P = 0.168 | null summary | indirect | B2 | reported statistic; source summary remains null | | safety comorbidity | Mostaza 2022 | P = 0.044 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | AmatSantos 2024 | P = 0.776 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | AmatSantos 2024 | P = 0.619 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | AmatSantos 2024 | P = 0.040 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | AmatSantos 2024 | P = 0.776 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | AmatSantos 2024 | P = 0.619 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | AmatSantos 2024 | P = 0.040 | positive summary | review | B2 | reported statistic; source summary remains positive | | contextual other | Wang 2023 | P = 0.02 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2023 | P = 0.02 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2023 | P = 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2023 | P = 0.28 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Wang 2023 | P = 0.03 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Wang 2023 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | longevity | Yamal 2023 | P = 0.04 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | longevity | Yamal 2023 | P = 0.02 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | longevity | Yamal 2023 | P ≤ .001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | longevity | Yamal 2023 | P = 0.005 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | longevity | Yamal 2023 | P = 0.004 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | longevity | Yamal 2023 | P = 0.009 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Rivera 2025 | P = 0.007 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Rivera 2025 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Rivera 2025 | P = 0.011 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Rivera 2025 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Rivera 2025 | P < 0.05 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Rivera 2025 | P = 0.06 | positive summary | indirect | B2 | reported statistic; source summary remains positive | | contextual other | Shaddy 2024 | P = 0.42 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Shaddy 2024 | P = 0.54 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Shaddy 2024 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Shaddy 2024 | P = 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Shaddy 2024 | P = 0.32 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Shaddy 2024 | P = 0.50 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Marengo 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Heffernan 2023 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Heffernan 2023 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Heffernan 2023 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Heffernan 2023 | P > 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Sarfo 2024 | P = 0.009 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Sarfo 2024 | P = 0.012 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Sarfo 2024 | P = 0.049 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Sarfo 2024 | P = 0.42 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Sarfo 2024 | P = 0.013 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Sarfo 2024 | P = 0.029 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Hajjar 2020 | P = 0.06 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Hajjar 2020 | P = 0.07 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Hajjar 2020 | P = 0.20 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Hajjar 2020 | P = 0.52 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Hajjar 2020 | P = 0.005 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Hajjar 2020 | P = 0.008 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed | | contextual other | Senanayake 2026 | — | null | indirect | B2 | no significant effect on contextual other | | contextual other | Lee 2024 | P = 0.06 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lee 2024 | P = 0.26 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lee 2024 | P = 0.62 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lee 2024 | P = 0.59 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lee 2024 | P = 0.44 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Lee 2024 | P = 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P < 0.001 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P = 0.006 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P = 0.02 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P = 0.005 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P < 0.001 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | immune | Diego 2024 | P = 0.001 | significant statistic | mechanistic | C1 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.028 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.008 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.028 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.035 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.032 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | muscle function | Rossios 2023 | P = 0.003 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | immune inflammation | Silva-Santos 2024 | P = 0.0041 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Yang 2025 | P = 0.06 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Yang 2025 | P = 0.005 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Yang 2025 | P = 0.037 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Yang 2025 | P = 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Johnson 2024 | P = 0.70 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Johnson 2024 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Johnson 2024 | P = 0.71 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Johnson 2024 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Henley 2023 | P = 0.044 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Henley 2023 | P = 0.087 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Henley 2023 | P = 0.47 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Henley 2023 | P = 0.48 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Henley 2023 | P = 0.54 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Henley 2023 | P = 0.03 | negative summary | indirect | B2 | reported statistic; source summary remains negative | | contextual other | Shaddy 2025 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Shaddy 2025 | P = 0.0004 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | longevity | Jin 2025 | — | unclear | indirect | B2 | unclear effect on longevity | | longevity | Murray-Thomas 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | longevity | Murray-Thomas 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P = 0.0039 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P = 0.0245 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P = 0.0245 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P < 0.0001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P = 0.8242 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Willette 2025 | P < 0.0001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Chimura 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Chimura 2025 | P = 0.36 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Chimura 2025 | P = 0.004 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Chimura 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear | | contextual other | Shaddy 2023 | — | null | indirect | B2 | no significant effect on contextual other | | contextual other | Kilic 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Kilic 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Kilic 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Kilic 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Kilic 2026 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null | | contextual other | Pepine 2026 | P = 0.20 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Pepine 2026 | P = 0.20 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Pepine 2026 | P = 0.92 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Pepine 2026 | P < 0.0001 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | contextual other | Pepine 2026 | P = 0.037 | significant statistic | review | B2 | significant statistic; source-level direction remains null | | contextual other | Pepine 2026 | P = 0.38 | null summary | review | B2 | reported statistic; source summary remains null | | contextual other | Alanis 2025 | P = 0.762 | null summary | mechanistic | C1 | reported statistic; source summary remains null | | safety comorbidity | Gross 2012 | — | null | review | B2 | no significant effect on safety comorbidity | | mortality survival | Ishikawa 2025 | — | unclear | indirect | B2 | unclear effect on mortality survival | | contextual other | Vicente-Gabriel 2024 | — | null | indirect | B2 | no significant effect on contextual other | | contextual other | Lu 2025 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lu 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lu 2025 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | contextual other | Lu 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null | | cardiometabolic | Azizzadeh 2026 | — | null | indirect | B2 | no significant effect on cardiometabolic | | safety comorbidity | Sun 2016 | — | unclear | indirect | B2 | unclear effect on safety comorbidity | | safety comorbidity | Tanriover 2023 | — | null | indirect | B2 | no significant effect on safety comorbidity | | contextual other | Carmo 2025 | — | null | review | B2 | no significant effect on contextual other | | longevity | Kakaletsis 2024 | — | unclear | review | B1 | unclear effect on longevity | | longevity | Li 2023 | — | null | indirect | B2 | no significant effect on longevity | | longevity | Secondary 2023 | — | unclear | review | B1 | unclear effect on longevity | | cardiometabolic | Zhang 2025 | P = 0.02 | negative summary | direct | A1 | reported statistic; source summary remains negative | | frailty | Keller 2019 | — | unclear | mechanistic | C1 | unclear effect on frailty | | contextual other | Golder 2026 | — | null | indirect | B2 | no significant effect on contextual other |

Table 3: Cross-Domain Tensions

Additional corpus sources included animal/preclinical evidence; | Tension kind | Severity | source A | source B | Outcome class | Summary | Practical implication | | --- | --- | --- | --- | --- | --- | --- | | mechanism vs clinical | 4 | Keller 2019 | Meattini 2025 | frailty | Keller 2019 (frailty, mechanistic) vs Meattini 2025 (contextual other, direct) | mechanism vs clinical (load-bearing) | | mechanism vs clinical | 4 | Keller 2019 | Zhang 2025 | frailty | Keller 2019 (frailty, mechanistic) vs Zhang 2025 (cardiometabolic, direct) | mechanism vs clinical (load-bearing) | | null vs positive | 3 | Secondary 2023 | Li 2023 | longevity | Secondary 2023 (unclear) vs Li 2023 (null) on longevity | null vs positive (notable) | | disagreement | 4 | Secondary 2023 | Yamal 2023 | longevity | Secondary 2023 (unclear) vs Yamal 2023 (mixed) on longevity | disagreement (load-bearing) | | agreement | 1 | Secondary 2023 | Jin 2025 | longevity | Secondary 2023 (unclear) vs Jin 2025 (unclear) on longevity | agreement (minor) | | agreement | 1 | Secondary 2023 | Murray-Thomas 2025 | longevity | Secondary 2023 (unclear) vs Murray-Thomas 2025 (unclear) on longevity | agreement (minor) | | agreement | 1 | Secondary 2023 | Kakaletsis 2024 | longevity | Secondary 2023 (unclear) vs Kakaletsis 2024 (unclear) on longevity | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | Henley 2023 | contextual other | Shaddy 2023 (null) vs Henley 2023 (negative) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Wang 2023 | contextual other | Shaddy 2023 (null) vs Wang 2023 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Vicente-Gabriel 2024 | contextual other | Shaddy 2023 (null) vs Vicente-Gabriel 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Lee 2024 | contextual other | Shaddy 2023 (null) vs Lee 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Johnson 2024 | contextual other | Shaddy 2023 (null) vs Johnson 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Shaddy 2024 | contextual other | Shaddy 2023 (null) vs Shaddy 2024 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | AmatSantos 2024 | contextual other | Shaddy 2023 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Shaddy 2023 | Willette 2025 | contextual other | Shaddy 2023 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Sarfo 2024 | contextual other | Shaddy 2023 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Alanis 2025 | contextual other | Shaddy 2023 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | Meattini 2025 | contextual other | Shaddy 2023 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Shaddy 2025 | contextual other | Shaddy 2023 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | Chimura 2025 | contextual other | Shaddy 2023 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Bene 2025 | contextual other | Shaddy 2023 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | Rivera 2025 | contextual other | Shaddy 2023 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Marengo 2025 | contextual other | Shaddy 2023 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2023 | Yang 2025 | contextual other | Shaddy 2023 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2023 | Lu 2025 | contextual other | Shaddy 2023 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Carmo 2025 | contextual other | Shaddy 2023 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Senanayake 2026 | contextual other | Shaddy 2023 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Kilic 2026 | contextual other | Shaddy 2023 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Pepine 2026 | contextual other | Shaddy 2023 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2023 | Golder 2026 | contextual other | Shaddy 2023 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Shaddy 2023 | Hajjar 2020 | contextual other | Shaddy 2023 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Shaddy 2023 | Heffernan 2023 | contextual other | Shaddy 2023 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Wang 2023 | contextual other | Henley 2023 (negative) vs Wang 2023 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Vicente-Gabriel 2024 | contextual other | Henley 2023 (negative) vs Vicente-Gabriel 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Lee 2024 | contextual other | Henley 2023 (negative) vs Lee 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Johnson 2024 | contextual other | Henley 2023 (negative) vs Johnson 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Shaddy 2024 | contextual other | Henley 2023 (negative) vs Shaddy 2024 (null) on contextual other | null vs positive (notable) | | disagreement | 5 | Henley 2023 | AmatSantos 2024 | contextual other | Henley 2023 (negative) vs AmatSantos 2024 (positive) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Henley 2023 | Sarfo 2024 | contextual other | Henley 2023 (negative) vs Sarfo 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Alanis 2025 | contextual other | Henley 2023 (negative) vs Alanis 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Shaddy 2025 | contextual other | Henley 2023 (negative) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Bene 2025 | contextual other | Henley 2023 (negative) vs Bene 2025 (null) on contextual other | null vs positive (notable) | | disagreement | 5 | Henley 2023 | Rivera 2025 | contextual other | Henley 2023 (negative) vs Rivera 2025 (positive) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Henley 2023 | Marengo 2025 | contextual other | Henley 2023 (negative) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Lu 2025 | contextual other | Henley 2023 (negative) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Carmo 2025 | contextual other | Henley 2023 (negative) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Senanayake 2026 | contextual other | Henley 2023 (negative) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Kilic 2026 | contextual other | Henley 2023 (negative) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Pepine 2026 | contextual other | Henley 2023 (negative) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Henley 2023 | Golder 2026 | contextual other | Henley 2023 (negative) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Henley 2023 | Hajjar 2020 | contextual other | Henley 2023 (negative) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | disagreement | 4 | Li 2023 | Yamal 2023 | longevity | Li 2023 (null) vs Yamal 2023 (mixed) on longevity | disagreement (load-bearing) | | null vs positive | 3 | Li 2023 | Jin 2025 | longevity | Li 2023 (null) vs Jin 2025 (unclear) on longevity | null vs positive (notable) | | null vs positive | 3 | Li 2023 | Murray-Thomas 2025 | longevity | Li 2023 (null) vs Murray-Thomas 2025 (unclear) on longevity | null vs positive (notable) | | null vs positive | 3 | Li 2023 | Kakaletsis 2024 | longevity | Li 2023 (null) vs Kakaletsis 2024 (unclear) on longevity | null vs positive (notable) | | agreement | 1 | Wang 2023 | Vicente-Gabriel 2024 | contextual other | Wang 2023 (null) vs Vicente-Gabriel 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Lee 2024 | contextual other | Wang 2023 (null) vs Lee 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Johnson 2024 | contextual other | Wang 2023 (null) vs Johnson 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Shaddy 2024 | contextual other | Wang 2023 (null) vs Shaddy 2024 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Wang 2023 | AmatSantos 2024 | contextual other | Wang 2023 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Wang 2023 | Willette 2025 | contextual other | Wang 2023 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Wang 2023 | Sarfo 2024 | contextual other | Wang 2023 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Alanis 2025 | contextual other | Wang 2023 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Wang 2023 | Meattini 2025 | contextual other | Wang 2023 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Wang 2023 | Shaddy 2025 | contextual other | Wang 2023 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Wang 2023 | Chimura 2025 | contextual other | Wang 2023 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Wang 2023 | Bene 2025 | contextual other | Wang 2023 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Wang 2023 | Rivera 2025 | contextual other | Wang 2023 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Wang 2023 | Marengo 2025 | contextual other | Wang 2023 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Wang 2023 | Yang 2025 | contextual other | Wang 2023 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Wang 2023 | Lu 2025 | contextual other | Wang 2023 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Carmo 2025 | contextual other | Wang 2023 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Senanayake 2026 | contextual other | Wang 2023 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Kilic 2026 | contextual other | Wang 2023 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Pepine 2026 | contextual other | Wang 2023 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Wang 2023 | Golder 2026 | contextual other | Wang 2023 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Wang 2023 | Hajjar 2020 | contextual other | Wang 2023 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Wang 2023 | Heffernan 2023 | contextual other | Wang 2023 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Tanriover 2023 | Gross 2012 | safety comorbidity | Tanriover 2023 (null) vs Gross 2012 (null) on safety comorbidity | agreement (minor) | | null vs positive | 3 | Tanriover 2023 | Sun 2016 | safety comorbidity | Tanriover 2023 (null) vs Sun 2016 (unclear) on safety comorbidity | null vs positive (notable) | | agreement | 1 | Tanriover 2023 | Mostaza 2022 | safety comorbidity | Tanriover 2023 (null) vs Mostaza 2022 (null) on safety comorbidity | agreement (minor) | | disagreement | 4 | Yamal 2023 | Jin 2025 | longevity | Yamal 2023 (mixed) vs Jin 2025 (unclear) on longevity | disagreement (load-bearing) | | disagreement | 4 | Yamal 2023 | Murray-Thomas 2025 | longevity | Yamal 2023 (mixed) vs Murray-Thomas 2025 (unclear) on longevity | disagreement (load-bearing) | | disagreement | 4 | Yamal 2023 | Kakaletsis 2024 | longevity | Yamal 2023 (mixed) vs Kakaletsis 2024 (unclear) on longevity | disagreement (load-bearing) | | agreement | 1 | Vicente-Gabriel 2024 | Lee 2024 | contextual other | Vicente-Gabriel 2024 (null) vs Lee 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Johnson 2024 | contextual other | Vicente-Gabriel 2024 (null) vs Johnson 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Shaddy 2024 | contextual other | Vicente-Gabriel 2024 (null) vs Shaddy 2024 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Vicente-Gabriel 2024 | AmatSantos 2024 | contextual other | Vicente-Gabriel 2024 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Vicente-Gabriel 2024 | Willette 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Vicente-Gabriel 2024 | Sarfo 2024 | contextual other | Vicente-Gabriel 2024 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Alanis 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Vicente-Gabriel 2024 | Meattini 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Vicente-Gabriel 2024 | Shaddy 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Vicente-Gabriel 2024 | Chimura 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Vicente-Gabriel 2024 | Bene 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Vicente-Gabriel 2024 | Rivera 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Vicente-Gabriel 2024 | Marengo 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Vicente-Gabriel 2024 | Yang 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Vicente-Gabriel 2024 | Lu 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Carmo 2025 | contextual other | Vicente-Gabriel 2024 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Senanayake 2026 | contextual other | Vicente-Gabriel 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Kilic 2026 | contextual other | Vicente-Gabriel 2024 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Pepine 2026 | contextual other | Vicente-Gabriel 2024 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Vicente-Gabriel 2024 | Golder 2026 | contextual other | Vicente-Gabriel 2024 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Vicente-Gabriel 2024 | Hajjar 2020 | contextual other | Vicente-Gabriel 2024 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Vicente-Gabriel 2024 | Heffernan 2023 | contextual other | Vicente-Gabriel 2024 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Johnson 2024 | contextual other | Lee 2024 (null) vs Johnson 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Shaddy 2024 | contextual other | Lee 2024 (null) vs Shaddy 2024 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Lee 2024 | AmatSantos 2024 | contextual other | Lee 2024 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Lee 2024 | Willette 2025 | contextual other | Lee 2024 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Sarfo 2024 | contextual other | Lee 2024 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Alanis 2025 | contextual other | Lee 2024 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Lee 2024 | Meattini 2025 | contextual other | Lee 2024 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Shaddy 2025 | contextual other | Lee 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Lee 2024 | Chimura 2025 | contextual other | Lee 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Bene 2025 | contextual other | Lee 2024 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Lee 2024 | Rivera 2025 | contextual other | Lee 2024 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Marengo 2025 | contextual other | Lee 2024 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Lee 2024 | Yang 2025 | contextual other | Lee 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Lee 2024 | Lu 2025 | contextual other | Lee 2024 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Carmo 2025 | contextual other | Lee 2024 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Senanayake 2026 | contextual other | Lee 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Kilic 2026 | contextual other | Lee 2024 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Pepine 2026 | contextual other | Lee 2024 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lee 2024 | Golder 2026 | contextual other | Lee 2024 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Lee 2024 | Hajjar 2020 | contextual other | Lee 2024 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Lee 2024 | Heffernan 2023 | contextual other | Lee 2024 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Diego 2024 | Shen 2025 | immune | Diego 2024 (null) vs Shen 2025 (null) on immune | agreement (minor) | | mechanism vs clinical | 4 | Diego 2024 | Meattini 2025 | immune | Diego 2024 (immune, mechanistic) vs Meattini 2025 (contextual other, direct) | mechanism vs clinical (load-bearing) | | mechanism vs clinical | 4 | Diego 2024 | Zhang 2025 | immune | Diego 2024 (immune, mechanistic) vs Zhang 2025 (cardiometabolic, direct) | mechanism vs clinical (load-bearing) | | agreement | 1 | Johnson 2024 | Shaddy 2024 | contextual other | Johnson 2024 (null) vs Shaddy 2024 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Johnson 2024 | AmatSantos 2024 | contextual other | Johnson 2024 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Johnson 2024 | Willette 2025 | contextual other | Johnson 2024 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Johnson 2024 | Sarfo 2024 | contextual other | Johnson 2024 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Alanis 2025 | contextual other | Johnson 2024 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Johnson 2024 | Meattini 2025 | contextual other | Johnson 2024 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Johnson 2024 | Shaddy 2025 | contextual other | Johnson 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Johnson 2024 | Chimura 2025 | contextual other | Johnson 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Johnson 2024 | Bene 2025 | contextual other | Johnson 2024 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Johnson 2024 | Rivera 2025 | contextual other | Johnson 2024 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Johnson 2024 | Marengo 2025 | contextual other | Johnson 2024 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Johnson 2024 | Yang 2025 | contextual other | Johnson 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Johnson 2024 | Lu 2025 | contextual other | Johnson 2024 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Carmo 2025 | contextual other | Johnson 2024 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Senanayake 2026 | contextual other | Johnson 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Kilic 2026 | contextual other | Johnson 2024 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Pepine 2026 | contextual other | Johnson 2024 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Johnson 2024 | Golder 2026 | contextual other | Johnson 2024 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Johnson 2024 | Hajjar 2020 | contextual other | Johnson 2024 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Johnson 2024 | Heffernan 2023 | contextual other | Johnson 2024 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Shaddy 2024 | AmatSantos 2024 | contextual other | Shaddy 2024 (null) vs AmatSantos 2024 (positive) on contextual other | null vs positive (notable) | | null vs positive | 3 | Shaddy 2024 | Willette 2025 | contextual other | Shaddy 2024 (null) vs Willette 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2024 | Sarfo 2024 | contextual other | Shaddy 2024 (null) vs Sarfo 2024 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Alanis 2025 | contextual other | Shaddy 2024 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2024 | Meattini 2025 | contextual other | Shaddy 2024 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2024 | Shaddy 2025 | contextual other | Shaddy 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2024 | Chimura 2025 | contextual other | Shaddy 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2024 | Bene 2025 | contextual other | Shaddy 2024 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2024 | Rivera 2025 | contextual other | Shaddy 2024 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2024 | Marengo 2025 | contextual other | Shaddy 2024 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2024 | Yang 2025 | contextual other | Shaddy 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2024 | Lu 2025 | contextual other | Shaddy 2024 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Carmo 2025 | contextual other | Shaddy 2024 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Senanayake 2026 | contextual other | Shaddy 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Kilic 2026 | contextual other | Shaddy 2024 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Pepine 2026 | contextual other | Shaddy 2024 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2024 | Golder 2026 | contextual other | Shaddy 2024 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Shaddy 2024 | Hajjar 2020 | contextual other | Shaddy 2024 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Shaddy 2024 | Heffernan 2023 | contextual other | Shaddy 2024 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Sarfo 2024 | contextual other | AmatSantos 2024 (positive) vs Sarfo 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Alanis 2025 | contextual other | AmatSantos 2024 (positive) vs Alanis 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Shaddy 2025 | contextual other | AmatSantos 2024 (positive) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Bene 2025 | contextual other | AmatSantos 2024 (positive) vs Bene 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | AmatSantos 2024 | Rivera 2025 | contextual other | AmatSantos 2024 (positive) vs Rivera 2025 (positive) on contextual other | agreement (minor) | | null vs positive | 3 | AmatSantos 2024 | Marengo 2025 | contextual other | AmatSantos 2024 (positive) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Lu 2025 | contextual other | AmatSantos 2024 (positive) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Carmo 2025 | contextual other | AmatSantos 2024 (positive) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Senanayake 2026 | contextual other | AmatSantos 2024 (positive) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Kilic 2026 | contextual other | AmatSantos 2024 (positive) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Pepine 2026 | contextual other | AmatSantos 2024 (positive) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | AmatSantos 2024 | Golder 2026 | contextual other | AmatSantos 2024 (positive) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | AmatSantos 2024 | Hajjar 2020 | contextual other | AmatSantos 2024 (positive) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Willette 2025 | Sarfo 2024 | contextual other | Willette 2025 (unclear) vs Sarfo 2024 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Alanis 2025 | contextual other | Willette 2025 (unclear) vs Alanis 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Willette 2025 | Meattini 2025 | contextual other | Willette 2025 (unclear) vs Meattini 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Willette 2025 | Shaddy 2025 | contextual other | Willette 2025 (unclear) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Willette 2025 | Chimura 2025 | contextual other | Willette 2025 (unclear) vs Chimura 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Willette 2025 | Bene 2025 | contextual other | Willette 2025 (unclear) vs Bene 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Marengo 2025 | contextual other | Willette 2025 (unclear) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Willette 2025 | Yang 2025 | contextual other | Willette 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Willette 2025 | Lu 2025 | contextual other | Willette 2025 (unclear) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Carmo 2025 | contextual other | Willette 2025 (unclear) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Senanayake 2026 | contextual other | Willette 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Kilic 2026 | contextual other | Willette 2025 (unclear) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Pepine 2026 | contextual other | Willette 2025 (unclear) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Willette 2025 | Golder 2026 | contextual other | Willette 2025 (unclear) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Willette 2025 | Hajjar 2020 | contextual other | Willette 2025 (unclear) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | agreement | 1 | Willette 2025 | Heffernan 2023 | contextual other | Willette 2025 (unclear) vs Heffernan 2023 (unclear) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Alanis 2025 | contextual other | Sarfo 2024 (null) vs Alanis 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Sarfo 2024 | Meattini 2025 | contextual other | Sarfo 2024 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Sarfo 2024 | Shaddy 2025 | contextual other | Sarfo 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Sarfo 2024 | Chimura 2025 | contextual other | Sarfo 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Sarfo 2024 | Bene 2025 | contextual other | Sarfo 2024 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Sarfo 2024 | Rivera 2025 | contextual other | Sarfo 2024 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Sarfo 2024 | Marengo 2025 | contextual other | Sarfo 2024 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Sarfo 2024 | Yang 2025 | contextual other | Sarfo 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Sarfo 2024 | Lu 2025 | contextual other | Sarfo 2024 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Carmo 2025 | contextual other | Sarfo 2024 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Senanayake 2026 | contextual other | Sarfo 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Kilic 2026 | contextual other | Sarfo 2024 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Pepine 2026 | contextual other | Sarfo 2024 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Sarfo 2024 | Golder 2026 | contextual other | Sarfo 2024 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Sarfo 2024 | Hajjar 2020 | contextual other | Sarfo 2024 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Sarfo 2024 | Heffernan 2023 | contextual other | Sarfo 2024 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Alanis 2025 | Meattini 2025 | contextual other | Alanis 2025 (null) vs Meattini 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Alanis 2025 | Shaddy 2025 | contextual other | Alanis 2025 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Alanis 2025 | Chimura 2025 | contextual other | Alanis 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Alanis 2025 | Bene 2025 | contextual other | Alanis 2025 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Alanis 2025 | Rivera 2025 | contextual other | Alanis 2025 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Alanis 2025 | Marengo 2025 | contextual other | Alanis 2025 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Alanis 2025 | Yang 2025 | contextual other | Alanis 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Alanis 2025 | Lu 2025 | contextual other | Alanis 2025 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Alanis 2025 | Carmo 2025 | contextual other | Alanis 2025 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Alanis 2025 | Senanayake 2026 | contextual other | Alanis 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Alanis 2025 | Kilic 2026 | contextual other | Alanis 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Alanis 2025 | Pepine 2026 | contextual other | Alanis 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Alanis 2025 | Golder 2026 | contextual other | Alanis 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Alanis 2025 | Hajjar 2020 | contextual other | Alanis 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Alanis 2025 | Heffernan 2023 | contextual other | Alanis 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | mechanism vs clinical | 4 | Alanis 2025 | Zhang 2025 | contextual other | Alanis 2025 (contextual other, mechanistic) vs Zhang 2025 (cardiometabolic, direct) | mechanism vs clinical (load-bearing) | | null vs positive | 3 | Meattini 2025 | Shaddy 2025 | contextual other | Meattini 2025 (unclear) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Meattini 2025 | Chimura 2025 | contextual other | Meattini 2025 (unclear) vs Chimura 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Meattini 2025 | Bene 2025 | contextual other | Meattini 2025 (unclear) vs Bene 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Marengo 2025 | contextual other | Meattini 2025 (unclear) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Meattini 2025 | Yang 2025 | contextual other | Meattini 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Meattini 2025 | Lu 2025 | contextual other | Meattini 2025 (unclear) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Carmo 2025 | contextual other | Meattini 2025 (unclear) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Senanayake 2026 | contextual other | Meattini 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Kilic 2026 | contextual other | Meattini 2025 (unclear) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Pepine 2026 | contextual other | Meattini 2025 (unclear) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Meattini 2025 | Golder 2026 | contextual other | Meattini 2025 (unclear) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Meattini 2025 | Hajjar 2020 | contextual other | Meattini 2025 (unclear) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | agreement | 1 | Meattini 2025 | Heffernan 2023 | contextual other | Meattini 2025 (unclear) vs Heffernan 2023 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2025 | Chimura 2025 | contextual other | Shaddy 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2025 | Bene 2025 | contextual other | Shaddy 2025 (null) vs Bene 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2025 | Rivera 2025 | contextual other | Shaddy 2025 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2025 | Marengo 2025 | contextual other | Shaddy 2025 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Shaddy 2025 | Yang 2025 | contextual other | Shaddy 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Shaddy 2025 | Lu 2025 | contextual other | Shaddy 2025 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2025 | Carmo 2025 | contextual other | Shaddy 2025 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2025 | Senanayake 2026 | contextual other | Shaddy 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2025 | Kilic 2026 | contextual other | Shaddy 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2025 | Pepine 2026 | contextual other | Shaddy 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Shaddy 2025 | Golder 2026 | contextual other | Shaddy 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Shaddy 2025 | Hajjar 2020 | contextual other | Shaddy 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Shaddy 2025 | Heffernan 2023 | contextual other | Shaddy 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Bene 2025 | contextual other | Chimura 2025 (unclear) vs Bene 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Marengo 2025 | contextual other | Chimura 2025 (unclear) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | agreement | 1 | Chimura 2025 | Yang 2025 | contextual other | Chimura 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) | | null vs positive | 3 | Chimura 2025 | Lu 2025 | contextual other | Chimura 2025 (unclear) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Carmo 2025 | contextual other | Chimura 2025 (unclear) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Senanayake 2026 | contextual other | Chimura 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Kilic 2026 | contextual other | Chimura 2025 (unclear) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Pepine 2026 | contextual other | Chimura 2025 (unclear) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Chimura 2025 | Golder 2026 | contextual other | Chimura 2025 (unclear) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Chimura 2025 | Hajjar 2020 | contextual other | Chimura 2025 (unclear) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | agreement | 1 | Chimura 2025 | Heffernan 2023 | contextual other | Chimura 2025 (unclear) vs Heffernan 2023 (unclear) on contextual other | agreement (minor) | | agreement | 1 | Jin 2025 | Murray-Thomas 2025 | longevity | Jin 2025 (unclear) vs Murray-Thomas 2025 (unclear) on longevity | agreement (minor) | | agreement | 1 | Jin 2025 | Kakaletsis 2024 | longevity | Jin 2025 (unclear) vs Kakaletsis 2024 (unclear) on longevity | agreement (minor) | | null vs positive | 3 | Bene 2025 | Rivera 2025 | contextual other | Bene 2025 (null) vs Rivera 2025 (positive) on contextual other | null vs positive (notable) | | agreement | 1 | Bene 2025 | Marengo 2025 | contextual other | Bene 2025 (null) vs Marengo 2025 (null) on contextual other | agreement (minor) | | null vs positive | 3 | Bene 2025 | Yang 2025 | contextual other | Bene 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Bene 2025 | Lu 2025 | contextual other | Bene 2025 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Bene 2025 | Carmo 2025 | contextual other | Bene 2025 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Bene 2025 | Senanayake 2026 | contextual other | Bene 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Bene 2025 | Kilic 2026 | contextual other | Bene 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Bene 2025 | Pepine 2026 | contextual other | Bene 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Bene 2025 | Golder 2026 | contextual other | Bene 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Bene 2025 | Hajjar 2020 | contextual other | Bene 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Bene 2025 | Heffernan 2023 | contextual other | Bene 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Murray-Thomas 2025 | Kakaletsis 2024 | longevity | Murray-Thomas 2025 (unclear) vs Kakaletsis 2024 (unclear) on longevity | agreement (minor) | | null vs positive | 3 | Rivera 2025 | Marengo 2025 | contextual other | Rivera 2025 (positive) vs Marengo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Lu 2025 | contextual other | Rivera 2025 (positive) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Carmo 2025 | contextual other | Rivera 2025 (positive) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Senanayake 2026 | contextual other | Rivera 2025 (positive) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Kilic 2026 | contextual other | Rivera 2025 (positive) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Pepine 2026 | contextual other | Rivera 2025 (positive) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Rivera 2025 | Golder 2026 | contextual other | Rivera 2025 (positive) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Rivera 2025 | Hajjar 2020 | contextual other | Rivera 2025 (positive) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Marengo 2025 | Yang 2025 | contextual other | Marengo 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Marengo 2025 | Lu 2025 | contextual other | Marengo 2025 (null) vs Lu 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Marengo 2025 | Carmo 2025 | contextual other | Marengo 2025 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Marengo 2025 | Senanayake 2026 | contextual other | Marengo 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Marengo 2025 | Kilic 2026 | contextual other | Marengo 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Marengo 2025 | Pepine 2026 | contextual other | Marengo 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Marengo 2025 | Golder 2026 | contextual other | Marengo 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Marengo 2025 | Hajjar 2020 | contextual other | Marengo 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Marengo 2025 | Heffernan 2023 | contextual other | Marengo 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Lu 2025 | contextual other | Yang 2025 (unclear) vs Lu 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Carmo 2025 | contextual other | Yang 2025 (unclear) vs Carmo 2025 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Senanayake 2026 | contextual other | Yang 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Kilic 2026 | contextual other | Yang 2025 (unclear) vs Kilic 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Pepine 2026 | contextual other | Yang 2025 (unclear) vs Pepine 2026 (null) on contextual other | null vs positive (notable) | | null vs positive | 3 | Yang 2025 | Golder 2026 | contextual other | Yang 2025 (unclear) vs Golder 2026 (null) on contextual other | null vs positive (notable) | | disagreement | 4 | Yang 2025 | Hajjar 2020 | contextual other | Yang 2025 (unclear) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | agreement | 1 | Yang 2025 | Heffernan 2023 | contextual other | Yang 2025 (unclear) vs Heffernan 2023 (unclear) on contextual other | agreement (minor) | | agreement | 1 | Lu 2025 | Carmo 2025 | contextual other | Lu 2025 (null) vs Carmo 2025 (null) on contextual other | agreement (minor) | | agreement | 1 | Lu 2025 | Senanayake 2026 | contextual other | Lu 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lu 2025 | Kilic 2026 | contextual other | Lu 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lu 2025 | Pepine 2026 | contextual other | Lu 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Lu 2025 | Golder 2026 | contextual other | Lu 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Lu 2025 | Hajjar 2020 | contextual other | Lu 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Lu 2025 | Heffernan 2023 | contextual other | Lu 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Carmo 2025 | Senanayake 2026 | contextual other | Carmo 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Carmo 2025 | Kilic 2026 | contextual other | Carmo 2025 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Carmo 2025 | Pepine 2026 | contextual other | Carmo 2025 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Carmo 2025 | Golder 2026 | contextual other | Carmo 2025 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Carmo 2025 | Hajjar 2020 | contextual other | Carmo 2025 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Carmo 2025 | Heffernan 2023 | contextual other | Carmo 2025 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | disagreement | 4 | Azizzadeh 2026 | Spiegeleer 2025 | cardiometabolic | Azizzadeh 2026 (null) vs Spiegeleer 2025 (mixed) on cardiometabolic | disagreement (load-bearing) | | agreement | 1 | Azizzadeh 2026 | Din 2026 | cardiometabolic | Azizzadeh 2026 (null) vs Din 2026 (null) on cardiometabolic | agreement (minor) | | null vs positive | 3 | Azizzadeh 2026 | Lin 2026 | cardiometabolic | Azizzadeh 2026 (null) vs Lin 2026 (unclear) on cardiometabolic | null vs positive (notable) | | null vs positive | 3 | Azizzadeh 2026 | Zhang 2025 | cardiometabolic | Azizzadeh 2026 (null) vs Zhang 2025 (negative) on cardiometabolic | null vs positive (notable) | | disagreement | 4 | Spiegeleer 2025 | Din 2026 | cardiometabolic | Spiegeleer 2025 (mixed) vs Din 2026 (null) on cardiometabolic | disagreement (load-bearing) | | disagreement | 4 | Spiegeleer 2025 | Lin 2026 | cardiometabolic | Spiegeleer 2025 (mixed) vs Lin 2026 (unclear) on cardiometabolic | disagreement (load-bearing) | | disagreement | 4 | Spiegeleer 2025 | Zhang 2025 | cardiometabolic | Spiegeleer 2025 (mixed) vs Zhang 2025 (negative) on cardiometabolic | disagreement (load-bearing) | | agreement | 1 | Senanayake 2026 | Kilic 2026 | contextual other | Senanayake 2026 (null) vs Kilic 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Senanayake 2026 | Pepine 2026 | contextual other | Senanayake 2026 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Senanayake 2026 | Golder 2026 | contextual other | Senanayake 2026 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Senanayake 2026 | Hajjar 2020 | contextual other | Senanayake 2026 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Senanayake 2026 | Heffernan 2023 | contextual other | Senanayake 2026 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Din 2026 | Lin 2026 | cardiometabolic | Din 2026 (null) vs Lin 2026 (unclear) on cardiometabolic | null vs positive (notable) | | null vs positive | 3 | Din 2026 | Zhang 2025 | cardiometabolic | Din 2026 (null) vs Zhang 2025 (negative) on cardiometabolic | null vs positive (notable) | | agreement | 1 | Kilic 2026 | Pepine 2026 | contextual other | Kilic 2026 (null) vs Pepine 2026 (null) on contextual other | agreement (minor) | | agreement | 1 | Kilic 2026 | Golder 2026 | contextual other | Kilic 2026 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Kilic 2026 | Hajjar 2020 | contextual other | Kilic 2026 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Kilic 2026 | Heffernan 2023 | contextual other | Kilic 2026 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | agreement | 1 | Pepine 2026 | Golder 2026 | contextual other | Pepine 2026 (null) vs Golder 2026 (null) on contextual other | agreement (minor) | | disagreement | 4 | Pepine 2026 | Hajjar 2020 | contextual other | Pepine 2026 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Pepine 2026 | Heffernan 2023 | contextual other | Pepine 2026 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | disagreement | 4 | Golder 2026 | Hajjar 2020 | contextual other | Golder 2026 (null) vs Hajjar 2020 (mixed) on contextual other | disagreement (load-bearing) | | null vs positive | 3 | Golder 2026 | Heffernan 2023 | contextual other | Golder 2026 (null) vs Heffernan 2023 (unclear) on contextual other | null vs positive (notable) | | null vs positive | 3 | Gross 2012 | Sun 2016 | safety comorbidity | Gross 2012 (null) vs Sun 2016 (unclear) on safety comorbidity | null vs positive (notable) | | agreement | 1 | Gross 2012 | Mostaza 2022 | safety comorbidity | Gross 2012 (null) vs Mostaza 2022 (null) on safety comorbidity | agreement (minor) | | null vs positive | 3 | Sun 2016 | Mostaza 2022 | safety comorbidity | Sun 2016 (unclear) vs Mostaza 2022 (null) on safety comorbidity | null vs positive (notable) | | disagreement | 4 | Hajjar 2020 | Heffernan 2023 | contextual other | Hajjar 2020 (mixed) vs Heffernan 2023 (unclear) on contextual other | 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
Lin 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Din 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Spiegeleer 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Shen 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Bene 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Meattini 2025	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	signed claims without significance signal
Mostaza 2022	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
AmatSantos 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Wang 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Yamal 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Rivera 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	positive effect — see Tables 1/2
Shaddy 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Marengo 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Heffernan 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Sarfo 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Hajjar 2020	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	internal contradiction across endpoints
Senanayake 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Lee 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Diego 2024	C1	SYRCLE (animal)	low	n/a	low	moderate	moderate	n/a	high	low	hypothesis-generating (preclinical mechanism)	primary endpoint did not reach significance
Rossios 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Silva-Santos 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Yang 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Johnson 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Henley 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	negative effect — see Tables 1/2
Shaddy 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Jin 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Murray-Thomas 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Willette 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Chimura 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Shaddy 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Kilic 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Pepine 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Alanis 2025	C1	SYRCLE (animal)	low	n/a	low	moderate	moderate	n/a	high	low	hypothesis-generating (preclinical mechanism)	primary endpoint did not reach significance
Gross 2012	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Ishikawa 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Vicente-Gabriel 2024	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Lu 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Azizzadeh 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Sun 2016	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	signed claims without significance signal
Tanriover 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Carmo 2025	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Kakaletsis 2024	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Li 2023	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance
Secondary 2023	B1	AMSTAR-2 (review)	unclear	unclear	unclear	unclear	moderate	moderate	moderate	unclear	supporting (synthesis evidence)	signed claims without significance signal
Zhang 2025	A1	Cochrane RoB-2	low	low	moderate	low	low	low	moderate	low	load-bearing (direct clinical RCT)	negative effect — see Tables 1/2
Keller 2019	C1	SYRCLE (animal)	low	n/a	low	moderate	moderate	n/a	high	low	hypothesis-generating (preclinical mechanism)	signed claims without significance signal
Golder 2026	B2	ROBINS-I	n/a	n/a	moderate	moderate	moderate	high	moderate	moderate	contextual (observational signal)	primary endpoint did not reach significance

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).

Additional corpus sources included animal/preclinical evidence; | Citation | Section | Type | Value | Units | | --- | --- | --- | --- | --- | | Lin 2026 | discussion | unit value | 12 weeks | weeks | | Lin 2026 | discussion | sample size | n = 77 | — | | Lin 2026 | discussion | unit value | 0.4 kg | kg | | Spiegeleer 2025 | discussion | p-value | P = 0.002 | — | | Spiegeleer 2025 | discussion | percentage | 37% | % | | Spiegeleer 2025 | discussion | odds ratio | OR = 0.63 | — | | Spiegeleer 2025 | discussion | percentage | 95% | % | | Spiegeleer 2025 | discussion | percentage | 95% | % | | Meattini 2025 | results | odds ratio | OR = 0.052 | — | | Meattini 2025 | results | confidence interval | 95% CI 0.017-0.155 | 95%CI | | Meattini 2025 | results | odds ratio | OR = 0.057 | — | | Meattini 2025 | results | confidence interval | 95% CI 0.021-0.159 | 95%CI | | Meattini 2025 | results | odds ratio | OR = 0.08 | — | | Yamal 2023 | discussion | unit value | 13 years | years | | Heffernan 2023 | abstract | unit value | 10m/s | m/s | | Heffernan 2023 | abstract | unit value | 10m/s | m/s | | Jin 2025 | results | risk ratio | RR: 0.62 | — | | Jin 2025 | results | confidence interval | 95% CI: 0.45 to 0.86 | 95%CI | | Willette 2025 | discussion | p-value | P > 0.05 | — | | Chimura 2025 | abstract | percentage | 95% | % | | Chimura 2025 | abstract | percentage | 95% | % | | Sun 2016 | results | percentage | 95% | % | | Kakaletsis 2024 | abstract | percentage | 46.2% | % | | Kakaletsis 2024 | abstract | percentage | 12.7% | % | | Kakaletsis 2024 | abstract | percentage | 13.9% | % | | Kakaletsis 2024 | abstract | percentage | 13.9% | % | | Secondary 2023 | abstract | unit value | 200 mg | mg | | Secondary 2023 | abstract | unit value | 10 mg | mg | | Zhang 2025 | abstract | p-value | P = 0.02 | — | | Zhang 2025 | abstract | unit value | 4.1 mmHg | mmHg | | Keller 2019 | abstract | unit value | 30 mg/kg/day | mg/kg/day |

References

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Spiegeleer 2025. The association between statins and gait speed reserve in older adults: effects of concomitant medication. GeroScience, 2025. DOI: 10.1007/s11357-025-01682-x. PMID: 40332452.
Shen 2025. Sensitization to common foods and early vascular aging: associations and the mitigating effects of health behaviors. BMC Public Health, 2025. DOI: 10.1186/s12889-025-21951-w. PMID: 39979927.
Bene 2025. Effect of Cardioprotection on the Right Ventricular Function in Breast Cancer Patients Receiving Potentially Cardiotoxic Therapy: A SAFE Trial Substudy. Echocardiography (Mount Kisco, N.y.), 2025. DOI: 10.1111/echo.70291. PMID: 40965835.
Meattini 2025. Cardioprotection in patients with anthracycline-treated breast cancer: final analysis from the 2 × 2 randomized, placebo-controlled, double-blind SAFE trial. ESMO Open, 2025. DOI: 10.1016/j.esmoop.2025.105116. PMID: 40403385.
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AmatSantos 2024. Ramipril After Transcatheter Aortic Valve Implantation in Patients Without Reduced Ejection Fraction: The RASTAVI Randomized Clinical Trial. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2024. DOI: 10.1161/JAHA.124.035460. PMID: 39291483.
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Yamal 2023. Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker. JAMA Network Open, 2023. DOI: 10.1001/jamanetworkopen.2023.44998. PMID: 38048133.
Rivera 2025. From bench to bedside: investigating SGLT2 inhibitors as a novel strategy against chemotherapy-induced cardiomyopathy. Frontiers in Cardiovascular Medicine, 2025. DOI: 10.3389/fcvm.2025.1647747. PMID: 41059442.
Shaddy 2024. Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial. Circulation, 2024. DOI: 10.1161/CIRCULATIONAHA.123.066605. PMID: 39319469.
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Heffernan 2023. Estimated pulse wave velocity as a measure of vascular aging. PLOS ONE, 2023. DOI: 10.1371/journal.pone.0280896. PMID: 36701358.
Sarfo 2024. Effect of a Cardiovascular Polypill on Poststroke Cognition Among Ghanaians: Secondary Analysis of a Randomized Clinical Trial. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2024. DOI: 10.1161/JAHA.124.034346. PMID: 39082406.
Hajjar 2020. Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment. JAMA Network Open, 2020. DOI: 10.1001/jamanetworkopen.2020.12252. PMID: 32761160.
Senanayake 2026. Treatment gaps in guideline-directed medical therapy for HFrEF in Singapore: findings from a multicentre retrospective cohort study. BMJ Open, 2026. DOI: 10.1136/bmjopen-2025-107127. PMID: 41819588.
Lee 2024. Comparative estimation of the effects of antihypertensive medications on schizophrenia occurrence: a multinational observational cohort study. BMC Psychiatry, 2024. DOI: 10.1186/s12888-024-05578-6. PMID: 38365637.
Diego 2024. Modulation of TNF ‐α, interleukin‐6, and interleukin‐10 by nebivolol–valsartan and nebivolol–lisinopril polytherapy in SHR rats. Pharmacology Research & Perspectives, 2024. DOI: 10.1002/prp2.1189. PMID: 38504425.
Rossios 2023. ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial. PLOS ONE, 2023. DOI: 10.1371/journal.pone.0292402. PMID: 37862321.
Silva-Santos 2024. Lisinopril increases lung ACE2 levels and SARS-CoV-2 viral load and decreases inflammation but not disease severity in experimental COVID-19. Frontiers in Pharmacology, 2024. DOI: 10.3389/fphar.2024.1414406. PMID: 39070798.
Yang 2025. Sacubitril/valsartan and quality of life assessed using the EuroQol Five-dimension Three-level questionnaire level sum score (EQ-5D-3L-LSS) in patients with HFrEF and HFmrEF/HFpEF. European Heart Journal. Cardiovascular Pharmacotherapy, 2025. DOI: 10.1093/ehjcvp/pvaf064. PMID: 40839760.
Johnson 2024. Sodium Intake and Incident Atrial Fibrillation in Individuals With Vascular Disease. JAMA Network Open, 2024. DOI: 10.1001/jamanetworkopen.2024.21589. PMID: 38990569.
Henley 2023. Effects of candesartan on cerebral microvascular function in mild cognitive impairment: Results of two clinical trials. International Journal of Stroke, 2023. DOI: 10.1177/17474930231153313. PMID: 36645213.
Shaddy 2025. Association between NT‐proBNP changes and clinical outcomes in paediatric patients with heart failure: Insights from PANORAMA‐HF and PARADIGM‐HF. ESC Heart Failure, 2025. DOI: 10.1002/ehf2.15326. PMID: 40353367.
Jin 2025. Guideline-directed medical therapy and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction: analysis of two nationwide retrospective cohort studies. BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-098195. PMID: 40858368.
Murray-Thomas 2025. Non-adherence to medications prescribed to patients with heart failure in general practice: prevalence, risk factors and association with mortality and hospitalisation. Open Heart, 2025. DOI: 10.1136/openhrt-2025-003373. PMID: 40992794.
Willette 2025. Intrathecal enalapril reduces adhesion formation in experimentally induced digital flexor tendon sheath injuries in horses. Veterinary Surgery, 2025. DOI: 10.1111/vsu.14186. PMID: 39498787.
Chimura 2025. Comprehensive Analysis of the Effects of Sacubitril/Valsartan According to Sex Among Patients With Heart Failure and Reduced Ejection Fraction in PARADIGM ‐ HF. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.038249. PMID: 40265590.
Shaddy 2023. Baseline Characteristics of Pediatric Patients With Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction in the PANORAMA-HF Trial. Circulation. Heart Failure, 2023. DOI: 10.1161/CIRCHEARTFAILURE.122.009816. PMID: 36601956.
Kilic 2026. Evaluation of preoperative ACE inhibitors for renal protection in cardiac surgery. Medicine, 2026. DOI: 10.1097/MD.0000000000037760. PMID: 41894295.
Pepine 2026. Women’s IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR): a randomised controlled trial. Open Heart, 2026. DOI: 10.1136/openhrt-2026-004115. PMID: 41932694.
Alanis 2025. Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested Myocardial Injury. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.037718. PMID: 40145294.
Gross 2012. Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients. ISRN Pediatrics, 2012. DOI: 10.5402/2012/436046. PMID: 22811928.
Ishikawa 2025. Antihypertensive therapy to prevent cardiac death: A study of combined ACE inhibitors and β-blockers—a retrospective cohort study in Tsunan Town, Japan. PLOS One, 2025. DOI: 10.1371/journal.pone.0328142. PMID: 41134847.
Vicente-Gabriel 2024. Relationship between addictions and obesity, physical activity and vascular aging in young adults (EVA-Adic study): a research protocol of a cross-sectional study. Frontiers in Public Health, 2024. DOI: 10.3389/fpubh.2024.1322437. PMID: 38344236.
Lu 2025. Pgk1 activation restores endothelial metabolic homeostasis to alleviate vascular aging and atherosclerosis. Cardiovascular Diabetology, 2025. DOI: 10.1186/s12933-025-02976-2. PMID: 41206451.
Azizzadeh 2026. Prevalence and determinants of vascular aging in Austria – a holistic view: the LEAD study. Journal of Hypertension, 2026. DOI: 10.1097/HJH.0000000000004227. PMID: 41537373.
Sun 2016. Comparison of the Efficacy and Safety of Different ACE Inhibitors in Patients With Chronic Heart Failure. Medicine, 2016. DOI: 10.1097/MD.0000000000002554. PMID: 26871774.
Tanriover 2023. Early aging and premature vascular aging in chronic kidney disease. Clinical Kidney Journal, 2023. DOI: 10.1093/ckj/sfad076. PMID: 37915901.
Carmo 2025. Methylarginine levels and their impact on vascular aging: a systematic review. Vascular Biology, 2025. DOI: 10.1530/VB-25-0004. PMID: 41378901.
Kakaletsis 2024. Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis. J Hum Hypertens, 2024. DOI: 10.1038/s41371-024-00961-y. PMID: 39317753.
Li 2023. Vascular Aging: Assessment and Intervention. Clinical Interventions in Aging, 2023. DOI: 10.2147/CIA.S423373. PMID: 37609042.
Secondary 2023. Secondary Use of PARALLEL-HF Data. 2023.
Zhang 2025. A Randomized Controlled Trial on the Efficacy and Safety of a Calcium-Channel Blocker and an Angiotensin-Converting Enzyme Inhibitor in Chinese and European Patients with Hypertension. Am J Hypertens, 2025. DOI: 10.1093/ajh/hpae152. PMID: 39657776.
Keller 2019. Chronic Treatment With the ACE Inhibitor Enalapril Attenuates the Development of Frailty and Differentially Modifies Pro-and Anti-inflammatory Cytokines in Aging Male and Female C57BL/6 Mice. J Gerontol A Biol Sci Med Sci, 2019. DOI: 10.1093/gerona/gly219. PMID: 30256910.
Golder 2026. A Case of Lisinopril‐Induced Hallucinations. Journal of General and Family Medicine, 2026. DOI: 10.1002/jgf2.70099. PMID: 42022470.

Background References

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

Ioannidis 2005. Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.

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/X34VM

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.

Integrity check: not recorded

Published: May 28, 2026

Provenance chain: Available → View

SHA-256: sha256:59fe55f4d5e...

Publication ID: 9ab2e887-2e5b-429a...

Machine-readable exports

Claim Cards Passport JSON RO-Crate JSON

RESEARKA

Research Synthesis: Ace Inhibitors Aging

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

Frailty Outcomes

Immune Outcomes

Longevity Outcomes

Safety and Comorbidity Outcomes

Immune and Inflammation Outcomes

Mortality and Survival Outcomes

Muscle Function Outcomes

Key Findings

Cardiometabolic Outcomes

Contextual Adjacent Evidence Outcomes

Frailty Outcomes

Immune Outcomes

Longevity Outcomes

Safety and Comorbidity Outcomes

Immune and Inflammation Outcomes

Mortality and Survival Outcomes

Muscle Function Outcomes

Limitations

Gaps Identified

Evidence Summary

Interpretation constraints

Conclusion

Research Synthesis: Ace Inhibitors Aging

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

Frailty Outcomes

Immune Outcomes

Longevity Outcomes

Safety and Comorbidity Outcomes

Immune and Inflammation Outcomes

Mortality and Survival Outcomes

Muscle Function Outcomes

Cross-Domain Synthesis

Boundary-condition synthesis

Metabolic-Functional Tradeoff Framework

Discussion

Evidence Summary

Interpretation constraints

Limitations