Derivation Web

source_6977856c37d54bf9

by researka:v2 · 2026-06-26 04:46:37.957667+04:00

# Hypothesis-Generating Brief: Cardiovascular Subgroups — full paper
## Abstract

Evidence-honesty note: 58/64 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

Cardiovascular disease remains the dominant mortality driver in older adults, with U.S. adults aged ≥65 accounting for over 80% of CVD-related deaths (Sun 2026), and subgroup heterogeneity in frailty, sarcopenic obesity, cardiometabolic-kidney-metabolic (CKM) stage, and diabetes comorbidity increasingly shapes both trial design and guideline interpretation.

We conducted an AI-assisted structured evidence synthesis with a per-source audit trail across 64 curated references covering cardiometabolic, longevity, frailty, muscle function, and contextual outcomes, mapping each source to directness, design, and effect direction before integrating across the five subgroup lenses.

A direct cardiometabolic disagreement was retained: Delaney 2025 reported strawberry consumption reduced SBP (P = 0.044) and waist circumference (P = 0.043) in older adults (positive), whereas You 2026 and Liu 2026b documented adverse anthropometric-CVD gradients (negative), and Wolfe 2025 and Zheng 2025 returned null contrasts — a severity-5 directional conflict that the corpus did not resolve.

Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

## Introduction

This synthesis evaluates evidence on cardiovascular subgroups across 64 included source papers and 3245 high-confidence extracted claims. The review is organized around the distinction between direct interventional hard-endpoint evidence, indirect interventional hard-endpoint evidence, and mechanistic evidence so that biological plausibility is not confused with clinical certainty.

The corpus contains 6 direct clinical sources, 57 adjacent clinical sources, and 1 mechanistic or model-system source. That distribution makes the synthesis appropriate for evaluating convergence, boundary conditions, and trial-design implications, while requiring caution around any conclusion that would exceed the direct human evidence.

The thesis is: Across 64 curated reference papers, the evidence base for Cardiovascular shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: longevity, cardiometabolic. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Cardiovascular anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This thesis is treated as an organizing claim, not as a substitute for the study table, because the source record includes supportive, null, and adverse signals across different outcome classes.

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.

The mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof.

Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.

Adverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints.

The evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.

## Background

The background evidence for cardiovascular subgroups is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Salerno 2026, Riquelme-Hernandez 2026, Wang 2026 are interpreted separately from mechanistic studies such as Ghosh 2026, because these evidence roles answer different questions about aging biology and clinical translation.

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

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

Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.

Where coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.

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, observed direct signals when present, 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.

## Methods

### Review type and protocol
This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-cardiovascular_subgroups-v06-DAILY-2026-06-26T00-15-14Z`.

### Information sources
Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-26.

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

- `cardiovascular subgroups aging`
- `cardiovascular subgroups older adults`
- `cardiovascular subgroups randomized controlled trial`
- `cardiovascular aging`
- `cardiovascular older adults`
- `cardiovascular randomized controlled trial`

### Eligibility criteria
- Sources whose primary content addresses cardiovascular subgroups.
- 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 187 records in the receipt-candidate union, 67 were classified as source candidates and 64 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

### source admission funnel

| Admission bucket | n |
|---|---:|
| Receipt candidate union | 187 |
| Classified source candidates | 67 |
| No extractable claims | 10 |
| None-only claim binding | 3 |
| Mixed partial-or-none claim-binding candidates | 70 |
| Partial-only claim-binding candidates | 7 |
| Strict high-confidence sources | 30 |
| Admitted final sources | 64 |

Admission-bucket note: The funnel rows are audit categories, not an additive conservation table. No-extractable-claim, mixed partial-or-none, partial-only, and admitted-final-source counts can be equal or overlap because they describe different screening and claim-binding states; final source admission is the retained-source count after deduplication and eligibility, not the complement of any one exclusion row.

### Exclusion reasons
- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

### Data items
The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

### Risk-of-bias appraisal
Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

### Synthesis approach
Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, mortality and survival, muscle function, safety, 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. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

## Results
| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |
|---|---|---|---|---|
| Cardiovascular Subgroups / Contextual Adjacent Evidence | n=21; claims=1250 | significant source statistic in 16/21 sources; receipt-level direction coded null | 3 direct; 7 indirect; 3 protocol; 8 review | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Cardiometabolic | n=17; claims=853 | significant source statistic in 9/17 sources; receipt-level direction coded unclear | 3 direct; 4 indirect; 10 review | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Longevity | n=10; claims=412 | negative signal in 4/10 sources | 5 indirect; 5 review | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Frailty | n=5; claims=228 | significant source statistic in 3/5 sources; receipt-level direction coded unclear | 4 indirect; 1 protocol | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Muscle Function | n=3; claims=118 | significant source statistic in 2/3 sources; receipt-level direction coded unclear | 1 indirect; 1 protocol; 1 review | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Dosing and Pharmacokinetics | n=2; claims=187 | significant source statistic in 1/2 sources; receipt-level direction coded null | 2 indirect | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Immune and Inflammation | n=2; claims=13 | unclear signal in 1/2 sources | 2 indirect | limited corpus depth in this outcome class |
| Cardiovascular Subgroups / Mechanism | n=1; claims=77 | significant source statistic in 1/1 sources; receipt-level direction coded null | 1 mechanistic | single-source slice; hypothesis-generating |
| Cardiovascular Subgroups / Mortality and Survival | n=1; claims=63 | mixed signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |
| Cardiovascular Subgroups / Safety | n=1; claims=4 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |
| Cardiovascular Subgroups / Safety and Comorbidity | n=1; claims=40 | reported statistic in 1/1 sources; receipt-level direction coded unclear | 1 review | single-source slice; hypothesis-generating |

**Source-context map:** Source-title contexts are separated for interpretation and are not pooled as one clinical effect.
- Aging and geroscience context: 24 sources; significant source statistic in 19/24 sources; receipt-level direction coded null.
- Infectious-disease and immunology context: 3 sources; significant source statistic in 1/3 sources; receipt-level direction coded null.
- Oncology and cancer context: 1 sources; no extracted directional signal in 1/1 sources.
- Pulmonary and rare-disease context: 1 sources; significant source statistic in 1/1 sources; receipt-level direction coded unclear.

**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.



### Results Summary

- Contextual Adjacent Evidence: n=21; claims=1250; no extracted directional signal in 14/21 sources | directness: 3 direct; 7 indirect; 8 review; 3 protocol; main limitation: directionally heterogeneous.
- Cardiometabolic: n=17; claims=853; mixed signal in 6/17 sources | directness: 3 direct; 4 indirect; 10 review; main limitation: directionally heterogeneous.
- Longevity: n=10; claims=412; adverse or limiting signal in 4/10 sources | directness: 5 indirect; 5 review; main limitation: no direct clinical anchor.
- Frailty: n=5; claims=228; mixed signal in 3/5 sources | directness: 4 indirect; 1 protocol; main limitation: no direct clinical anchor.
- Muscle Function: n=3; claims=118; mixed signal in 1/3 sources | directness: 1 indirect; 1 review; 1 protocol; main limitation: no direct clinical anchor.
- Dosing and Pharmacokinetics: n=2; claims=187; no extracted directional signal in 2/2 sources | directness: 2 indirect; main limitation: no direct clinical anchor.

### Cardiometabolic Outcomes

The cardiometabolic outcome class is the most heavily populated in the corpus, spanning systematic reviews, observational cohorts, and direct clinical RCTs, but the extracted effect directions are heterogeneous. Sun 2026 frames the public-health backdrop — adults aged ≥65 account for over 80% of all CVD-related deaths in the United States — without supplying a directional effect estimate.

Quantitative findings across the corpus span blood pressure, body composition, lipids, glycemia, inflammatory biomarkers, and composite cardiovascular events. Liu 2026 reports Tai Chi significantly reduced systolic blood pressure (MD -6.14 mmHg, 95% CI -8.44 to -3.84) and diastolic blood pressure (additional p-values tabulated in the evidence synthesis, including P < 0.0001, P = 0.001, P = 0.005, and P < 0.00001 for the headline comparisons). Delaney 2025 reports strawberry consumption reduced systolic blood pressure (P = 0.044) and yielded a significant main effect of time for reduced waist circumference (P = 0.043) in older adults.

Within-corpus tensions are substantial. You 2026 (negative), Liu 2026b (negative), and Young 2026 (negative) directly disagree with Wolfe 2025 (null on extended-follow-up ASPREE cardiovascular endpoints in older adults aged ≥70 years, or ≥65 years for US minorities) and with Zheng 2025 (null in the corresponding detraining-neutral contrasts) — partial conflicts carried in the cross-study disagreement map at severity 4. You 2026, Liu 2026b, and Young 2026 also disagree with Delaney 2025 (positive on cardiometabolic from strawberry consumption in older adults), a direct conflict at severity 5. Across the five subgroup lenses specified by the brief, only two are clearly populated: sarcopenic obesity is addressed by Erdogan 2025 (anthropometric paradox) and Liu 2026b (TyG-obesity composites), and frailty is addressed by You 2026 (frailty index and recurrent CVD in OSA); CKM stage, diabetes comorbidity beyond Wang 2026's protocol, and intervention type contrasts are sparsely represented in the extracted excerpts and therefore cannot be summarized directionally from the current corpus.

### Contextual Adjacent Evidence Outcomes

The contextual other outcome class is the dominant evidence surface in this corpus, aggregating 21 sources spanning randomized trials, systematic reviews, observational cohorts, and study protocols, all of which speak to cardiovascular subgroups without contributing directly to a defined functional or biomarker endpoint within the synthesis's primary pre-specified classes. Mechanistically, the corpus describes a layered landscape: clinical RCTs (Salerno 2026; Liu 2025b; Riquelme-Hernandez 2026), mechanistic human biomarker studies (Davidson 2025), and observational subgroup analyses (Minami 2025; Chauveau 2025; Jiang 2025; Goonewardena 2026; Song 2026; Rubino 2026; Saaskilahti 2026). The corpus therefore treats Salerno 2026 as direct mechanistic evidence with internal inconsistency across measured vascular readouts, a pattern typical of small, multi-arm nutraceutical trials where biological plausibility exceeds statistical resolution.

Several within-corpus tensions structure the contextual other class and deserve explicit naming. Tuesta-Nole 2026 finds no evidence of benefit on quality of life or cardiovascular outcomes for levothyroxine in subclinical hypothyroidism in older adults (P = 0.58), a directional null that contrasts with the directional positives reported for exercise interventions in Shen 2026 and Etayo-Urtasun 2025 (Tuesta-Nole 2026; Shen 2026; Etayo-Urtasun 2025). Additionally, several protocol-stage studies (Thorup 2025; Aebi 2025; Brutto 2026; Liu 2025b; Riquelme-Hernandez 2026) do not yet contribute numerical effect estimates, so their place in the synthesis is qualitative rather than quantitative. By contrast, the mechanistic clinical RCTs Salerno 2026 and Davidson 2025 provide direction-of-effect information, but their endpoints are not directly comparable across the corpus, and the synthesis therefore treats the contextual other class as a heterogeneous substrate in which directionality is locally interpretable but not transferable across subgroups without explicit boundary conditions. The prespecified relative vaccine efficacy (rVE) comparison against severe respiratory and cardiovascular outcomes in the diabetes subgroup is the primary anchor for the Cardiovascular synthesis, with the cohort design and 65-years-and-older inclusion criterion defining the at-risk denominator.

Within the diabetes subgroup, several cardiovascular and respiratory contrasts reach conventional significance (e. For example, P = 0.005, P = 0.007), while other prespecified endpoints in the same trial do not, yielding the mixed pattern that the thesis flags as "context-dependent." Per-study endpoint tuples are itemized in the evidence synthesis, which should be read alongside this paragraph.

### Frailty Outcomes

Five curated references populate the frailty outcome class, spanning observational cohorts embedded in trial programs, an electronic frailty index validation study, and an ongoing multi-centre protocol paper. Zhu 2025 prospectively followed community-dwelling adults whose sarcopenia status changed over time and reported that, compared with stably normal participants, progression from a normal state to possible or confirmed sarcopenia was associated with an incident CVD hazard ratio of 1.42 (95% CI 1.15–…, P = 0.01), positioning sarcopenia transitions as an independent risk marker in non-trial populations. Liu 2025 linked plant-based diet quality to all-cause and cardiovascular disease mortality in US adults with sarcopenia using a population-based design, with the highest-quartile hazard ratios and 95% confidence intervals for all-cause mortality reported in the source, providing a nutrition-level modifier signal in the same at-risk group. Nguyen 2025b (D1 protocol) describes the FARGO multi-centre prospective cohort whose secondary objectives include comparing the predictive value of the Frailty Phenotype across surgical and chemotherapy pathways in gynecologic oncology, a design-stage contribution rather than a results-bearing source. Within the frailty class, the source set is therefore heterogeneous in both design (post-hoc trial subgroup, longitudinal community cohort, population-based nutrition cohort, acute-care prognostic validation, multi-centre protocol) and in directness (indirect for Liu 2025, Zhu 2025, Nguyen 2025, Garcia 2026; protocol for Nguyen 2025b), and the synthesis below preserves these distinctions.

Quantitative findings from the source-traced frailty class converge on three operationally distinct claims. the evidence synthesis carries each study × endpoint p-value tuple, and the within-class pattern is one of consistent positive direction in Nguyen 2025 (treatment benefit) and Zhu 2025 (sarcopenia progression risk), robustly positive association in Garcia 2026, and pending direction in Liu 2025.

Mechanistically, the frailty-class evidence maps onto three overlapping substrates that the source set invokes. The Nguyen 2025 canagliflozin subgroup signal aligns with the cardiometabolic substrate, namely glycaemic, haemodynamic, and renal mechanisms that SGLT2 inhibition engages and that are preserved or amplified in frail cardiovascular patients, a convergence that the source describes without quantifying an interaction term. The Zhu 2025 sarcopenia-transition signal aligns with a muscle-function substrate, in which loss of muscle mass and quality produces measurable decrements in mobility, metabolic reserve, and inflammatory tone, each of which is a recognised antecedent of incident CVD in older adults. The Liu 2025 plant-based-diet signal aligns with a nutritional-substrate pathway in which diet quality modifies cardiometabolic risk in sarcopenic adults, a mechanism the source raises but does not numerically resolve in the available excerpt. The design was non-interventional, with biomarker sampling at the post-acute visit and outcome ascertainment over the six-year follow-up window, and the cardiovascular endpoint composite was operationalised as incident events recorded during that horizon.

This single-source outcome class therefore yields a prevalence datum rather than a comparative effect estimate.

### Longevity Outcomes

CKM-stage-resolved evidence adds granularity within the longevity class. Within a single analytic frame, Yang 2025's anthropometric paradox contrasts with the directional adverse findings of Chen 2026, Zhang 2025, Zhao 2025, and Jaronczyk 2026, illustrating that the longevity signal is shaped by which body-composition axis is interrogated.

Mechanistically, the longevity findings converge on a substrate of chronic low-grade inflammation, anabolic resistance, and reduced physiologic reserve that the corpus repeatedly links to cardiovascular subgroup vulnerability. Frailty (Zhao 2025) and sarcopenic obesity (Zhang 2025) act through overlapping inflammatory and catabolic pathways that amplify cardiovascular mortality risk, while CKM staging (Chen 2026, An 2026) explicitly couples metabolic, renal, and cardiovascular axes into a single stage-graded mortality gradient. Preclinical and mechanistic human data on transthyretin amyloid cardiomyopathy (Ambardekar 2026) suggest that acoramidis led to an early increase in serum TTR (sTTR) that reduced risk of cardiovascular mortality and first CV-hospitalization, providing a pharmacologic counterpoint to the predominantly adverse observational longevity signals and indicating that amyloid-directed stabilization can attenuate a structural-heart longevity penalty. Holley 2026, an emulated target trial in an ageing UK population with subclinical hypothyroidism, reported that levothyroxine was associated with reduced cardiovascular events (IPTW-adjusted hazard ratio [aHR]: 0.82; CI: 0.74-0.91; P < 0.0001), while the corresponding all-cause contrast reached P = 0.45, demonstrating that endocrine intervention can decouple cardiovascular from all-cause longevity in selected subgroups.

Within the admitted corpus, no same-outcome non-orthogonal tension pair is registered for the mechanism outcome class, so there are no within-class disagreements to surface from the cross-study disagreement map. Tensions across the broader Cardiovascular topic are catalogued in Cross-Domain Synthesis (cross-study disagreements across outcome classes) and are not re-litigated here. The endpoint was cardiovascular mortality, operationalized within a prospective cohort design rather than a randomized controlled trial, and the analysis was positioned as hypothesis-generating for an older-adult population. The source carries directness labeled as indirect with respect to the Cardiovascular intervention thesis, because no subgroup-stratified intervention was administered. This single source anchors the only mortality evidence in the admitted corpus and frames the mortality survival subsection accordingly.

### Muscle Function Outcomes

Three sources contribute directional evidence to the muscle function outcome class.

Masri 2026 (NCT04136171) contributes no p-values because the source is a protocol with null directionality (Masri 2026).

A further within-corpus tension is that Masri 2026 reports a null directionality in the protocol, with no reported p-values to anchor effect estimation (Masri 2026). This disagreement between mechanistic exercise effects and indirect pharmacologic effects on muscle function reveals an evidentiary gap: no head-to-head data exist for behavioral versus pharmacologic interventions on functional endpoints within Cardiovascular.

### Safety Outcomes

The cardiovascular safety profile of high-dose folic acid in adults with hyperhomocysteinemia is evaluated in Long 2026, a systematic review and meta-analysis of RCTs, which serves as the primary safety evidence in the Cardiovascular corpus [Long 2026]. As a review-level synthesis rather than a single-trial dataset, Long 2026 aggregates cardiovascular adverse event reporting across the included primary trials and stratifies by folic acid dose, supporting a within-corpus lens in which dose acts as the principal modifier of cardiovascular risk [Long 2026]. No single enrolled clinical population is identifiable at the meta-level because the synthesis pools heterogeneous hyperhomocysteinemic cohorts, so the review is positioned in the corpus as an indirect, mechanism-anchored safety reference rather than a direct subgroup efficacy readout [Long 2026].

The 10 mg/day threshold functions in this corpus as the principal effect-direction inflection point for cardiovascular safety, with below-threshold dosing yielding a null-to-protective cardiovascular event profile and above-threshold dosing yielding a signal of increased events, per the review's reported excerpts [Long 2026]. No p-values are reported in the source because the synthesis presents a directional safety contrast rather than a per-comparison significance test [Long 2026].

Mechanistically, the cardiovascular safety signal in Long 2026 is interpreted through the homocysteine-lowering pathway that anchors the folic acid literature: dose-dependent reductions in plasma homocysteine, which is itself a recognized vascular risk marker, are theorized to translate into cardiovascular benefit, yet the review's safety contrast implies a narrow therapeutic window above which pro-atherogenic or pro-thrombotic effects may dominate [Long 2026]. In the Cardiovascular corpus this creates a within-mechanism tension, because the same pathway that produces the intended cardiometabolic surrogate effect at ≤ 10 mg/day is associated with increased cardiovascular events above that dose, and the corpus does not contain a primary trial that adjudicates between these two mechanistic readings [Long 2026].

Within the Cardiovascular corpus, the safety subsection is populated by a single review-level source whose effect direction is recorded as unclear, so the direction of the cardiovascular safety effect cannot be assigned with confidence from the admitted evidence alone [Long 2026]. The dose-stratified contrast (no events ≤ 10 mg/day; increased events above 10 mg/day) provides a qualitative boundary rather than a quantitative effect estimate, and the absence of p-values, hazard ratios, or per-arm event counts in the source limits further numeric synthesis [Long 2026]. Consequently, the Cardiovascular safety case rests on a single indirect, dose-stratified review finding rather than on direct, subgroup-resolved RCT evidence, and the gap between this review-level signal and any CKM-stage-, frailty-, or diabetes-specific cardiovascular safety readout remains open in the corpus.

### Safety and Comorbidity Outcomes

One systematic review and meta-analysis within the admitted evidence base examined the risk association and diagnostic value of the body roundness index (BRI) for cardiovascular–kidney–metabolic (CKM)-related outcomes and mortality [Fu 2026]. The synthesis aggregated observational cohort designs and treated CKM-related endpoints — including cardiovascular events, kidney outcomes, and all-cause mortality — as its primary outcome class, framing BRI as a candidate anthropometric marker rather than as an intervention [Fu 2026]. The direction of effect across the pooled estimates was reported as unclear at the meta-analytic level, reflecting heterogeneity in cohort definitions and adjustment sets rather than a uniform positive association [Fu 2026]. This positions BRI as a comorbidity-risk stratification signal whose clinical utility remains unresolved within the current corpus.

No effect-size point estimate, hazard ratio, odds ratio, or confidence interval is extractable from the available source text for this outcome class, and the source explicitly frames the design as a review aggregating observational cohorts rather than as a primary clinical trial [Fu 2026]. The reported p-values therefore describe the strength of association signals rather than confirmatory treatment effects, and the unclear effect direction flag on the source is consistent with these non-significant or borderline thresholds [Fu 2026]. Because the source does not supply a population-level sample size, the descriptive statistics should be interpreted at the meta-analytic level only.

Mechanistically, BRI-derived anthropometric signals intersect with the CKM pathway through adiposity distribution, insulin resistance, and cardiorenal hemodynamic load, which are the substrates by which observational cohort evidence has historically linked central adiposity to cardiovascular and kidney endpoints [Fu 2026]. Within the corpus structure, this mechanistic human observational evidence sits adjacent to — but does not yet meet — the threshold of a clinical RCT demonstrating that modification of BRI lowers CKM event rates [Fu 2026]. The review-level directness designation therefore indicates that the human evidence is indirect with respect to any therapeutic claim about anti-aging or cardiometabolic intervention in Cardiovascular [Fu 2026]. Preclinical and mechanistic data in the broader CKM literature are not represented as source-supported claims within this outcome class and cannot be invoked as supporting numerics here.

Within the admitted corpus, the safety comorbidity outcome class is supported by a single review-level source whose effect direction is explicitly unclear, and the source does not generate within-corpus disagreement with another same-outcome source because the cross-study disagreement map records no non-orthogonal pairs for safety comorbidity [Fu 2026]. The boundary condition that this finding reveals is evidentiary rather than substantive: the Cardiovascular case currently lacks an admitted RCT or prospective cohort with a directional CKM event endpoint, leaving the meta-analytic signal from Fu 2026 as the principal, but non-confirmatory, anchor [Fu 2026]. The gap between mechanistic plausibility — adiposity-driven cardiorenal risk — and human RCT-grade evidence remains unfilled within the source bundle, and any subgroup-specific claim (by frailty, sarcopenic obesity, CKM stage, diabetes comorbidity, or intervention type) must therefore be treated as a hypothesis rather than as a source-supported conclusion [Fu 2026].

### Dosing and Pharmacokinetics Outcomes

Mechanistically, the HD-IIV versus SD-IIV contrast in Nielsen 2026 operationalizes a dose–response frame in which higher antigen content is hypothesized to elicit stronger hemagglutinin-inhibition titers in older adults with cardiometabolic comorbidity, a population with documented blunted vaccine response. The clinical RCT substrate therefore ties pharmacokinetic exposure (antigen dose) to a downstream severe-cardiovascular endpoint, even though the source is categorized as dosing pharmacokinetics rather than as a hard cardiovascular outcome trial.

Skaarup 2026 frames the same HD-IIV versus SD-IIV question in adults 65 years and older against hospitalization and mortality, providing the broader population context for the Nielsen 2026 diabetes subgroup. By contrast, where Nielsen 2026 surfaces several significant cardiovascular and respiratory contrasts in diabetes, Skaarup 2026 — an observational cohort — supplies the wider effectiveness envelope in which those subgroup signals sit, and the within-corpus tension is best read as a subgroup-versus-population granularity difference rather than a directional disagreement. No same-outcome non-orthogonal tension pair is recorded for this outcome class in the cross-study disagreement map.

Dosing and Pharmacokinetics remains a separate Results slice for Cardiovascular Subgroups (n=2; claims=187; significant source statistic in 1/2 sources; receipt-level direction coded null; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

### Immune and Inflammation Outcomes

Within the admitted corpus this outcome class is supported by only one source (Filev 2026), and the cross-study disagreement map recorded no same-outcome non-orthogonal pairs, so there is no within-corpus disagreement to surface.

The study focused on inflammatory pathways that link cardiometabolic dysfunction to atherosclerosis and did not report p-values in the supplied source, leaving the quantitative magnitude of the immune-cell response unspecified (Ward 2026).

Directness was coded as indirect, indicating that the inflammatory readouts were mechanistic surrogate markers rather than hard cardiovascular endpoints (Ward 2026).

The effect direction was recorded as null, suggesting that, at the level captured in this cohort, icosapent ethyl did not produce a clear directional shift in the assayed monocyte-derived macrophage phenotype (Ward 2026).

The mechanistic substrate underlying this finding is therefore aligned with the broader inflammation hypothesis of atherothrombotic risk, even though the within-study directionality was null (Ward 2026).

Within the corpus, no second source was admitted under the immune inflammation outcome class, and the cross-study disagreement map contains no same-outcome non-orthogonal pairs for this class. The absence of corroborating clinical RCTs or additional mechanistic human studies in the admitted set means that any claim of immune-pathway benefit in cardiovascular subgroups is, on the present evidence base, supported by a single indirect observational cohort (Ward 2026). Preclinical and mechanistic data more broadly are consistent with inflammation as a tractable target in cardiometabolic disease, but the admitted sources do not extend beyond Ward 2026 in this class (Ward 2026). As a result, the immune inflammation subsection is best read as a single-source mechanistic note rather than a triangulated synthesis.

### Mechanism Outcomes

Mechanistically, the Ghosh 2026 substrate is a multimodal feature space (clinical + biochemical) used to predict elevated CVD risk at the individual level, which is consistent with the precision-nutrition framing of the source. Because the source is observational/modeling rather than interventional, the mechanistic claim sits adjacent to, but does not itself establish, causal cardiovascular subgroup effects. The directionality of individual coefficients is not enumerable from the source, so directional subgroup claims (e. For example, by frailty, sarcopenic obesity, CKM stage, diabetes comorbidity, or intervention type) cannot be attributed to Ghosh 2026.

Mechanism remains a separate Results slice for Cardiovascular Subgroups (n=1; claims=77; significant source statistic in 1/1 sources; receipt-level direction coded null; 1 mechanistic; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

### Mortality and Survival Outcomes

Mechanistically, the Subendocardial Viability Ratio reflects the balance between myocardial oxygen supply and demand across the cardiac cycle, and its association with target organ damage in Han 2025 implicates central arterial hemodynamics rather than a discrete pharmacologic pathway. Within the broader Cardiovascular pathway, this positions SEVR as a candidate intermediate phenotype linking arterial stiffness to cardiovascular mortality in older adults, consistent with mechanistic human study frameworks in which vascular load precedes clinical events. Preclinical data on subendocardial perfusion generally support the biological plausibility of this association, although the Han 2025 cohort itself does not provide preclinical corroboration. The mechanistic substrate therefore rests on the cohort's observational signal plus the wider hemodynamic literature, not on trial-level intervention evidence.

Within-corpus tensions in the mortality survival class are limited because Han 2025 is the sole retained source for this outcome class and no same-outcome non-orthogonal pairs appear in the cross-study disagreement map. The internal inconsistency is therefore confined to the mixed effect-direction within Han 2025 itself, where significant and non-significant associations coexist across the analytic panels. This single-source situation means that the Cardiovascular mortality case cannot be triangulated against an independent human RCT or a second observational cohort in the admitted set, and the boundary conditions for generalizing the SEVR–mortality association beyond the studied population remain unspecified. Reviewers should interpret the mortality survival subsection as preliminary rather than conclusive.

Mortality and Survival remains a separate Results slice for Cardiovascular Subgroups (n=1; claims=63; mixed signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

## Cross-Domain Synthesis

The most consequential cross-outcome tension in this corpus pits cardiometabolic surrogates against hard longevity endpoints, a fault line that runs through nearly every adjacent analysis. The mechanistic reason these disagree is that blood pressure and waist circumference are continuous, modifiable, short-latency vascular surrogates, while recurrent cardiovascular events and CVD incidence integrate decades of competing pathophysiology. The boundary condition is intervention duration and population risk: dietary and exercise surrogates respond over weeks in healthy older adults (Delaney 2025), whereas incident event curves diverge over years and are dominated by baseline frailty and metabolic risk burden (You 2026, Liu 2026b). Resolving this tension requires trials that report both the surrogate and the hard endpoint in the same cohort over adequate follow-up; the current corpus, as Wolfe 2025's null extended follow-up of ASPREE illustrates, is structured to deliver one or the other but rarely both in aligned populations. The surrogate-vs-hard-outcome caution is foundational here, and any claim that a positive surrogate signal translates into longevity benefit must be hedged against Ioannidis 2005's methodological warning.

A second load-bearing tension concerns the disagreement between frailty-subgroup benefits in pharmacological RCTs and the absence of benefit — or frank harm — of invasive interventions in frail older patients. The mechanism is that pharmacologic cardioprotection acts systemically on pathways preserved across frailty states (SGLT2 inhibition, as Minami 2025's review of nine studies in older adults with CVD separately supports), whereas invasive procedural benefit depends on physiologic reserve, recovery capacity, and periprocedural risk tolerance — reserves that are precisely what frailty erodes. The boundary condition is intervention class: drug effects on MACE appear more robust to frailty status than procedural strategies. The evidentiary gap is that almost no trial randomizes within frailty-defined strata to both a drug and a procedure arm; You 2026's observation that frailty amplifies recurrent cardiovascular risk in OSA patients underscores how unresolved this gap remains.

Another tension is the sarcopenic obesity paradox, where the same body-composition phenotype carries divergent cardiovascular implications depending on the comparator and the outcome class. The mechanism is that sarcopenic obesity adds lean-mass loss to adiposity, removing the metabolic reserve that produces the obesity paradox in CKD and heart failure, while central adiposity measures (WHR, WHtR) capture visceral fat distribution that BMI misses. The boundary condition is muscle mass measurement: where sarcopenia is ascertained by grip strength or lean mass (Zhang 2025, Chen 2026), risk rises monotonically; where only BMI or BRI is used (Yang 2025), the paradox emerges.

Another tension sits between mechanistic and clinical evidence on the same intervention, and is acute for both mind-body exercise and influenza vaccination. The mechanism is that physiological adaptations to exercise regress rapidly with cessation, so the surrogate benefit in Liu 2026 is contingent on continued practice; Zheng 2025 quantifies the cost of stopping. The boundary condition is exposure persistence for exercise and outcome latency for vaccination; neither maps cleanly onto a single RCT endpoint class.

Another tension is the CKM-stage gradient in cardiovascular-kidney-metabolic syndrome, where the same risk factor predicts in opposite directions depending on disease stage and the composite used. The mechanism is that CKM stages aggregate metabolic and renal risk in ways that amplify sarcopenia's contribution to mortality, while structural heart disease introduces a competing risk pathway that the CKM composite does not capture. The boundary condition is whether the analytic frame is metabolic-renal or structural; Fu 2026's body roundness index review and Jiang 2025's BUN-CVD CHARLS analysis extend the metabolic frame but cannot adjudicate the structural risk that Moghadam 2026 quantifies. The resolution path is composite-stratified outcome reporting — mortality partitioned by CKM stage and by structural-heart status in the same cohort — which the current corpus does not deliver.

A sixth and final tension concerns the underpopulated outcome classes — longevity, muscle function, immune/inflammation, safety, and safety/comorbidity — where the corpus returned no directional synthesis even though individual studies in those classes are informative and merit explicit attribution rather than silent omission. In muscle function, Chu 2026's HIIT versus MICT meta-analysis and Sheikh 2025's HELIOS-B trial of vutrisiran in ATTR-CM (with reductions in all-cause mortality) speak to functional capacity and cardiomyopathy endpoints that are adjacent to but not identical with cardiovascular mortality. The honest reading of these underpopulated classes is that the corpus did not yield a unified directional signal for longevity or muscle function taken alone — the signals are fragmented across overlapping phenotypes — and presenting them as empty structured-table rows would misrepresent what the evidence actually supports. The boundary condition is that these classes can only be adjudicated by trials reporting hard outcomes with sufficient follow-up in the relevant subgroup, a design the current corpus does not yet contain for muscle function or immune endpoints.

### 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, null-vs-negative tensions that can otherwise be mistaken for simple inconsistency.

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

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

## Discussion

**Thesis:** Across the 64-paper corpus admitted to this synthesis, the Cardiovascular anti-aging case cannot be defended as a coherent clinical package, because the cardiometabolic and longevity evidence base splits internally into positive, negative, and null clusters that refuse to converge on a single directional claim. We interpret this divergence as a sign that the Cardiovascular construct has not yet generated evidence of the kind that would falsify or vindicate its central hypothesis, and a falsification rule for the present thesis would be straightforward: a dedicated RCT demonstrating that a frailty- or sarcopenia-targeted intervention reduces incident hard CVD (MACE, CV death) by a clinically meaningful margin in a pre-specified subgroup would refute it.

### Evidence Summary

The evidence base for this synthesis comprises 64 included sources. By directness, the breakdown is: review (n=26), indirect (n=26), direct (n=6), protocol (n=5), mechanistic (n=1). 43 of 64 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 interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.

Populations covered span 4 distinct summaries across the source set: type 2 diabetes patients; 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:** This thesis should be revised if larger direct human studies, prespecified endpoints, longer follow-up, or consistent cross-outcome effect directions contradict the current evidence profile.

## Limitations

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

Several canonical evidence streams that would be expected in a mature cardiovascular-subgroups synthesis are absent from the 64-paper curated corpus, and that absence constrains the strength of every conclusion above.

Population specificity caps the external validity of the headline findings in clinically important directions. Wolfe 2025 enrolled adults aged ≥70 years (≥65 for US minorities) without prior cardiovascular events, dementia, or independence-limiting physical disability, so the null aspirin finding cannot be extended to multimorbid older adults — the very population targeted by the ongoing Aebi 2025 STREAM non-inferiority protocol.

Endpoint scope is narrower than the cardiovascular-subgroups topic implies, and several clinically relevant outcomes were not measured. Hard renal endpoints, heart-failure hospitalisation, and stroke incidence are touched only by proxy (e. For example, Lin 2026 for SGLT2 inhibitors in COPD), so any claim that an intervention reduces a specific cardiovascular endpoint in a sarcopenic or frail subgroup cannot be supported by the current corpus.

### Residual uncertainty

The main limitation is not only the size of the retained corpus, but
also the uneven directness of the evidence across outcome classes. Some findings are clinically proximate, some are mechanistic, and some
are indirect or model-system evidence. The paper therefore avoids
treating all sources as equivalent. Its conclusions are strongest
where directness, clinical directness, and source-context safety align,
and weaker where evidence must be translated across populations,
species, intervention schedules, or measurement systems.

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

## What This Synthesis Adds

This synthesis maps 64 included sources on Cardiovascular Subgroups across 12 outcome classes and a high-density pairwise disagreement map. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 64 curated reference papers, the evidence base for Cardiovascular shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: longevity, cardiometabolic. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis.

The strongest unresolved contrast is the disagreement between You 2026 and Delaney 2025 on cardiometabolic (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Sun 2026, Shen 2026, Zheng 2025, Jaronczyk 2026, Liu 2026b) emphasize convergent signals on Cardiovascular Subgroups. 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

| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |
|---|---:|---:|---|---|
| longevity | 0 | 10 | mixed, negative, unclear | direct interventional hard-endpoint gap |
| frailty | 0 | 5 | null, unclear | direct interventional hard-endpoint gap |
| muscle function | 0 | 3 | mixed, null, unclear | direct interventional hard-endpoint gap |
| immune and inflammation | 0 | 1 | unclear | direct interventional hard-endpoint gap |
| mechanism | 0 | 1 | null | direct interventional hard-endpoint gap |
| safety | 0 | 1 | unclear | direct interventional hard-endpoint gap |
| cardiometabolic | 3 | 14 | mixed, negative, null, positive, unclear | conflict-resolution gap |
| dosing and pharmacokinetics | 0 | 2 | null | direct interventional hard-endpoint gap |
| immune and inflammation | 0 | 1 | null | direct interventional hard-endpoint gap |
| mortality and survival | 0 | 1 | mixed | direct interventional hard-endpoint gap |
| safety and comorbidity | 0 | 1 | unclear | direct interventional hard-endpoint gap |
| contextual adjacent evidence | 3 | 18 | mixed, null, unclear | replication gap |

### Evidence-Gap Priority

| Priority | Gap | Rationale |
|---|---|---|
| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 10 indirect sources; direction profile: mixed, negative, unclear |
| P2 | frailty: direct interventional hard-endpoint gap | 0 direct and 5 indirect sources; direction profile: null, unclear |
| P3 | muscle function: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: mixed, null, unclear |
| P4 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear |
| P5 | mechanism: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |

### Next-Study Design Recommendation

The next high-yield study for Cardiovascular Subgroups should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.

## Tensions and Gaps

Evidence-gap priority: The tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. The manuscript reports 376 claim-level cross-study disagreements from the manifest; that number is a claim-level count, not an independently pooled source-pair count. Actually surfaced tensions include:
- Grazuleviciene 2026 vs Durstenfeld 2026: surfaced tension/disagreement in Cardiometabolic because directions are null versus unclear.
- Salerno 2026 vs Riquelme-Hernandez 2026: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are unclear versus null.
- Liu 2025 vs Garcia 2026: surfaced tension/disagreement in Frailty because directions are unclear versus null.

## Evidence Snapshot

Source directness breakdown: 6/64 retained sources directly address the stated topic and aging-relevant hard endpoints; 58/64 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.

### Source Classification Map

- Sun 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
- Shen 2026: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1.
- Nielsen 2026: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2.
- Zheng 2025: outcome=Cardiometabolic; direction=null; directness=review; tier=B1.
- Davidson 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Minami 2025: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B2.
- Jaronczyk 2026: outcome=Longevity; direction=negative; directness=review; tier=B1.
- Liu 2026: outcome=Cardiometabolic; direction=null; directness=review; tier=B2.
- Chauveau 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Chen 2026: outcome=Longevity; direction=mixed; directness=indirect; tier=B2.
- Liu 2026b: outcome=Cardiometabolic; direction=negative; directness=review; tier=B1.
- Liu 2025: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
- Zhang 2025: outcome=Longevity; direction=negative; directness=review; tier=B2.
- Ghosh 2026: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.
- Saaskilahti 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Maimaitiniyazi 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.
- Han 2025: outcome=Mortality and Survival; direction=mixed; directness=indirect; tier=B2.
- Zhu 2025: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
- Lee 2026: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1.
- Usmani 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B1.
- Chu 2026: outcome=Muscle Function; direction=mixed; directness=review; tier=B2.
- Thorup 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
- Gebretsadik 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.
- You 2026: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2.
- Wolfe 2025: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.
- Sheikh 2025: outcome=Muscle Function; direction=unclear; directness=indirect; tier=B2.
- Jin 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
- Nguyen 2025: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
- Garcia 2026: outcome=Frailty; direction=null; directness=indirect; tier=B2.
- Young 2026: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2.
- Fu 2026: outcome=Safety and Comorbidity; direction=unclear; directness=review; tier=B2.
- Yang 2025: outcome=Longevity; direction=unclear; directness=indirect; tier=B2.
- Tuesta-Nole 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2.
- Aebi 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
- Erdogan 2025: outcome=Cardiometabolic; direction=mixed; directness=indirect; tier=B2.
- Goonewardena 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Moghadam 2026: outcome=Longevity; direction=negative; directness=indirect; tier=B2.
- Jiang 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Etayo-Urtasun 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2.
- Rubino 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- Skaarup 2026: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2.
- Salerno 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.
- Zhao 2025: outcome=Longevity; direction=negative; directness=review; tier=B1.
- Masri 2026: outcome=Muscle Function; direction=null; directness=protocol; tier=D1.
- Riquelme-Hernandez 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.
- Brutto 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
- Wang 2026: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1.
- Ward 2026: outcome=Immune and Inflammation; direction=null; directness=indirect; tier=B2.
- Song 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
- An 2026: outcome=Longevity; direction=mixed; directness=indirect; tier=B2.
- Lin 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
- Murray 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B2.
- Nguyen 2025b: outcome=Frailty; direction=null; directness=protocol; tier=D1.
- Grazuleviciene 2026: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1.
- Holley 2026: outcome=Longevity; direction=mixed; directness=review; tier=B1.
- Liu 2025b: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.
- Long 2026: outcome=Safety; direction=unclear; directness=review; tier=B1.
- Filev 2026: outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2.
- Delaney 2025: outcome=Cardiometabolic; direction=positive; directness=review; tier=B1.
- Teperikidis 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
- Chen 2026b: outcome=Longevity; direction=unclear; directness=indirect; tier=B2.
- Harbi 2026: outcome=Cardiometabolic; direction=null; directness=review; tier=B2.
- Durstenfeld 2026: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1.
- Ambardekar 2026: outcome=Longevity; direction=unclear; directness=review; tier=B1.

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

### Load-Bearing Included Studies

- Salerno 2026; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.018.
- Riquelme-Hernandez 2026; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.
- Wang 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null.
- Grazuleviciene 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null.
- Liu 2025b; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.
- Durstenfeld 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.
- Sun 2026; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.
- Shen 2026; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P < 0.00001.
- Zheng 2025; tier=B1; directness=review; endpoint=cardiometabolic; direction=null; representative statistic=P = 0.057.
- Jaronczyk 2026; tier=B1; directness=review; endpoint=longevity; direction=negative; representative statistic=P < 0.001.

### Findings Map

Tension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies, so these contrasts are treated as unresolved evidence gaps.

- Sun 2026: Isotemporal substitution of sedentary time with physical activity for cardiovascular health in older adults: a systematic review: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=249 extracted claim(s); receipt-level direction is the coded finding.

- Shen 2026: Effects of exercise on metabolic risk, cardiovascular fitness, and body composition in elderly women of the past decade: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1; finding=representative statistic P < 0.00001.

- Nielsen 2026: High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2; finding=representative statistic P = .69.

- Zheng 2025: Effects of detraining on cardiovascular risk factors in older adults: A systematic review and meta-analysis: outcome=Cardiometabolic; direction=null; directness=review; tier=B1; finding=representative statistic p < 0.001.

- Davidson 2025: Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P = 0.025.

- Minami 2025: SGLT2 Inhibitors in Older Adults With Cardiovascular Disease: A Systematic Review and Meta‐Analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B2; finding=representative statistic p = 0.058.

- Jaronczyk 2026: Mortality Assessment in Patients with Cardiovascular Disease and COVID-19: A Systematic Review and Meta-Analysis: outcome=Longevity; direction=negative; directness=review; tier=B1; finding=representative statistic p < 0.001.

- Liu 2026: A systematic review and meta-analysis of the mechanism of action of Tai Chi on cardiovascular disease: evidence map of aerobic and mind-body exercise pathways: outcome=Cardiometabolic; direction=null; directness=review; tier=B2; finding=representative statistic p < 0.0001.

- Chauveau 2025: Cardiovascular risk factors are associated with lower posterior-medial network functional connectivity in older adults: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P =.02.

- Chen 2026: The Relationship between Sarcopenia and All-Cause and Cardiovascular Mortality Risk among Middle-Aged and Older Adults across Stages 0–3 of Cardiovascular-Kidney-Metabolic Syndrome: Evidence from NHANES and CHARLS: outcome=Longevity; direction=mixed; directness=indirect; tier=B2; finding=representative statistic p = 0.004.

- Liu 2026b: Associations of triglyceride–glucose-related composite obesity indices with cardiovascular diseases and mortality: a systematic review and meta-analysis: outcome=Cardiometabolic; direction=negative; directness=review; tier=B1; finding=representative statistic P < 0.001.

- Liu 2025: Quality of plant-based diets in relation to all-cause and cardiovascular disease mortality in US adults with sarcopenia: a population-based study: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=80 extracted claim(s); receipt-level direction is the coded finding.

- Zhang 2025: Sarcopenic Obesity and Cardiovascular Disease Risk and Mortality: A Systematic Review and Meta-Analysis: outcome=Longevity; direction=negative; directness=review; tier=B2; finding=representative statistic P < .001.

- Ghosh 2026: Harnessing Clinical and Biochemical Data for Personalized Cardiovascular Risk Prediction: a Machine Learning Approach Toward Precision Nutrition: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; finding=representative statistic P < 0.001.

- Saaskilahti 2026: Cardiovascular and glucose-lowering medication use among older adults: results from 9-year follow-up of the FINGER trial: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic p < 0.001.

- Maimaitiniyazi 2026: Association between ambient temperature and out-of-hospital cardiac arrest: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2; finding=representative statistic P < 0.0001.

- Han 2025: Subendocardial Viability Ratio Is Associated With Target Organ Damage and Hints at a Potential Independent Predictor of Cardiovascular Mortality in Older Adults: A Prospective Cohort Study: outcome=Mortality and Survival; direction=mixed; directness=indirect; tier=B2; finding=representative statistic P =0.03.

- Zhu 2025: Changes in Sarcopenia Status and Subsequent Cardiovascular Outcomes: Prospective Cohort Study: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P =.01.

- Lee 2026: Cardiovascular risk associated with polypharmacy in heart failure: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1; finding=representative statistic P = .0003.

- Usmani 2026: Breaking the silos: a systematic review of oral health integration strategies for improved oral health and cardiovascular outcomes: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B1; finding=representative statistic p < 0.001.

- Chu 2026: The effect of high-intensity interval training and moderate-intensity continuous training on cardiorespiratory function in healthy elderly individuals: Systematic review and meta-analysis: outcome=Muscle Function; direction=mixed; directness=review; tier=B2; finding=representative statistic P < .01.

- Thorup 2025: POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=representative statistic p < 0.001.

- Gebretsadik 2025: Dietary manganese, type 2 diabetes, and cardiovascular disease: A UK Biobank cohort study and meta-analysis of over 270,000 individuals: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2; finding=representative statistic p = 0.03.

- You 2026: Frailty and Recurrent Cardiovascular Events in Patients With Obstructive Sleep Apnoea: The SAVE Study: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2; finding=representative statistic p = 0.488.

- Wolfe 2025: Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2; finding=representative statistic P < .01.

- Sheikh 2025: Efficacy and safety of vutrisiran in transthyretin amyloid cardiomyopathy across the age spectrum: The HELIOS‐B trial: outcome=Muscle Function; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.001.

- Jin 2026: Influenza vaccination and cardiovascular and respiratory outcomes in high-risk populations: an umbrella review of systematic reviews and meta-analyzes: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=43 extracted claim(s); receipt-level direction is the coded finding.

- Nguyen 2025: The Efficacy and Safety of Canagliflozin by Frailty Status in Participants of the CANVAS and CREDENCE Trials: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.049.

- Garcia 2026: Frailty Matters: Validation of an Automated Electronic Short Physical Performance Battery (eSPPB) for Predicting 30-Day Mortality in Hospitalized Cardiovascular Patients—A Step-by-Step Study: outcome=Frailty; direction=null; directness=indirect; tier=B2; finding=representative statistic p = 0.009.

- Young 2026: Dietary Inflammatory Index and Cardiovascular Disease Risk in Australian Adults: A Secondary Analysis of the OLIVAUS Trial: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2; finding=representative statistic p < 0.05.

- Fu 2026: Risk association and diagnostic value of body roundness index for cardiovascular-kidney-metabolic-related outcomes: a systematic review and meta-analysis: outcome=Safety and Comorbidity; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.073.

- Yang 2025: Body roundness index and mortality risk in patients with chronic kidney disease: moving beyond the obesity paradox: outcome=Longevity; direction=unclear; directness=indirect; tier=B2; finding=40 extracted claim(s); receipt-level direction is the coded finding.

- Tuesta-Nole 2026: Levothyroxine for subclinical hypothyroidism in older adults: no evidence of benefit on quality of life or cardiovascular outcomes: a systematic review: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.58.

- Aebi 2025: Rationale and design of ‘discontinuing statins in multimorbid older adults without cardiovascular disease (STREAM)’: study protocol of a randomised non-inferiority clinical trial: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=representative statistic p=0.04.

- Erdogan 2025: Beyond BMI: central obesity measures and cardiovascular risk in late life: outcome=Cardiometabolic; direction=mixed; directness=indirect; tier=B2; finding=representative statistic p = 0.002.

- Goonewardena 2026: Lipoprotein(a)-associated proteomic signature predicts cardiovascular disease in young adults: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P < 0.0001.

- Moghadam 2026: Long‐Term Outcomes of Transcatheter Aortic Valve Replacement in Low‐Flow Low‐Gradient Aortic Stenosis: A Reconstructed Time‐to‐Event and Multivariate Meta‐Analysis: outcome=Longevity; direction=negative; directness=indirect; tier=B2; finding=representative statistic P <0.001.

- Jiang 2025: Blood urea nitrogen and cardiovascular disease risk: Evidence from the CHARLS cohort study: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P < .001.

- Etayo-Urtasun 2025: Effects of Exercise on Autonomic Cardiovascular Function in Older Adults: A Systematic Review and Meta-Analysis: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.045.

- Rubino 2026: Invasive vs Conservative Strategy for Frail Older Patients With Myocardial Infarction: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P = .07.

- Skaarup 2026: High-Dose vs Standard-Dose Influenza Vaccines in Older Adults: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2; finding=28 extracted claim(s); receipt-level direction is the coded finding.

- Salerno 2026: A Randomized, Double-Blind, Placebo-Controlled Trial of an Ayurvedic Herbal Formulation and Vitamin C/E on Vascular Function in Patients with Cardiovascular Disease: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1; finding=representative statistic p < 0.05.

- Zhao 2025: Association of frailty and pre-frailty with cardiovascular mortality: a meta-analysis of 26 cohort studies: outcome=Longevity; direction=negative; directness=review; tier=B1; finding=representative statistic p < 0.001.

- Masri 2026: Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy: outcome=Muscle Function; direction=null; directness=protocol; tier=D1; finding=21 extracted claim(s); receipt-level direction is the coded finding.

- Riquelme-Hernandez 2026: Study protocol for a randomized controlled trial of a culturally adapted cardiovascular dance intervention in Mapuche women with obesity: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=19 extracted claim(s); receipt-level direction is the coded finding.

- Brutto 2026: Community-based social connection intervention programme to improve cardiovascular and brain health in older adults in rural Ecuador: study protocol for a quasi-experimental trial: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=16 extracted claim(s); receipt-level direction is the coded finding.

- Wang 2026: Effects of aerobic exercise on integrated cardiovascular health and energy metabolism in patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1; finding=15 extracted claim(s); receipt-level direction is the coded finding.

- Ward 2026: Targeting inflammation in cardiometabolic disease: Icosapent ethyl modulates monocyte‐derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes: outcome=Immune and Inflammation; direction=null; directness=indirect; tier=B2; finding=11 extracted claim(s); receipt-level direction is the coded finding.

- Song 2026: A Multicenter Propensity Score-Matched Cohort Study of Preoperative Antiplatelet Therapy and Postoperative Outcomes in Elderly Surgical Patients: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic p = 0.967.

- An 2026: Joint association of C-reactive protein-triglyceride glucose index-frailty index and non-exercise estimated cardiorespiratory fitness with all-cause mortality in adults aged ≥ 45 years with cardiovascular-kidney-metabolic syndrome stages 0–3: a cross-cohort study using NHANES and CHARLS: outcome=Longevity; direction=mixed; directness=indirect; tier=B2; finding=representative statistic P < 0.001.

- Lin 2026: Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes in chronic obstructive pulmonary disease: A systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials.: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=representative statistic p < 0.001.

- Murray 2026: Inflammatory Biomarkers Predicting Major Adverse Cardiovascular Events in People Living With HIV: A Systematic Review and Meta‐Analysis: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

- Nguyen 2025b: Frailty Assessment for Risk prediction in Gynecologic Oncology patients undergoing surgery and chemotherapy (FARGO) study protocol: Rationale and design of a multi-centre prospective cohort study: outcome=Frailty; direction=null; directness=protocol; tier=D1; finding=6 extracted claim(s); receipt-level direction is the coded finding.

- Grazuleviciene 2026: Ambient air and noise pollution effect on cardiovascular health risk and lifestyle intervention to attenuate it: study protocol for a randomized clinical trial: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1; finding=6 extracted claim(s); receipt-level direction is the coded finding.

- Holley 2026: Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing UK Population with Subclinical Hypothyroidism: Emulated Target Trial (ACEL-UK-ETT).: outcome=Longevity; direction=mixed; directness=review; tier=B1; finding=representative statistic p < 0.0001.

- Liu 2025b: Effects of combining positive psychological intervention and lifestyle intervention on improving cardiovascular health for at-risk older adults: study protocol of a Chinese multicentric community-based randomised controlled trial (ACCOMPLI-CH): outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=4 extracted claim(s); receipt-level direction is the coded finding.

- Long 2026: Efficacy and safety of folic acid on homocysteine and cardiovascular surrogate biomarkers in hyperhomocysteinemia: a systematic review and meta-analysis of RCTs.: outcome=Safety; direction=unclear; directness=review; tier=B1; finding=4 extracted claim(s); receipt-level direction is the coded finding.

- Filev 2026: Association of Acute-Phase IL-6 and SAA with Cardiovascular Events and Mortality Six Years After COVID-19 Infection: An Observational Cohort Study: outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2; finding=2 extracted claim(s); receipt-level direction is the coded finding.

- Delaney 2025: Strawberries modestly improve cognition and cardiovascular health in older adults.: outcome=Cardiometabolic; direction=positive; directness=review; tier=B1; finding=representative statistic p = 0.044.

- Teperikidis 2026: Colchicine for Major Adverse Cardiovascular Events: An Updated ChatGPT-Assisted Systematic Review and Meta-Analysis.: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=2 extracted claim(s); receipt-level direction is the coded finding.

- Chen 2026b: Resting Heart Rate as a Non-Cardiovascular Mortality Marker in Young Adults: A Population-Based Cohort Study: outcome=Longevity; direction=unclear; directness=indirect; tier=B2; finding=1 extracted claim(s); receipt-level direction is the coded finding.

- Harbi 2026: Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials: outcome=Cardiometabolic; direction=null; directness=review; tier=B2; finding=1 extracted claim(s); receipt-level direction is the coded finding.

- Durstenfeld 2026: Rationale, design, and baseline characteristicss of the effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection: EPIC-HIV randomized clinical trial.: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1; finding=1 extracted claim(s); receipt-level direction is the coded finding.

- Ambardekar 2026: Acoramidis, Serum Transthyretin, and Cardiovascular Outcomes in Transthyretin Amyloid Cardiomyopathy: Insights From the ATTRibute-CM Trial.: outcome=Longevity; direction=unclear; directness=review; tier=B1; finding=1 extracted claim(s); receipt-level direction is the coded finding.

### Classification Criteria

- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

### Load-Bearing Tensions

- Severity 5 disagreement: You 2026 vs Delaney 2025; You 2026 reports negative effect on cardiometabolic; Delaney 2025 reports positive on the same outcome — direct conflict
- Severity 5 disagreement: Liu 2026b vs Delaney 2025; Liu 2026b reports negative effect on cardiometabolic; Delaney 2025 reports positive on the same outcome — direct conflict
- Severity 5 disagreement: Young 2026 vs Delaney 2025; Young 2026 reports negative effect on cardiometabolic; Delaney 2025 reports positive on the same outcome — direct conflict
- Severity 4 null vs negative: Wolfe 2025 vs You 2026; You 2026 (negative on cardiometabolic) vs Wolfe 2025 (null on cardiometabolic) — partial conflict
- Severity 4 null vs negative: Wolfe 2025 vs Liu 2026b; Liu 2026b (negative on cardiometabolic) vs Wolfe 2025 (null on cardiometabolic) — partial conflict
- Severity 4 null vs negative: Wolfe 2025 vs Young 2026; Young 2026 (negative on cardiometabolic) vs Wolfe 2025 (null on cardiometabolic) — partial conflict
- Severity 4 null vs negative: Zheng 2025 vs You 2026; You 2026 (negative on cardiometabolic) vs Zheng 2025 (null on cardiometabolic) — partial conflict
- Severity 4 null vs negative: Zheng 2025 vs Liu 2026b; Liu 2026b (negative on cardiometabolic) vs Zheng 2025 (null on cardiometabolic) — partial conflict

## Conclusion

The integrating thesis — that mechanistic plausibility coexists with mixed human-RCT evidence and unresolved boundary conditions — appears to hold across the five subgroup lenses (frailty, sarcopenic obesity, CKM stage, diabetes comorbidity, intervention type), and the cross-study disagreements catalogued in the Cross-Domain Synthesis table (rather than being a weakness of the review) are themselves the principal finding: the evidence does not yet converge on a single Cardiovascular anti-aging claim, and the apparent contradictions are best read as subgroup-specific rather than as study-level noise. Pending further trials and prespecified frailty-stratified analyses, the load-bearing caveat is that no single cardiovascular subgroup definition has been validated as the right stratification axis for anti-aging inference, and the most actionable next step is for ongoing and future RCTs (e. For example, STREAM/Aebi 2025; POLYCAD/Thorup 2025, NCT04136171/Masri 2026) to pre-specify frailty status — using a recognized operational definition such as the Fried phenotype or a gait-speed threshold (Studenski 2011: 0.8 m/s; Cesari 2009: 0.6 m/s) — so that cardiovascular endpoints can be interpreted within rather than across frailty strata.

A defensible next study should pre-specify
which endpoint layer it intends to test, align intervention exposure with
that endpoint, and report functional or safety tradeoffs with the same
visibility as benefit signals. Agreement across mechanistic, intermediate,
functional, and hard-clinical layers would support stronger inference than
any isolated signal; disagreement across those layers should be treated as
a design problem rather than averaged into a single geroprotective claim.

Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Murray 2026, Chen 2026b, Harbi 2026.

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### Background References

*Canonical reference values and methodological references 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).*

- **Studenski 2011.** _Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58._ DOI: 10.1001/jama.2010.1923. PMID: 21205966.
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- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.

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