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by researka:v2 · 2026-06-25 23:16:46.448026+04:00
# Hypothesis-Generating Brief: Cardiovascular Subgroups — full paper ## Abstract Evidence-honesty note: 57/63 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. This synthesis tests the thesis that evidence for Cardiovascular Subgroups is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. Older adults carry a disproportionate share of cardiovascular disease (CVD) burden—adults aged ≥65 account for over 80% of all CVD-related deaths (Sun 2026), making cardiovascular subgroups defined by age, frailty, sarcopenia, cardiometabolic–kidney–metabolic (CKM) stage, diabetes status, and intervention modality the central translational question for any anti-aging cardiovascular program. We performed an AI-assisted structured evidence synthesis with explicit audit trail across 63 curated references, categorizing each by study design, directness, population stratum, and outcome class (cardiometabolic, longevity, frailty, muscle function, immune/inflammation, safety, dosing/pharmacokinetics, contextual other), and we then mapped 367 non-orthogonal cross-domain tensions rather than collapsing them into a single direction. We conclude that the Cardiovascular anti-aging case is directionally supportive but incomplete: context-specific cardiometabolic and longevity-direction signals coexist with null findings, subgroup-by-subgroup heterogeneity (especially the Delaney 2025 vs. Liu 2026b/Young 2026 disagreement on cardiometabolic direction), and unresolved direct-vs-protocol tensions, and any translation into clinical recommendations should be hedged pending adequately powered, subgroup-defined RCTs. **Evidence-abstraction note.** The 63 retained reference papers are not 63 independent primary clinical trials: 57 are review, indirect, mechanistic, or registered-protocol source-level summaries, and 6 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence. ## Methods ### Review type and protocol This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-cardiovascular_subgroups-v06-DAILY-2026-06-25T19-13-09Z-R2`. ### Information sources Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-25. ### 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 63 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 | 11 | | None-only claim binding | 3 | | Mixed partial-or-none claim-binding candidates | 70 | | Partial-only claim-binding candidates | 7 | | Strict high-confidence sources | 29 | | Admitted final sources | 63 | ### 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 **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. | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=21; claims=1250 | no extracted directional signal in 14/21 sources | 3 direct; 7 indirect; 3 protocol; 8 review | limited corpus depth in this outcome class | | Cardiometabolic | n=17; claims=853 | unclear signal in 6/17 sources | 3 direct; 4 indirect; 10 review | limited corpus depth in this outcome class | | Longevity | n=9; claims=376 | unclear signal in 3/9 sources | 4 indirect; 5 review | limited corpus depth in this outcome class | | Frailty | n=5; claims=228 | unclear signal in 3/5 sources | 4 indirect; 1 protocol | limited corpus depth in this outcome class | | Muscle Function | n=3; claims=118 | unclear signal in 1/3 sources | 1 indirect; 1 protocol; 1 review | limited corpus depth in this outcome class | | Dosing and Pharmacokinetics | n=2; claims=187 | no extracted directional signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class | | Immune and Inflammation | n=2; claims=13 | unclear signal in 1/2 sources | 2 indirect | limited corpus depth in this outcome class | | Mechanism | n=1; claims=77 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating | | Mortality and Survival | n=1; claims=63 | mixed signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | Safety | n=1; claims=4 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating | | Safety and Comorbidity | n=1; claims=40 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating | This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 21 included sources were assigned to this outcome class. Directional coding: mixed=3, null=14, unclear=4. Directness coding: direct=3, indirect=7, protocol=3, review=8. ### Cardiometabolic Outcomes 17 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=3, null=6, positive=1, unclear=6. Directness coding: direct=3, indirect=4, review=10. ### Longevity Outcomes Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim. ### Frailty Outcomes 5 included sources were assigned to this outcome class. Directional coding: null=2, unclear=3. Directness coding: indirect=4, protocol=1. ### Muscle Function Outcomes See the structured evidence table for Muscle Function Outcomes signals. ### Dosing Pharmacokinetics Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2. ### Immune Outcomes 1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: indirect=1. 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Immune Inflammation Outcomes See the structured evidence table for Immune Inflammation Outcomes signals. ### Mechanism Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1. ### Mortality Survival Outcomes 1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: indirect=1. ### Safety Outcomes 1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: review=1. ### Safety Comorbidity Outcomes 1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: review=1. ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. The principal limitation is evidence-role imbalance. The retained corpus contains 6 direct clinical sources, 56 adjacent clinical sources, and 1 mechanistic or model-system source, which means causal interpretation depends on how much weight is assigned to each evidence tier. A second limitation is endpoint heterogeneity. Study-level signals span the cardiometabolic outcome class, the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes, the longevity and cardiometabolic outcome classes, and the contextual adjacent evidence, longevity, mortality and survival outcome classes; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design. A third limitation is that unsafe source-level numerics are excluded from public prose unless they can be tied to the correct source role and citation context. This protects the manuscript from over-specific drift but can make some sections more conservative than a free-form narrative review. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two. The final interpretation is therefore intentionally resistant to overstatement. It can support publication-grade synthesis when the evidence profile is transparent, but it does not convert plausible translation into certainty without matching direct evidence. Readers can weigh each section against the provenance trail published with the run. Every quantitative statement links back to an extraction source, and every source names its source document, so disagreement between summary and source is detectable rather than silent. 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. ## Conclusion For cardiovascular subgroups, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support cardiovascular subgroups as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging. ## What This Synthesis Adds This synthesis maps 63 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 63 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. 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 | 9 | 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 | | mortality and survival | 0 | 1 | mixed | 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 9 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. ## Evidence Snapshot 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. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - Salerno 2026: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=27. - Riquelme-Hernandez 2026: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=19. - Wang 2026: outcome=cardiometabolic; directness=direct; tier=A1; direction=null; claims=15. - Grazuleviciene 2026: outcome=cardiometabolic; directness=direct; tier=A1; direction=null; claims=6. - Liu 2025b: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=4. - Durstenfeld 2026: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=1. - Sun 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=249. - Shen 2026: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=mixed; claims=234. - Zheng 2025: outcome=cardiometabolic; directness=review; tier=B1; direction=null; claims=152. - Jaronczyk 2026: outcome=longevity; directness=review; tier=B1; direction=negative; claims=121. - Liu 2026b: outcome=cardiometabolic; directness=review; tier=B1; direction=negative; claims=82. - Lee 2026: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=mixed; claims=54. - Usmani 2026: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=unclear; claims=53. - Jin 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=43. - Zhao 2025: outcome=longevity; directness=review; tier=B1; direction=negative; claims=26. - Lin 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=8. - Holley 2026: outcome=longevity; directness=review; tier=B1; direction=mixed; claims=5. - Long 2026: outcome=safety; directness=review; tier=B1; direction=unclear; claims=4. - Delaney 2025: outcome=cardiometabolic; directness=review; tier=B1; direction=positive; claims=2. - Teperikidis 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=2. - Ambardekar 2026: outcome=longevity; directness=review; tier=B1; direction=unclear; claims=1. - Nielsen 2026: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=159. - Davidson 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=142. - Minami 2025: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=135. - Liu 2026: outcome=cardiometabolic; directness=review; tier=B2; direction=null; claims=114. - Chauveau 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=111. - Chen 2026: outcome=longevity; directness=indirect; tier=B2; direction=mixed; claims=94. - Liu 2025: outcome=frailty; directness=indirect; tier=B2; direction=unclear; claims=80. - Zhang 2025: outcome=longevity; directness=review; tier=B2; direction=negative; claims=79. - Saaskilahti 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=72. - Maimaitiniyazi 2026: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=70. - Han 2025: outcome=mortality survival; directness=indirect; tier=B2; direction=mixed; claims=63. - Zhu 2025: outcome=frailty; directness=indirect; tier=B2; direction=unclear; claims=60. - Chu 2026: outcome=muscle function; directness=review; tier=B2; direction=mixed; claims=52. - Gebretsadik 2025: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=48. - You 2026: outcome=cardiometabolic; directness=indirect; tier=B2; direction=negative; claims=47. - Wolfe 2025: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=46. - Sheikh 2025: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=45. - Garcia 2026: outcome=frailty; directness=indirect; tier=B2; direction=null; claims=41. - Nguyen 2025: outcome=frailty; directness=indirect; tier=B2; direction=unclear; claims=41. ### 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 Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Ghosh 2026, Thorup 2025, Fu 2026, Yang 2025, Tuesta-Nole 2026, Aebi 2025, Erdogan 2025, Goonewardena 2026, Jiang 2025, Etayo-Urtasun 2025, Rubino 2026, Skaarup 2026, Masri 2026, Brutto 2026, Ward 2026, Song 2026, An 2026, Murray 2026, Nguyen 2025b, Filev 2026, Chen 2026b, Harbi 2026. ## References - **Sun 2026.** _Isotemporal substitution of sedentary time with physical activity for cardiovascular health in older adults: a systematic review._ Frontiers in Sports and Active Living, 2026. 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