Hypothesis-Generating Brief: Vascular age

Hypothesis-Generating Brief: Vascular age

Abstract

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

Evidence-honesty note: 14/15 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 paper synthesizes evidence on Vascular age across 15 included source papers and 417 high-confidence extracted claims.

The evidence profile contains 1 direct clinical source, 13 adjacent clinical sources, and 1 mechanistic or model-system source, with 14 cross-study disagreements across the evidence base.

No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.

The conclusion is that Vascular age should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.

Methods

Classification criteria: Outcome class assignment follows the primary endpoint or claim role recorded in the manifest, with contextual adjacent evidence separated from cardiometabolic, immune, safety, functional, and other endpoint classes. Directness is coded as direct when the source tests the named exposure or construct in the target population with aging-relevant clinical or hard endpoints; indirect when human evidence uses surrogate or adjacent endpoints; mechanistic when the evidence is preclinical, pathway, or model-based; and review when the source synthesizes rather than directly tests effects. Evidence tier records the same hierarchy before claims are interpreted.

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-vascular_age-v06-DAILY-2026-06-26T20-01-58Z-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: 2026-06-26.

Search strategy

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

• vascular age AND aging AND human
• vascular age AND older adults
• vascular age AND randomized controlled trial
• arterial stiffness AND aging AND human
• arterial stiffness AND older adults
• arterial stiffness AND randomized controlled trial
• vascular aging AND aging AND human
• vascular aging AND older adults
• vascular aging AND randomized controlled trial
• coronary artery calcium AND aging AND human

Eligibility criteria

• Sources whose primary content addresses vascular age.
• 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 180 records in the receipt-candidate union, 60 were classified as source candidates and 15 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	180
Classified source candidates	60
No extractable claims	13
None-only claim binding	0
Mixed partial-or-none claim-binding candidates	17
Partial-only claim-binding candidates	3
Strict high-confidence sources	2
Admitted final sources	15

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

• Exclusion accounting is captured in the source-admission funnel above: retrieval, deduplication, claim-binding, and strict high-confidence admission reduce source candidates to the retained source set. The audit buckets are overlapping and non-additive, so the manuscript does not infer a simple excluded = candidates - admitted count.

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, deficiency prevalence, longevity, mechanism, 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.

Evidence Landscape

Source directness breakdown: 1/15 retained sources directly address the stated topic and aging-relevant hard endpoints; 14/15 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

• Sheng 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Nguyen 2026: outcome=Population / prevalence; direction=unclear; directness=indirect; tier=B2.
• Wang 2024: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1.
• Werlang 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Rodilla 2026: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.
• Alanis 2025: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.
• Luo 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2.
• Vicente-Gabriel 2024: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
• Azizzadeh 2026: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.
• Lu 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Kozlik 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Joshi 2025: outcome=Safety and Comorbidity; direction=null; directness=protocol; tier=D1.
• Mian 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Carmo 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.
• Kakaletsis 2024: outcome=Longevity; direction=unclear; directness=review; tier=B1.

Substantive evidence synthesis: The manifest includes 15 retained sources, 1 direct-source row(s), and receipt-level directional coding across null=7, unclear=8. Receipt-level direction is not a statement that the source abstracts lack directional statistics; source-level signals are reported separately. Representative source-level signals are: Sheng 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic; finding=representative statistic P <0.001; source-level statistic reported; claims=102; Nguyen 2026: outcome=Population / prevalence; direction=unclear; directness=indirect; tier=B2; result=Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated; finding=representative statistic p = 0.047; source-level statistic reported; claims=64; Wang 2024: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1; result=Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart; finding=representative statistic p < 0.05; source-level statistic reported; claims=54; Werlang 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=The EVA Study: Early Vascular Aging in Women With History of Preeclampsia; finding=representative statistic P =0.011; source-level statistic reported; claims=29; Luo 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; result=Effects of L-citrulline supplementation and watermelon intake on arterial stiffness and endothelial function in; finding=representative statistic p = 0.0007; source-level statistic reported; claims=22; Lu 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Estimating Vascular Age to Evaluate the Association Between Aging and Cardiovascular Disease; finding=14 extracted claim(s); receipt-level direction is the coded finding; claims=14; Mian 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Arterial Age and Early Vascular Aging, But Not Chronological Age, Are Associated With Faster Thoracic Aortic Aneurysm; finding=representative statistic P =0.001; source-level statistic reported; claims=8; Kakaletsis 2024: outcome=Longevity; direction=unclear; directness=review; tier=B1; result=Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis.; finding=4 extracted claim(s); receipt-level direction is the coded finding; claims=4. These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating.

Key Findings

Key findings from source synthesis:

• Wang 2024: Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart; representative statistic p < 0.05; source-level statistic reported; outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1.
• Sheng 2025: Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic; representative statistic P <0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Nguyen 2026: Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated; representative statistic p = 0.047; source-level statistic reported; outcome=Population / prevalence; direction=unclear; directness=indirect; tier=B2.
• Werlang 2023: The EVA Study: Early Vascular Aging in Women With History of Preeclampsia; representative statistic P =0.011; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
• Alanis 2025: Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested; representative statistic P =0.762; source-level statistic reported; outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.

Source-level findings by outcome class:

• Cardiometabolic: Wang 2024 (Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart; representative statistic p < 0.05; source-level statistic reported; direction=unclear; directness=direct; tier=A1); Rodilla 2026 (Vascular age as a key for a team-based approach to manage blood pressure bridging community pharmacists and primary; 28 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2); Azizzadeh 2026 (Prevalence and determinants of vascular aging in Austria – a holistic view: the LEAD study; 16 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).
• Contextual Adjacent Evidence: Sheng 2025 (Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic; representative statistic P <0.001; source-level statistic reported; direction=unclear; directness=indirect; tier=B2); Werlang 2023 (The EVA Study: Early Vascular Aging in Women With History of Preeclampsia; representative statistic P =0.011; source-level statistic reported; direction=unclear; directness=indirect; tier=B2); Luo 2025 (Effects of L-citrulline supplementation and watermelon intake on arterial stiffness and endothelial function in; representative statistic p = 0.0007; source-level statistic reported; direction=unclear; directness=review; tier=B2).
• Population / prevalence: Nguyen 2026 (Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated; representative statistic p = 0.047; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).
• Longevity: Kakaletsis 2024 (Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis.; 4 extracted claim(s); receipt-level direction is the coded finding; direction=unclear; directness=review; tier=B1).
• Mechanism: Alanis 2025 (Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested; representative statistic P =0.762; source-level statistic reported; direction=null; directness=mechanistic; tier=C1).
• Safety and Comorbidity: Joshi 2025 (Arterial stiffness in acute decompensated heart failure and acute kidney injury: a prospective observational cohort; 10 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=protocol; tier=D1).

Synthesis interpretation: These source-level findings connect risk-marker, mechanistic, and intervention-adjacent signals into follow-up hypotheses, not a clinical efficacy claim. Direct/interventional rows define the ceiling for applied interpretation; indirect prevalence, risk-association, mechanistic, protocol, and review rows define context and uncertainty. Representative coded source verdicts remain: Sheng 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic; finding=representative statistic P <0.001; source-level statistic reported; claims=102; Nguyen 2026: outcome=Population / prevalence; direction=unclear; directness=indirect; tier=B2; result=Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated; finding=representative statistic p = 0.047; source-level statistic reported; claims=64; Wang 2024: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1; result=Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart; finding=representative statistic p < 0.05; source-level statistic reported; claims=54; Werlang 2023: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=The EVA Study: Early Vascular Aging in Women With History of Preeclampsia; finding=representative statistic P =0.011; source-level statistic reported; claims=29. The bounded conclusion follows from source direction, outcome class, evidence tier, and directness rather than from source count alone. Publication-year note: citation years follow the manifest metadata; when DOI/PubMed dates differ, the source should be treated as bibliographic/in-press metadata and not used for year-specific claims.

Results

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Vascular age / Contextual Adjacent Evidence	n=8; claims=214	significant source statistic in 4/8 sources; receipt-level direction coded unclear	5 indirect; 1 protocol; 2 review	limited corpus depth in this outcome class
Vascular age / Cardiometabolic	n=3; claims=98	significant source statistic in 1/3 sources; receipt-level direction coded null	1 direct; 2 indirect	limited corpus depth in this outcome class
Vascular age / Population / prevalence	n=1; claims=64	significant source statistic in 1/1 sources; receipt-level direction coded unclear	1 indirect	single-source slice; hypothesis-generating
Vascular age / Longevity	n=1; claims=4	unclear signal in 1/1 sources	1 review	single-source slice; hypothesis-generating
Vascular age / Mechanism	n=1; claims=27	reported statistic in 1/1 sources; receipt-level direction coded null	1 mechanistic	single-source slice; hypothesis-generating
Vascular age / Safety and Comorbidity	n=1; claims=10	no extracted directional signal in 1/1 sources	1 protocol	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: 11 sources; significant source statistic in 5/11 sources; receipt-level direction coded unclear.
• Skeletal and muscle 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.

Contextual Adjacent Evidence Outcomes

Contextual Adjacent Evidence remains a separate Results slice for Vascular age (n=8; claims=214; significant source statistic in 4/8 sources; receipt-level direction coded unclear; 5 indirect; 1 protocol; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Sheng 2025 (Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic; representative statistic P <0.001; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).
• Werlang 2023 (The EVA Study: Early Vascular Aging in Women With History of Preeclampsia; representative statistic P =0.011; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).
• Luo 2025 (Effects of L-citrulline supplementation and watermelon intake on arterial stiffness and endothelial function in; representative statistic p = 0.0007; source-level statistic reported; direction=unclear; directness=review; tier=B2).
• Kozlik 2026 (Vascular Endothelial Function, Carotid Intima–Media Thickness and Coronary Artery Calcification in Women; representative statistic p = 0.253; source-level statistic reported; direction=null; directness=indirect; tier=B2).

Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.

Cardiometabolic Outcomes

Cardiometabolic remains a separate Results slice for Vascular age (n=3; claims=98; significant source statistic in 1/3 sources; receipt-level direction coded null; 1 direct; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Wang 2024 (Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart; representative statistic p < 0.05; source-level statistic reported; direction=unclear; directness=direct; tier=A1).
• Rodilla 2026 (Vascular age as a key for a team-based approach to manage blood pressure bridging community pharmacists and primary; 28 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).
• Azizzadeh 2026 (Prevalence and determinants of vascular aging in Austria – a holistic view: the LEAD study; 16 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=indirect; tier=B2).

Safety and Comorbidity Outcomes

Safety and Comorbidity remains a separate Results slice for Vascular age (n=1; claims=10; no extracted directional signal in 1/1 sources; 1 protocol; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Joshi 2025 (Arterial stiffness in acute decompensated heart failure and acute kidney injury: a prospective observational cohort; 10 extracted claim(s); receipt-level direction is the coded finding; direction=null; directness=protocol; tier=D1).

Mechanism Outcomes

Mechanism remains a separate Results slice for Vascular age (n=1; claims=27; reported 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. Source-level findings are:

• Alanis 2025 (Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested; representative statistic P =0.762; source-level statistic reported; direction=null; directness=mechanistic; tier=C1).

Population / prevalence Outcomes

Population / prevalence remains a separate Results slice for Vascular age (n=1; claims=64; significant source statistic in 1/1 sources; receipt-level direction coded unclear; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Nguyen 2026 (Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated; representative statistic p = 0.047; source-level statistic reported; direction=unclear; directness=indirect; tier=B2).

Longevity Outcomes

Longevity remains a separate Results slice for Vascular age (n=1; claims=4; unclear signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Kakaletsis 2024 (Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis.; 4 extracted claim(s); receipt-level direction is the coded finding; direction=unclear; directness=review; tier=B1).

Limitations

Forward-dated citation note: citations are treated as bibliographic/in-press metadata for reproducibility; they are not used for year-specific claims, and readers should verify them against the public source records before relying on chronology-sensitive interpretations.

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

The curated corpus of 15 reference papers is heavily skewed toward observational, mechanistic, and protocol-level evidence and contains almost no long-term, hard-outcome randomized trials in non-diabetic adults, which sharply constrains what the synthesis can defensibly claim. Only one source (Wang 2024) is classified as an RCT with a clinical/functional endpoint, and even that trial is a 24-week intervention in postmenopausal women using a Tai Chi-based program; there is no large, multi-year mortality or major adverse cardiovascular events (MACE) trial of any vascular-age-modifying therapy in the general adult population represented in the corpus (Wang 2024). Mechanistic and animal-model work is represented by Alanis 2025, and protocol-only documents (Vicente-Gabriel 2024; Joshi 2025) describe studies whose results are not yet in the evidence base, so any outcome they foreshadow cannot be quantitatively supported. Consequently, headline claims linking vascular age modification to lifespan, hard cardiovascular events, or functional survival in non-diabetic adults cannot be drawn from this corpus alone.

Population specificity is another central limitation: the enrolled samples are narrow, demographically concentrated, and in several cases sex-restricted, so external validity to the broader adult population is constrained. Wang 2024 enrolled middle-aged and older postmenopausal women, Werlang 2023 sampled women with a history of preeclampsia, and Nguyen 2026 restricted enrollment to middle-aged and older men stratified by testosterone status, meaning that men outside the hypogonadism spectrum, premenopausal women, and adolescents are not represented in these clinical or mechanistic strands. The EVA-Adic protocol (Vicente-Gabriel 2024) explicitly targets young adults with addictions, yet the published evidence is not yet available, so the young-adult gap remains unfilled. In short, the corpus is enriched for postmenopausal women, men with low testosterone, and central-European cohorts, and conclusions about vascular age in other demographic strata should be regarded as extrapolations rather than direct inferences.

The endpoint scope of the corpus is another limitation: many clinically relevant outcomes are not measured, are measured only as surrogates, or are reported with insufficient follow-up duration to support causal interpretation. Vascular age itself is typically derived from surrogate measures such as estimated pulse wave velocity (ePWV ≥10 m/s in Sheng 2025), carotid intima-media thickness (Kozlik 2026), or pulse-wave-velocity-based arterial age (Mian 2023), and the broader literature has long cautioned that surrogate endpoint associations do not guarantee hard-outcome validity (Ioannidis 2005). Functional endpoints tied to gait speed, grip strength, or sarcopenia cutoffs (e. For example, the EWGSOP2 thresholds of 27 kg for men and 16 kg for women, Cruz-Jentoft 2019) are not measured in any source, and standard mobility thresholds such as 0.8 m/s (Studenski 2011) and 0.6 m/s (Cesari 2009) are not directly engaged by this corpus, which means the vascular-age-to-physical-function pathway cannot be quantitatively bridged from the current evidence base.

Design-limit note: Protocol, mechanistic, observational, or cross-sectional sources (Alanis 2025; Vicente-Gabriel 2024; Joshi 2025) are retained for context but cannot support causal claims individually. They bound the evidence map and should not be read as direct clinical efficacy evidence.

Conclusion

For clinical practice, the current evidence supports a hypothesis that vascular age indices may serve as useful risk-stratification adjuncts in adults with, or at risk for, cardiometabolic disease, but does not yet justify marketing any specific intervention as a proven standalone anti-aging therapy on the basis of the vascular-age pathway alone. Lifestyle, dietary, and exercise strategies that improve general cardiovascular health retain their established general-health support independent of, and separate from, any unproven claim that they reverse vascular aging in a geroprotective sense, and off-label pharmacologic use of vascular-age-modifying compounds for anti-aging indications should remain within the boundary of pending further trials until hard-outcome randomized data accrue. Several limitations bound this synthesis: the inclusion of forward-dated 2026 citations (Nguyen 2026, Rodilla 2026, Azizzadeh 2026, Lu 2026, Kozlik 2026) means that the reproducibility of their reported numerics cannot yet be independently verified by reanalysis, and any downstream meta-analysis built on this evidence base should treat those effect sizes as provisional. Directness is also uneven, with only one direct randomized trial (Wang 2024) anchoring a body otherwise dominated by indirect, mechanistic, protocol, and review-level designs, which constrains how confidently vascular age can be linked to patient-important outcomes. Until those gaps are closed, the prudent interpretation is that vascular age appears to be a biologically coherent and statistically informative marker of cardiometabolic risk whose translation into a discrete anti-aging intervention remains, on present evidence, incomplete.

Direct-source ceiling: The direct clinical source set is Wang 2024 (tier=A1; directness=direct; direction=unclear). The remaining 14 included sources are indirect, review, protocol, or mechanistic/contextual evidence, so they can refine scope and uncertainty but do not outweigh the direct source role. The conclusion remains bounded by 14 same-outcome tensions and the source-level evidence hierarchy.

What This Synthesis Adds

This synthesis maps 15 included sources on Vascular Age across 6 outcome classes and 14 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 15 curated reference papers, the evidence base for Vascular shows a context-dependent profile. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Vascular 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 mechanism vs clinical between Werlang 2023 and Wang 2024 on contextual adjacent evidence (severity 3/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Kakaletsis 2024) emphasize convergent signals on Vascular Age. 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	1	unclear	direct interventional hard-endpoint gap
cardiometabolic	1	2	null, unclear	replication gap
contextual adjacent evidence	0	8	null, unclear	direct interventional hard-endpoint gap
mechanism	0	1	null	direct interventional hard-endpoint gap
deficiency prevalence	0	1	unclear	direct interventional hard-endpoint gap
safety and comorbidity	0	1	null	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: unclear
P2	cardiometabolic: replication gap	1 direct and 2 indirect sources; direction profile: null, unclear
P3	contextual adjacent evidence: direct interventional hard-endpoint gap	0 direct and 8 indirect sources; direction profile: null, unclear
P4	mechanism: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P5	deficiency prevalence: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: unclear

Next-Study Design Recommendation

The next high-yield study for Vascular Age 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

Directional coding note: Null or no extracted directional signal means no coded positive, negative, or mixed effect was extracted for that specific outcome class; it is not an absence-of-support finding. Positive, negative, mixed, unclear, and null are outcome-specific codes, so a bounded rationale can be supported by adjacent or different outcome evidence while another outcome remains null or unclear. Contextual claims contain bibliographic background, mechanism, methods, exposure definitions, or population context rather than effect-direction evidence. When an outcome-class summary uses no extracted directional signal, it should state the source proportion, such as X/Y sources, to avoid ambiguity.

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

Load-Bearing Included Studies

• Wang 2024; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.01.
• Kakaletsis 2024; tier=B1; directness=review; endpoint=longevity; direction=unclear.
• Sheng 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001.
• Nguyen 2026; tier=B2; directness=indirect; endpoint=deficiency prevalence; direction=unclear; representative statistic=P < 0.0001.
• Werlang 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.0007.
• Rodilla 2026; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.
• Luo 2025; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.00001.
• Azizzadeh 2026; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.
• Kozlik 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.253.
• Lu 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear.

Findings Map

• Sheng 2025: Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic Predisposition on Coronary Artery Disease: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P <0.001; source-level statistic reported.

• Nguyen 2026: Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle‐Age and Older Men With Low Testosterone: outcome=Population / prevalence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.047; source-level statistic reported.

• Wang 2024: Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart Rate Sensors: A 24-Week RCT Study Based on the New Compilation of Tai Chi (Bafa Wubu): outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1; finding=representative statistic p < 0.05; source-level statistic reported.

• Werlang 2023: The EVA Study: Early Vascular Aging in Women With History of Preeclampsia: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P =0.011; source-level statistic reported.

• Rodilla 2026: Vascular age as a key for a team-based approach to manage blood pressure bridging community pharmacists and primary healthcare physicians—The TOGETHER trial: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2; finding=28 extracted claim(s); receipt-level direction is the coded finding.

• Alanis 2025: Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested Myocardial Injury: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; finding=representative statistic P =0.762; source-level statistic reported.

• Luo 2025: Effects of L-citrulline supplementation and watermelon intake on arterial stiffness and endothelial function in middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.0007; source-level statistic reported.

• Vicente-Gabriel 2024: Relationship between addictions and obesity, physical activity and vascular aging in young adults (EVA-Adic study): a research protocol of a cross-sectional study: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=20 extracted claim(s); receipt-level direction is the coded finding.

• Azizzadeh 2026: Prevalence and determinants of vascular aging in Austria – a holistic view: the LEAD study: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2; finding=16 extracted claim(s); receipt-level direction is the coded finding.

• Lu 2026: Estimating Vascular Age to Evaluate the Association Between Aging and Cardiovascular Disease: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=14 extracted claim(s); receipt-level direction is the coded finding.

• Kozlik 2026: Vascular Endothelial Function, Carotid Intima–Media Thickness and Coronary Artery Calcification in Women: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic p = 0.253; source-level statistic reported.

• Joshi 2025: Arterial stiffness in acute decompensated heart failure and acute kidney injury: a prospective observational cohort study protocol in a tertiary hospital setting: outcome=Safety and Comorbidity; direction=null; directness=protocol; tier=D1; finding=10 extracted claim(s); receipt-level direction is the coded finding.

• Mian 2023: Arterial Age and Early Vascular Aging, But Not Chronological Age, Are Associated With Faster Thoracic Aortic Aneurysm Growth: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P =0.001; source-level statistic reported.

• Carmo 2025: Methylarginine levels and their impact on vascular aging: a systematic review: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2; finding=5 extracted claim(s); receipt-level direction is the coded finding.

• Kakaletsis 2024: Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis.: outcome=Longevity; direction=unclear; directness=review; tier=B1; finding=4 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 3 indirectness gap: Wang 2024 vs Rodilla 2026; Wang 2024 (direct, A1) vs Rodilla 2026 (indirect) on cardiometabolic — direct vs indirect must be kept separate
• Severity 3 indirectness gap: Wang 2024 vs Azizzadeh 2026; Wang 2024 (direct, A1) vs Azizzadeh 2026 (indirect) on cardiometabolic — direct vs indirect must be kept separate
• Severity 3 mechanism vs clinical: Werlang 2023 vs Wang 2024; Wang 2024 (direct, cardiometabolic) vs Werlang 2023 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome
• Severity 3 mechanism vs clinical: Mian 2023 vs Wang 2024; Wang 2024 (direct, cardiometabolic) vs Mian 2023 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome
• Severity 3 mechanism vs clinical: Vicente-Gabriel 2024 vs Wang 2024; Wang 2024 (direct, cardiometabolic) vs Vicente-Gabriel 2024 (protocol, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome
• Severity 3 mechanism vs clinical: Wang 2024 vs Alanis 2025; Wang 2024 (direct, cardiometabolic) vs Alanis 2025 (mechanistic, mechanism) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome
• Severity 3 mechanism vs clinical: Wang 2024 vs Joshi 2025; Wang 2024 (direct, cardiometabolic) vs Joshi 2025 (protocol, safety comorbidity) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome
• Severity 3 mechanism vs clinical: Wang 2024 vs Luo 2025; Wang 2024 (direct, cardiometabolic) vs Luo 2025 (review, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome

References

• Sheng 2025. Integrating Vascular Aging and Genetic Risk: The Combined Impact of Estimated Pulse Wave Velocity and Genetic Predisposition on Coronary Artery Disease. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.125.042610. PMID: 41368830.
• Nguyen 2026. Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle‐Age and Older Men With Low Testosterone. Aging Cell, 2026. DOI: 10.1111/acel.70457. PMID: 41986916.
• Wang 2024. Impact of a Precision Intervention for Vascular Health in Middle-Aged and Older Postmenopausal Women Using Polar Heart Rate Sensors: A 24-Week RCT Study Based on the New Compilation of Tai Chi (Bafa Wubu). Sensors (Basel, Switzerland), 2024. DOI: 10.3390/s24175832. PMID: 39275744.
• Werlang 2023. The EVA Study: Early Vascular Aging in Women With History of Preeclampsia. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2023. DOI: 10.1161/JAHA.122.028116. PMID: 37026558.
• Rodilla 2026. Vascular age as a key for a team-based approach to manage blood pressure bridging community pharmacists and primary healthcare physicians—The TOGETHER trial. Frontiers in Public Health, 2026. DOI: 10.3389/fpubh.2025.1723100. PMID: 41613082.
• Alanis 2025. Accelerated Vascular Aging as a Possible Mechanism of Troponin I Release in the Absence of Clinically Manifested Myocardial Injury. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.037718. PMID: 40145294.
• Luo 2025. Effects of L-citrulline supplementation and watermelon intake on arterial stiffness and endothelial function in middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Nutrition, 2025. DOI: 10.3389/fnut.2025.1632952. PMID: 41323997.
• Vicente-Gabriel 2024. Relationship between addictions and obesity, physical activity and vascular aging in young adults (EVA-Adic study): a research protocol of a cross-sectional study. Frontiers in Public Health, 2024. DOI: 10.3389/fpubh.2024.1322437. PMID: 38344236.
• Azizzadeh 2026. Prevalence and determinants of vascular aging in Austria – a holistic view: the LEAD study. Journal of Hypertension, 2026. DOI: 10.1097/HJH.0000000000004227. PMID: 41537373.
• Lu 2026. Estimating Vascular Age to Evaluate the Association Between Aging and Cardiovascular Disease. Aging Cell, 2026. DOI: 10.1111/acel.70503. PMID: 42087283.
• Kozlik 2026. Vascular Endothelial Function, Carotid Intima–Media Thickness and Coronary Artery Calcification in Women. Journal of Clinical Medicine, 2026. DOI: 10.3390/jcm15114087. PMID: 42278949.
• Joshi 2025. Arterial stiffness in acute decompensated heart failure and acute kidney injury: a prospective observational cohort study protocol in a tertiary hospital setting. BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-097718. PMID: 40550719.
• Mian 2023. Arterial Age and Early Vascular Aging, But Not Chronological Age, Are Associated With Faster Thoracic Aortic Aneurysm Growth. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2023. DOI: 10.1161/JAHA.122.029466. PMID: 37581401.
• Carmo 2025. Methylarginine levels and their impact on vascular aging: a systematic review. Vascular Biology, 2025. DOI: 10.1530/VB-25-0004. PMID: 41378901.
• Kakaletsis 2024. Advanced vascular aging and outcomes after acute ischemic stroke: a systematic review and meta-analysis. J Hum Hypertens, 2024. DOI: 10.1038/s41371-024-00961-y. PMID: 39317753.

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.
• Cesari 2009. Cesari M, Kritchevsky SB, Newman AB, et al. Added value of physical performance measures in predicting adverse health-related events. J Gerontol A Biol Sci Med Sci. 2009;64(7):772-779. DOI: 10.1093/gerona/glp012. PMID: 19349594.
• Cruz-Jentoft 2019. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31. DOI: 10.1093/ageing/afy169. PMID: 30312372.
• 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.