Cardiovascular aging as a modifiable biological process: Mechanisms, clinical phenotypes, and translational opportunities

Table 2 Representative preclinical and human studies of interventions relevant to cardiovascular aging

Ref.	Model/population	Study design or phase	Primary endpoint(s)	Adverse events	Main findings	Translational evidence and interpretation
Roos et al[107]	Aged/atherosclerotic mice (n = NA)	Preclinical (animal)	Vasomotor function, vascular stiffness, plaque size/composition	Not reported	Vascular senescent cells (↓); endothelial function (↑)	Preclinical
Karnewar et al[95]	ApoE-/- mice (advanced plaque) (n = NA)	Preclinical (animal)	Plaque stability (fibrous cap thickness), mortality	Not reported	Plaque stability (↓); mortality (↑ > 50%; stage-dependent effect)	Preclinical
Garrido et al[94]	Preclinical atherosclerosis models (n = NA)	Preclinical (mechanistic and intervention)	Senescence marker specificity, plaque burden, inflammation	Non-specific effects	Variable plaque effects (↑, context and lineage-specific)	Preclinical
Mannick et al[102]	Older adults (≥ 65 years) (n = 264)	Phase II	Influenza vaccine response (antibody titer)	Mostly grade 1-2: Mouth ulceration, headache, nausea, stomatitis, fatigue	Vaccine response (↑)	Early human evidence
Martens et al[108]	Healthy middle-aged/older adults (n = 24)	Pilot RCT	Blood NAD+ levels, aortic stiffness (PWV)	Well-tolerated; no serious AEs reported	Blood NAD+ (↑); aortic stiffness (pilot) (↓)	Early human evidence
Ridker et al[109]	Post-MI, hsCRP ≥ 2 mg/L (n = 10061)	Phase III	MACE (nonfatal MI, stroke, CV death)	Fatal infections (↑) (1.16% vs 0.69%); leukopenia	MACE (↓) (LDL-C independent)	Cardiovascular outcome evidence; not established for cardiovascular aging
Tardif et al[93]	Recent MI patients (n = 4745)	Phase III	Ischemic CV events (CV death, resuscitated arrest, MI, stroke, urgent revascularization)	Gastrointestinal symptoms: Colchicine 23% vs placebo 20.8%	Ischemic CV events (↓)	Cardiovascular outcome evidence; not an aging-specific indication
Ridker et al[110]	Patients with post-MI or multivessel coronary disease and type 2 diabetes or metabolic syndrome (n = 4786)	Randomized, double-blind, placebo-controlled phase III trial	Major adverse CV events and inflammatory biomarkers	Liver enzyme levels, leukopenia, and selected non-basal-cell skin cancers (↑)	Low-dose methotrexate did not reduce CV events or circulating IL-1β, IL-6, or CRP	Neutral CV outcome; pathway-specific effects of anti-inflammatory therapy
Justice et al[96]	Patients with idiopathic pulmonary fibrosis (n = 14)	Open-label pilot study	Retention and completion rates	1 SAE (pneumonia, resolved)	Intermittent dasatinib plus quercetin showed feasibility and exploratory functional improvement	First-in-human senolytic evidence; no CV efficacy endpoint

The table summarizes representative preclinical and human studies of interventions relevant to cardiovascular aging. The evidence spans experimental animal studies, early human investigations, and large-scale randomized cardiovascular outcome trials. The inclusion of cardiovascular outcome trials indicates clinical evidence for the corresponding biological pathway but does not imply that these interventions are established or approved specifically for cardiovascular aging. NA: Not applicable; MI: Myocardial infarction; hsCRP: High-sensitivity C-reactive protein; NAD⁺: Nicotinamide adenine dinucleotide; RCT: Randomized controlled trial; PWV: Pulse wave velocity; MACE: Major adverse cardiovascular events; CV: Cardiovascular; AE: Adverse event; LDL-C: Low-density lipoprotein cholesterol; IL: Interleukin; CRP: C-reactive protein.