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

Table 1 Major molecular mechanisms of cardiovascular aging discussed in this review[111-117]

Aging mechanism or biomarker category	Representative biomarkers or pathways	Sample and assessment method	Potential clinical or cardiovascular relevance	Ref.
DNA damage and telomere attrition	γ-H2AX, 8-oxo-dG, telomere length	Immunofluorescence, comet assay, qPCR in leukocytes	DNA damage and telomere shortening induce EC and VSMC senescence, accelerating atherosclerosis and myocardial aging	Blackburn et al[32]; Deng et al[33]; Li et al[34]; Bloom et al[41]
Mitochondrial dysfunction and oxidative stress	mtROS, SIRT3/PGC-1α, ATP loss	Seahorse assay, ROS probes, WB	Excess mtROS triggers vascular inflammation and cardiac fibrosis; restoring SIRT3 improves endothelial function	Dai et al[22]; Goodman et al[23]; Dai et al[24]; Bachschmid et al[40]; Bloom et al[41]; Mondragon et al[49]
Nutrient sensing imbalance (mTOR/AMPK/SIRT axis)	mTOR, AMPK, SIRT1	WB, phosphoprotein analysis	Overactive mTOR and low SIRT1/AMPK promote metabolic inflammation, endothelial dysfunction, and cardiac hypertrophy	Zhan et al[46]; Fontana et al[88]; Qu et al[89]; Justice et al[96]; Greenberg et al[97]; Zhang et al[99]
Cellular senescence and SASP secretion	p16INK4a, p21CIP1, SA-β-gal, IL-6/IL-1β/TNF-α (SASP)	qPCR, IHC, ELISA	Senescent ECs and VSMCs release SASP, chronic inflammation, plaque instability and impaired repair	Di Micco et al[9]; Gorgoulis et al[12]; Owens et al[15]; Mehdizadeh et al[16]; Wang et al[18]; Honda et al[19]; Garrido et al[94]; Karnewar et al[95]
Clonal hematopoiesis of indeterminate potential	DNMT3A, TET2, ASXL1, JAK2 mutations; VAF ≥ 2%	Targeted DNA sequencing (NGS) in peripheral blood	Identifies an age-related hematopoietic state associated with atherosclerotic CVD, heart failure, arrhythmias, and valvular disease	Jaiswal et al[111]; Tan et al[112]
Stem cell exhaustion and impaired regeneration	CD34+ EPCs, c-Kit+ cardiac progenitors	Flow cytometry, colony forming assay	Reduced progenitor pool limits endothelial repair and neovascularization in aging hearts and vessels	Mehdizadeh et al[16]; Sorokina et al[75]
Inflammaging and immune dysregulation	CRP, IL-6, NLRP3 inflammasome activation	ELISA, transcriptomics	Low-grade systemic inflammation drives endothelial activation and cardiac fibrosis; IL-1β blockade reduces events in elderly	Khalafi et al[56]; Müller and Di Benedetto[57]; Danesh et al[58]; Zhou et al[59]; Thompson and Nidorf[92]; Tardif et al[93]
Altered intercellular communication (exosomes/SASP spread)	Exosomal miR-21/miR-126, NF-κB, NLRP3	Nanoparticle tracking, qPCR, WB	Senescent cell-derived exosomes propagate inflammatory signals and fibrotic remodeling across cardiac tissues	Acosta et al[10]; Admasu et al[11]; Gorgoulis et al[12]
Extracellular vesicles	EV surface antigens (EV aging index); endothelial micro-vesicles (EMVs: CD31+/42b-)	Nanoparticle tracking, flow cytometry, ELISA in serum/plasma	EVs mediate endothelial dysfunction and senescence-associated vascular dysfunction; EMVs increase with age and correlate with endothelial vasodilator dysfunction; EV aging index stratifies CV risk	Burrello et al[80]; DeSouza et al[113]
Epigenetic aging biomarkers	Horvath clock, Hannum clock, PhenoAge, GrimAge, epigenetic age acceleration	DNA methylation arrays or sequencing in peripheral blood	Quantify biological age and age acceleration; associated with subclinical atherosclerosis, arterial stiffness, heart failure, and cardiovascular mortality	Allegra et al[27]; Sánchez-Cabo et al[28]; Chen et al[29]; Fox et al[30]; Joyce et al[31]; Yamada[81]; Hannum et al[82]; Horvath[83]; Ammous et al[84]; Feng et al[85]
Proteomic aging clocks	Multi-marker protein panels, including 204-protein and organ-specific proteomic age scores	Olink, SomaScan, or mass-spectrometry-based plasma proteomics	Estimate systemic and organ-specific biological age and predict incident cardiovascular disease, multimorbidity, and mortality	Argentieri et al[114]; Robinson et al[115]
Metabolomic and lipidomic aging scores	MetaboPhenoAge; lipidomic metabolic age score	Mass spectrometry or NMR spectroscopy in plasma or serum	Capture metabolic aging and may predict incident cardiovascular disease and cardiometabolic risk beyond chronological age	You et al[116]; Wang et al[117]
Circulating inflammatory and myocardial stress biomarkers	hsCRP, IL-6, TNF-α, GDF-15, sST2, galectin-3, NT-proBNP, hs-cTn	ELISA, immunoassay, serum or plasma	Reflect inflammaging, myocardial stress, fibrosis, and subclinical cardiovascular injury; may support risk stratification in older adults	Giovannini et al[73]; Oppong et al[76]; Parikh et al[77]; Keng et al[78]
Circulating microRNAs	miR-23a-3p, miR-92a-3p, and other age-associated microRNAs	qPCR, small-RNA sequencing in plasma or serum	May reflect vascular inflammation, endothelial dysfunction, and cardiovascular risk in older adults	La Grotta et al[79]

The table integrates mechanistic biomarkers, circulating indicators, molecular aging clocks, and multi-omics measures relevant to cardiovascular aging. Evidence categories reflect the predominant supporting data and do not imply clinical validation or routine applicability. mTOR: Mechanistic target of rapamycin; AMPK: Adenosine 5’-monophosphate-activated protein kinase; SIRT: Sirtuin (silent information regulator); SASP: Senescence-associated secretory phenotype; γ-H2AX: The phosphorylated form of histone H2AX; 8-oxo-dG: 8-hydroxy-2’-deoxyguanosine; mtROS: Mitochondrial reactive oxygen species; SIRT: Sirtuin (silent information regulator); PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; IL: Interleukin; TNF-α: Tumor necrosis factor α; ATP: Adenosine triphosphate; VAF: Variant allele fraction; CD: Cluster of differentiation; CRP: C-reactive protein; NLRP3: NOD-like receptor thermal protein domain associated protein 3; NF-κB: Nuclear factor kappa-B; EV: Extracellular vesicle; EMV: Endothelial microvesicle; hsCRP: High-sensitivity C-reactive protein; GDF-15: Growth differentiation factor-15; sST2: Soluble suppression of tumorigenicity 2; NT-proBNP: N-terminal pro-B-type natriuretic peptide; hs-cTn: High-sensitivity cardiac troponin; WB: Western blot; qPCR: Quantitative polymerase chain reaction; ROS: Reactive oxygen species; IHC: Immunohistochemistry; ELISA: Enzyme-linked immunosorbent assay; NGS: Next-generation sequencing; NMR: Nuclear magnetic resonance; CVD: Cardiovascular disease; CV: Cardiovascular; EC: Endothelial cell; EPC: Endothelial progenitor cell; VSMC: Vascular smooth muscle cell.