Decoding Cardiac Aging: Integrative Genetic, Cellular, and Molecular Insights Through a Data-Driven Perspective

Abstract

Background: Cardiac ageing is driven by interlocking defects in mitochondrial quality control, telomere–senescence biology, endothelial–microvascular homeostasis, extracellular-matrix remodelling, and proteostasis, culminating in diastolic dysfunction, arrhythmia substrate, and impaired reserve in older adults. Mechanistic mapping and translational appraisal are needed to prioritize tractable therapeutic nodes. Objective: To synthesize genetic, cellular, and molecular mechanisms of cardiac ageing; distinguish physiological from pathological trajectories; and evaluate translational strategies spanning lifestyle, pharmacology, and targeted molecular approaches. Methods: We conducted a prespecified narrative review (searches to 10 November 2025) across MEDLINE, Embase, Web of Science, and Cochrane CENTRAL, plus trial registries and reference lists. Dual screening and domain-appropriate appraisal were applied. Evidence was thematically organized across mitochondria/oxidative stress, telomere–senescence, endothelial dysfunction, fibroblast activation, proteostasis/autophagy, epigenetics, and nodal pathways (mTOR, AMPK, FOXO, SIRT1/PGC-1α, Wnt/β-catenin, TGF-β, NF-κB). Results: Of 5,633 records, 4,419 were screened; 698 full texts were assessed; 186 studies were included (human observational n=74; human interventional n=12; animal n=82; in-vitro n=18). Consistent signals implicate diminished AMPK–SIRT1/PGC-1α and FOXO activity, heightened TGF-β/Wnt profibrotic drive, and chronic NF-κB–mediated inflammaging. Exercise robustly engages mitochondrial and autophagic programs; mTOR modulation and senescence-targeted strategies show preclinical efficacy but require cautious human translation. Conclusion: Cardiac ageing reflects convergent failures in energy, repair, and matrix homeostasis. Near-term impact is most likely from exercise-centred programs, with selective evaluation of mTOR and senescence-directed therapies in rigorously phenotyped older adults. Harmonized endpoints and multi-omic biomarkers are priorities for trials