The role of cardiovascular aging in heart failure

Cardiovascular aging represents a critical factor contributing to the rising prevalence of heart failure in aging populations, as structural and functional changes occurring in the heart and vasculature during aging result in an increased susceptibility to heart failure. Different aging-related molecular mechanisms contribute to these cardiovascular changes. Among these molecular mechanisms are epigenetic modifications, including altered DNA methylation, loss of histone and decline in sirtuins, which disrupt genomic stability and cellular metabolism. In addition, aging-related telomere shortening and mitochondrial dysfunction exacerbate oxidative stress and compromise energy homeostasis, promoting cardiac remodeling and functional impairment. Moreover, the aging myocardium also exhibits dysregulated autophagy, impaired angiogenesis, and poor extracellular matrix remodeling, all of which contribute to diminished cardiac resilience. Furthermore, clonal hematopoiesis of indeterminate potential and dysregulated inflammatory pathways intensify systemic and local inflammation, aggravating heart failure progression. On top of that, immune cell infiltration and the senescence-associated secretory phenotype exacerbate inflammatory responses, fostering maladaptive cardiac remodeling. Lastly, poor regenerative capacity, driven by reduced cardiomyocyte turnover and polyploidy, further limits the heart's ability to recover from injury. This review explores the multifaceted nature of cardiovascular aging and its contribution to heart failure by discussing the molecular mechanisms involved therein, elucidating which offers novel therapeutic avenues and potential for targeted and personalized interventions that address specific molecular dysfunctions to mitigate heart failure in elderly populations. Integrating research efforts to translate these molecular insights into clinical interventions will be beneficial in addressing the global burden of heart failure in the context of an aging population.