Cardiac ageing: from hallmarks to therapeutic opportunities

Abstract

Cardiac ageing is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular, and functional changes associated with cardiac ageing and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of ageing, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of ageing on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac ageing and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological ageing. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of ageing populations worldwide.

Keywords: Cardiac ageing; Geroscience; Heart failure.

Graphical Abstract

Figure 1

Ageing-related cardiac structural and functional changes and underlying mechanisms. During ageing, impaired proteostasis, mitochondrial dysfunction, SASP factors and non-coding RNA mechanisms contribute to systemic inflammation, cardiac fibrosis, endothelial senescence and dysfunction, as well as cardiomyocyte senescence, hypertrophy, and reduced cardiomyogenesis. Resulting structural and functional changes include increased LV stiffness, LV wall thickening, left atrium enlargement, decreased maximal heart rate, diastolic dysfunction, and increased heart disease risk.

Figure 2

Exercise benefits for cardiac ageing and underlying mechanisms. Regular exercise improves key structural and functional phenotypes of cardiac ageing, including LV stiffness and myocardial thickening, diastolic dysfunction, and diminishing contractile reserves. HF risk is also reduced. These benefits have been attributed to protective, cardiomyogenic, hypertrophic angiogenic, and lymphangiogenic signalling pathways, non-coding RNA (ncRNA), and transcriptional regulators of cardiomyocyte growth, proliferation, and survival, as well as anti-senescence mechanisms. These molecular mechanisms contribute to reduced systemic inflammation, reduced endothelial senescence and dysfunction, and reduced cardiomyocyte senescence, loss, and hypertrophy as well as increased cardiomyogenesis.