Senescence mechanisms and targets in the heart

Abstract

Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat CVD. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, and valve interstitial cells) can lead to CVD, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat CVD.

Keywords: Ageing; Cardiovascular disease; Senescence; Senotherapy.

Graphical abstract

Figure 1

Markers of senescent cells. Senescent cells exhibit irreversible cell cycle arrest, elevation of p53, p21, and p16, elevation of DNA damage response markers p38 MAPK and γH2AX, hyperelongated mitochondria, elevated reactive oxygen species, increased senescence-associated β-galactosidase activity, senescence-associated heterochromatin foci (SAHF), and a senescence-associated secretory phenotype (SASP).

Figure 2

Molecular regulators of cellular senescence. Mechanisms that drive cellular senescence include the DNA damage response/telomere shortening, mTOR activation, metabolic dysfunction, circadian misalignment, SASP, tumour suppressor pathways, and epigenetic changes.

Figure 3

Tumour suppressor regulators of senescence. The p53/p21 and p16/Rb pathways play central roles in senescence via cell cycle arrest, ROS production, and activation of the DNA damage response.

Figure 4

Secretome of different cell types in the heart and examples of associated phenotypic changes. Senescent cardiac cells secrete different senescence-associated secretory phenotypes leading to paracrine signalling and exacerbation of the senescent phenotype. Several consequences of these secreted factors include fibrosis, myofibroblast activation, collagen synthesis, calcification, hypertrophy, and inflammation.

Figure 5

Senotherapeutic drugs. Senotherapies aim to eliminate senescent cells (senolytics), prevent acquisition of a senescent state (senostatics), or delay progression of senescence (SASP inhibitors).