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Review
. 2024 Feb 14;10(1):78.
doi: 10.1038/s41420-023-01792-5.

Cardiac cell senescence: molecular mechanisms, key proteins and therapeutic _targets

Yi Luan #  1 , Xiaofan Zhu #  2 , Yuxue Jiao #  1 , Hui Liu  3 , Zhen Huang  3 , Jinyan Pei  4 , Yawei Xu  5 , Yang Yang  6 , Kaidi Ren  7   8
Affiliations
Review

Cardiac cell senescence: molecular mechanisms, key proteins and therapeutic _targets

Yi Luan et al. Cell Death Discov. .

Abstract

Cardiac aging, particularly cardiac cell senescence, is a natural process that occurs as we age. Heart function gradually declines in old age, leading to continuous heart failure, even in people without a prior history of heart disease. To address this issue and improve cardiac cell function, it is crucial to investigate the molecular mechanisms underlying cardiac senescence. This review summarizes the main mechanisms and key proteins involved in cardiac cell senescence. This review further discusses the molecular modulators of cellular senescence in aging hearts. Furthermore, the discussion will encompass comprehensive descriptions of the key drugs, modes of action and potential _targets for intervention in cardiac senescence. By offering a fresh perspective and comprehensive insights into the molecular mechanisms of cardiac senescence, this review seeks to provide a fresh perspective and important theoretical foundations for the development of drugs _targeting this condition.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Cardiomyocytes and cardiac nonmyocytes interact with each other within the local microenvironment.
Cardiac nonmyocytes modulate cardiomyocytes by releasing signals, leading to cardiac senescence. Dysfunctional endothelial cells (ECs) release proinflammatory factors (IL-6 and IL-33), Ang II, and ET-1 to promote cardiomyocyte senescence. Fibroblasts induce senescence by producing IL-11, IL-33, and integrin. Immune cells release various signals to regulate cardiomyocyte senescence directly. Reciprocally, senescent dysfunctional cardiomyocytes undergo a senescence-associated secretory phenotype (SASP) to recruit immune cells. Aging cardiomyocytes produce SASP, VEGF, and exosomes to induce senescence in ECs. Similarly, the functional impairment in fibroblasts is regulated by dysfunctional cardiomyocytes through the secretion of IL-6, CCN1, and exosomes.
Fig. 2
Fig. 2. Cellular and molecular signals affect cardiac senescence.
Cardiac cell dysfunction occurs in a cell- and tissue-specific manner: EC senescence is associated with atherosclerosis, and fibroblasts show cell cycle inhibition and SASP. Immune cells secrete SASP factors. Cardiomyocytes increase in size and lose contractility. At the molecular level, ROS and inflammation induce DNA damage and telomere shortening, leading to the expression of aging-related genes and SASP.
Fig. 3
Fig. 3. Molecular modulators of cellular senescence.
Many factors can trigger cellular senescence, including epigenetic regulation, metabolic regulation, SASP, telomere shortening, mTOR, and tumor suppressor pathways.
Fig. 4
Fig. 4. Promising therapies for _targeting cellular senescence in aging hearts.
Strategies _targeting senescence include clearance of senescent cells, modulation of senescent cells, and regulation of SASP secretion. Quercetin, dasatinib, and navitoclax have been proven to remove senescent cells. ROS inhibition, hypertension inhibition, and CR prevent SASP secretion.
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