Senescence Cardiomyopathy

Summary Aging is a critical risk factor for heart disease. Cellular senescence, characterized by cell cycle arrest, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes (CMs). Senescence precipitates the aging process in surrounding cells and the organ as a whole through paracrine mechanisms. Generalized autophagy is decreased during aging in many organs, including the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Mitophagy, a mitochondrion- selective form of autophagy, plays an essential role in mediating mitochondrial quality control mechanisms. We have recently shown that alternative mitophagy, an unconventional form of mitophagy that does not rely on the conventional mechanism of autophagy, plays a major role in mitochondrial quality control during myocardial ischemia when conventional autophagy/mitophagy is inactivated. Although suppression of generalized autophagy could promote senescence, senescent cells are metabolically active and rely on mitochondria; thus, alternative mitophagy may be stimulated in order to maintain mitochondrial function. Therefore, the major goal of this project is to elucidate the role of autophagy and mitochondrial quality control mechanisms, including mitophagy, in senescence of the heart and the CMs therein. Our overall hypothesis is that aging- and stress- induced suppression of autophagy promotes senescence in CMs. Suppression of general autophagy leads to the accumulation of YAP, the terminal effector of the Hippo pathway, and consequent stimulation of alternative mitophagy, which are required for the survival and the SASP of senescent CMs, thereby promoting cardiomyopathy. To prove our hypotheses, we will: Aim 1: Test whether downregulation of autophagy directly induces senescence in CMs through YAP-dependent mechanisms. Aim 2: Test whether alternative mitophagy promotes survival and the SASP in senescent CMs. Aim 3: Test whether YAP and alternative mitophagy mediate CM senescence and the cardiac aging phenotype in mouse models of aging. Using mouse models of cardiac senescence in which general autophagy is downregulated, the critical involvement of YAP activation and alternative mitophagy in senescence-mediated cardiac dysfunction will be demonstrated by conducting CM- and senescent cell-specific genetic manipulation of YAP and alternative mitophagy together with fate mapping of p16High senescent cells. Expression of specific diphtheria toxin fragment A in p16High cells also allows selective killing of senescent cells. We will show that unique molecular mechanisms more strongly activated in senescent CMs than in non- senescent cells, namely YAP and alternative mitophagy, promote the survival and the SASP of senescent CMs, thereby mediating the development of cardiomyopathy. Our study will provide important clues for the development of novel senolytics to alleviate cardiac dysfunction induced by CM senescence and aging. Project Number: 1R01HL179656-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Junichi Sadoshima | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $631,261 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17965601