Author(s): BEVINGTON, R., JOHNSON, A., HOCKEY, B., FAJARDO, V., PARISE, G., Institution: MCMASTER UNIVERSITY, Country: CANADA, Abstract-ID: 1148

INTRODUCTION:
During aging, the heart experiences adverse structural remodelling of the myocardium, which impairs ventricular function and increases the risk of heart failure [1]. Cellular senescence has become increasingly linked to these alterations as senescent cells accumulate with age, displaying permanent cell cycle arrest and dysfunction. In fact, senescent cardiomyocytes and fibroblasts in the myocardium are associated with pathological cardiomyopathies and contractile dysfunction [1]. Senolytics, like Dasatinib and Quercetin (D+Q), are drugs that selectively kill senescent cells and improve myocardial structure and function [1]. Aerobic exercise also has cardioprotective effects and shows promise in reducing cardiac senescence [2]. Therefore, we hypothesized that combining chronic senolytic treatment with aerobic exercise would enact a synergistic reduction of senescence, preserving myocardial structure and function during aging.
METHODS:
Male and female C57BL/6N mice (12-months-old) were randomly allocated to one of four groups (n=20 per group): naturally aged (VEH), aerobic exercise (2x/week treadmill running; EX), senolytic (D+Q via oral gavage biweekly; SEN) or both combined (exercise and D+Q; SENEX). Interventions lasted 9-months with myocardial structure assessed at the 6- and 9-month timepoints using high frequency ultrasound. A cohort of 4-month-old mice were used as a young control (n=10). Immunofluorescence staining with cardiac troponin T, wheat germ agglutinin, and p16 or p21 was used to measure the area of senescent cardiomyocytes. Senescence was also assessed using western blots for p16 and p21 protein expression from whole heart samples.
RESULTS:
From 6- to 9-months, the VEH mice displayed a marked decrease in the posterior wall thickness of the left ventricle (LV) (1.41±0.23 to 1.01±0.18 mm) (p<0.05), while the other interventions showed no change. Moreover, cardiomyocytes expressing a senescent marker were smaller in area (345.8±21.7 µm) than those not expressing a senescent marker (367.1±28.3 µm) (p<0.05). VEH hearts had elevated p16 and p21 expression (1.66±1.08 and 1.36±1.16 AU) compared to the YOUNG (0.54±0.29 and 0.20±0.06 AU) (p<0.05), but not any of the interventions. This culminated in a greater LV posterior wall thickening ability in the EX (43.0±6.0 %), SEN (45.5±20.8 %), SENEX (41.0±16.9%), and YOUNG (53.0±28.2 %) compared to the VEH (18.4±10.3 %) (p<0.05).
CONCLUSION:
Naturally aged mice exhibited elevated senescence as well as LV wall thinning and impaired myocardial function. Moreover, senescent cardiomyocytes had a smaller area, altogether suggesting that senescence drives myocardial atrophy. Importantly, exercise, senolytics, or both combined prevented LV wall thinning and functional declines with a partial removal of senescence, positioning these strategies as promising approaches to mitigate the age-related myocardial remodeling and functional decline.
REFERENCES:
1. Luan et al., Cell Death Discov, 2024
2. Werner at al., J Am Coll Cardiol, 2008