High Intrinsic Aerobic Endurance Capacity Preserves Cardiomyocyte Quality Control, Mitochondrial Fitness and Lifespan

Abstract

Growing evidence has established cardiorespiratory fitness (CRF) as a strong and reliable quantitative predictor of elderly mortality and cardiovascular events. To gain insight into potential mechanisms linking high CRF to increased healthspan and lifespan, we examined cardiomyocytes from rats selectively bred for low and high intrinsic aerobic capacity, the so-called low capacity runners (LCR) and high capacity runners (HCR). LCR vs HCR have been shown to differ in numerous ageing related diseases (including the metabolic syndrome and cardiovascular complications) and longevity. We hypothesized that differences in mitochondrial function, homeostatic performance and stress-resistance (i.e., fitness) underlie the ageing- and CRF-linked risks of developing chronic disease and multimorbidity. We demonstrated that autophagy/mitophagy is significantly diminished in old compared to younger rats, and is significantly lower in LCR vs HCR compared across all age groups (14%, 26% and 30% lower in LCR vs HCR at 7, 17 and 24-month-old, respectively). Accumulation of lipofuscin (the progressive buildup of intralysosomal debris) gradually increased with age (by 5-fold at 24 vs 7 months) reaching significantly higher levels in aged LCR vs HCR, in parallel with the decline in autophagic turnover, suggesting significant alteration in the balance between damage and repair. Indeed, impaired autophagy/mitophagy may perturb mitochondrial quality control as manifested by a pronounced age-dependent decrease in the ROS-threshold for opening of the permeability transition pore (50% decrease in 24-month vs 7-month-old; LCR>HCR) and hence a deterioration in fitness of the organelle, eventually, leading to a decline in cell function. In summary, observed changes in mitochondrial repair, turnover and fitness may contribute to a decreased functionality and increased vulnerability to injury of the aged heart that is more pronounced in LCR vs HCR, and may underlie differences in healthspan and lifespan.