High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging

Abstract

Background: High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats. Methods: Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies. Results: The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer's disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats. Conclusion:The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Associations that Cardiorespiratory Fitness and Body Mass Index Loss Have with Deficit Accumulation Frailty

“…For example, Kokkinos et al (3) report that among US veterans aged 30–95 yr, being in the lowest quintile of fitness based on a standardized treadmill test was associated with a hazard ratio of 4.09 (95% CI, 3.90–4.20) for mortality across 10.2 yr of follow-up compared with being in the highest quintile. Poorer fitness based on exercise tests is associated with increased vascular aging (30), greater levels of multimorbidity (4), poorer profiles of brain structure and function (31–33), and poorer biomarkers of aging (5). More generally, markers related to greater physical capacity are associated with many biomarkers of aging (1).…”

“…ower cardiorespiratory fitness and physical capacity accelerate aging (1). This can be seen with associations with increased mortality (2,3) and multimorbidity (4), shortened healthspan (1), and many biomarkers related to accelerated aging (3,5). Deficit accumulation frailty indices (FIs), which combine markers of age-related deficits in clinical characteristics, disease states, behaviors, and function, are increasingly used as markers of aging (6,7).…”