Mechanisms Mediating Increased Exercise Capacity, Aerobic Capacity and Healthful Aging Induced by Adenylyl Cyclase Type 5 Inhibition - Abstract
Abstract The mouse with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) is a longevity model, as it lives a third longer than littermates. More importantly, the AC5 KO is a model of healthful longevity, as reflected by enhanced exercise performance and protection, not only against obesity, diabetes, and metabolic syndrome, but also Alzheimer’s disease, cancer and myocardial ischemia and heart failure. All these salutary features are mediated by oxidative stress protection and enhanced mitochondrial function. The mechanisms are mediated by the decreases in cAMP and PKA and increases in Raf 1, and the MEK/ERK pathway, along with increases in SIRT1, FoxO3A, and MnSOD. The AC5 KO model of healthful longevity shares much in common with the Calorie Restriction model of healthful longevity. However, the longevity is not additive; actually, when calorie restriction is applied to the AC5 KO model, the result is deleterious, and survival is reduced from 3 years to one month. The purpose of this review is to highlight the unique features of the AC5 KO mouse with focus on mechanisms
that are relevant not only to healthful aging, but for enhancing exercise performance and aerobic capacity. The AC5 KO model’s ability to enhance exercise performance is paradoxical, since exercise capacity is usually mediated by increased beta-adrenergic receptor stimulation and increased cAMP, whereas cAMP and beta-adrenergic receptor signaling are reduced in the AC5 KO model. The AC5 KO’s protection against oxidative stress and enhanced mitochondrial signaling and enhanced aerobic capacity and the microbiome mediate the improved exercise performance and offset the need for an increase in cAMP. Thus, the AC5 KO model is uniquely designed for clinical translation of its beneficial effects, by using a pharmacological analog, which inhibits AC5.