Researchers have been investigating the role of sestrin in longevity in lower animals such as flies and nematodes for some years now. Upregulation extends life, downregulation shortens life, and initial investigations suggested that the effect operates through the usual stress response mechanisms involved in life extension in short-lived species. Researchers here establish that sestrin in flies and sestrin-1 in mice are necessary for many of the benefits of exercise, and upregulation of sestrin mimics the effects of exercise on metabolism. There is also other published research in mice from recent years to support this role for sestrin-1 in mammals, in that expression of this gene is upregulated by exercise and also improves the operation of the cellular maintenance processes of autophagy.
One promising therapeutic intervention to impede age-related functional decline is endurance exercise. Endurance training induces remodeling in muscle tissue that alters the metabolic health of the entire organism. Evidence from humans and model organisms strongly suggests that endurance exercise has substantially protective effects on various indices of healthspan. These changes are often thought to be at least partially mediated by exercise-induced upregulation of AMP-activated protein kinase (AMPK) and the insulin-AKT pathway.
Sestrins are small stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while Drosophila and C. elegans express one Sestrin orthologue. Once induced, Sestrins coordinate metabolic homeostasis by regulating multiple signaling pathways. Through its intrinsic oxidoreductase activity and by regulating autophagy, Sestrin can function as an antioxidant to reduce oxidative damage in cells. Importantly, while Sestrins downregulate TORC1/S6K signaling, they strongly activate TORC2/AKT signaling.
Here, using Sestrin-deficient fly and mouse models, we show that Sestrins play a critical role in mediating chronic exercise adaptations and exercise benefits. Genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism.