Cellular & Molecular Mechanisms of Cardiac Aging

Fly heartAging is a process whereby progressive decline of tissue homeostasis reduces system function and elevates risk of death. Age itself is a major risk factor for a range of human diseases, such as cancer, diabetes, neurodegeneration and heart disease. Specifically, aging is associated with an 8-fold increase of the incidence of sudden cardiac death (SCD), the leading cause of death in western countries. Resolving the contributing mechanisms of heart disease in any of its forms is a pressing goal of basic and translational aging research.

We have recently found that TGF-beta/activin signaling increases with age and negatively regulates autophagic activity. Consistently, suppression of TGF-beta/activin preserves cardiac function and autophagic activity with age. Surprisingly, we show that mTORC2, but not mTORC1, is required for TGF-beta/activin-regulated autophagy. Furthermore, activation of mTORC2 alone promotes autophagic activity, preserves cardiac function with aging, and prolongs lifespan. The mTOR pathway is one of the most important nutrient and longevity regulators, which consists of two distinct multiprotein complexes, mTORC1 and mTORC2. It has been shown that two mTOR complexes play opposite roles in tissue homeostasis and aging, although the underlying mechanisms remain largely unknown. The distinct regulation of autophagy by two mTOR complexes uncovered in our study may explain why mTORC1 and mTORC2 differentially control animal aging.