Temporal inhibition of autophagy reveals segmental reversal of aging with increased cancer risk

Abstract

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to aging. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the aging process, and whether autophagy restoration can counteract these aging effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan, however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumor formation. Thus our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumor suppressive and oncogenic, sequentially.