A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.

Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies.

Connecting autophagy to senescence in pathophysiology.

Cellular senescence is an extremely stable form of cell cycle arrest activated in response to stress. Autophagy, a lysosome-dependent cellular catabolic process, can also be triggered by cellular stresses. Both senescence and autophagy have been implicated in a similar range of pathophysiologies, including cancer, aging and age-related symptoms. Senescence is a heterogeneous phenotype that is composed of multiple effector mechanisms and autophagy was recently identified as a new effector of senescence. Autophagy seemingly has different impacts on cells responding to stress through a diversity of effects: recycling of metabolic waste, cell survival and protein expression regulation.