There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One emerging process that has been increasingly implicated is autophagy. First described in yeast, autophagy is a regulated process stimulated by stressful condition most notably starvation. Once activated, autophagy involves the recycling of old and damaged proteins and organelles in order to provide building blocks for new cellular components. Our initial interest in autophagy came when we demonstrated that the NAD-dependent deacetylase Sirt1 was an important regulator of autophagy (Lee et al., PNAS, 2008). We further demonstrated a connection between protein deacetylation and autophagy by also implicating the p300 histone acetyltransferase in the process (Lee at al., JBC, 2009). We have also analyzed the physiological role of autophagy using various mouse models. In particular, we have demonstrated that conditional knockouts of the essential autophagy gene Atg7 results in a diabetic state (Wu et al., Aging, 2009). Currently, we are pursuing the biological and physiological role of autophagy using both cellular and animal models. In particular, we have recently demonstrated an important connection between Atg7, p53 and cell cycle progression (Lee et al., Science, 2012). We have also described a role for autophagy in the secretion of bioactive molecules from the endothelium both in vitro and in vivo (Torisu et al., Nature Medicine, 2013) and a role for autophagy in atherosclerosis (Torisu et al, in preparation). We have also characterized a hypomorphic model of mTOR expression. mTOR is an important negative regulator of autophagy. Our results (Wu et al., Cell Reports, 2013) suggest that reducing mTOR can extend lifespan and slow aging in a segmental fashion. Ongoing studies are assessing the effects of impaired vascular autophagy in neuridegenerative disease as well as the in vivo physiology of mitophagy.
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