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 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 are actively pursuing the role of autophagy in various aspects of vascular biology (Nussenzweig et al., Circ Res., 2015). 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. We believe these effects may in part be due to the role of mTPR in modulating autphagic flux. We have also recently generated what we feel is the first in vivo reporer mouse that allows for the detection of mitophagy (Sun et al., in review). We believe this will be an important reagent for the field. This system is based on the fluorescent reporer Keima, previously described by a group in Japan. Ongoing studies are attepting to further understand the molecular regulation of mitophagy, as well as deriving small molecules that regulate mitophagic flux.

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Project End
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Budget End
Support Year
19
Fiscal Year
2015
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Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
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(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Torisu, Kumiko; Singh, Krishna K; Torisu, Takehiro et al. (2016) Intact endothelial autophagy is required to maintain vascular lipid homeostasis. Aging Cell 15:187-91
Finkel, Toren (2015) The metabolic regulation of aging. Nat Med 21:1416-23
Singh, Krishna K; Lovren, Fina; Pan, Yi et al. (2015) The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition. J Biol Chem 290:2547-59
Sun, Nuo; Yun, Jeanho; Liu, Jie et al. (2015) Measuring In Vivo Mitophagy. Mol Cell 60:685-96
Nussenzweig, Samuel C; Verma, Subodh; Finkel, Toren (2015) The role of autophagy in vascular biology. Circ Res 116:480-8
Parkhitko, Andrey A; Priolo, Carmen; Coloff, Jonathan L et al. (2014) Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res 12:48-57
Lee, In Hye; Finkel, Toren (2013) Metabolic regulation of the cell cycle. Curr Opin Cell Biol 25:724-9
Finkel, Toren (2012) Relief with rapamycin: mTOR inhibition protects against radiation-induced mucositis. Cell Stem Cell 11:287-8
Lee, In Hye; Kawai, Yoshichika; Fergusson, Maria M et al. (2012) Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336:225-8

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