Autophagy, the process that mediates degradation of intracellular constituents in lysosomes, is an essential component of the cellular quality control systems and of the cellular response to very different stressors. This project focuses on this role of different autophagic pathways as part of the cellular response to stress and aims to elucidate the contribution that the age-dependent changes in autophagy have on the inadequate response to stress in old organisms. During the previous period, we have identified a novel role of autophagy in the cellular response against lipotoxicity (with P4) and genotoxicity (with P3) that we will now explore in more detail in the context of aging, a condition in which we have identified a malfunctioning of two types of autophagy, macroautophagy (MA) and chaperone-mediated autophagy (CMA). In addition, we will incorporate analysis of endosomal microautophagy (eMI), an autophagic pathway that we identified in collaboration with P2, to our study. The overall goal of this proposal is 1) to elucidate the contribution of the impairment in autophagy with age to the functional deterioration and inability to orchestrate an efficient stress response in aging, 2) to understand the molecular mechanisms behind compensation among different autophagic pathways and 3) to devise interventions that could help overcome the autophagic failure in aging. The three original specific aims will be continued/expanded to address: 1) What happens to autophagy during stress? In this period we will focus on three stressors: lipotoxicity, proteotoxicity, and genotoxicity;2) What happens if autophagy does not work under stress conditions? We will utilize the recently generated conditional mouse models with compromised CMA and the ones with compromised MA to study their response to the three stressors and analyze the molecular basis of possible compensatory mechanisms among autophagic pathways; 3) Can we improve the response to stress by repairing autophagy? We will analyze the possible beneficial effect in the organ-specific response to stress of upregulating CMA by using genetic interventions and by continuing the development of chemical modulators of CMA. Relevance: Alterations in the ability to orchestrate an efficient response to stress underlie the basis of important age-related diseases. The studies in this project may provide the conceptual basis and tools for future efforts aimed at manipulating autophagy to improve the response to stress in the elderly and delay the onset of age-related diseases.

Public Health Relevance

A common characteristic of old organisms is their inability to efficiently respond to stress, which renders them vulnerable to different stressors. In fact, inadequate stress-responses have been shown to underlie the basis and/or to aggravate the course of common age-related diseases. This project investigates the contribution of malfunctioning of autophagy, one of the cellular defense systems, to the higher susceptibility of old organism to stress, and explores the possibility of upregulating this defensive mechanism with anti-aging purposes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Albert Einstein College of Medicine
United States
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Batista-Gonzalez, Ana; Singh, Rajat (2017) Lysosomal function in ?-cell survival during glucolipotoxicity. Ann Transl Med 5:471
Satori, Chad P; Ramezani, Marzieh; Koopmeiners, Joseph S et al. (2017) Checkpoints for Preliminary Identification of Small Molecules found Enriched in Autophagosomes and Activated Mast Cell Secretions Analyzed by Comparative UPLC/MSe. Anal Methods 9:46-54
Raz, Yotam; Guerrero-Ros, Ignacio; Maier, Andrea et al. (2017) Activation-Induced Autophagy Is Preserved in CD4+ T-Cells in Familial Longevity. J Gerontol A Biol Sci Med Sci 72:1201-1206
Martinez-Lopez, Nuria; Tarabra, Elena; Toledo, Miriam et al. (2017) System-wide Benefits of Intermeal Fasting by Autophagy. Cell Metab 26:856-871.e5
Maus, Mate; Cuk, Mario; Patel, Bindi et al. (2017) Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell Metab 25:698-712
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Martinez-Lopez, Nuria; Singh, Rajat (2016) Telemetric control of peripheral lipophagy by hypothalamic autophagy. Autophagy 12:1404-5
Martinez-Lopez, Nuria; Garcia-Macia, Marina; Sahu, Srabani et al. (2016) Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver. Cell Metab 23:113-27
Champa, Devora; Orlacchio, Arturo; Patel, Bindi et al. (2016) Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. Oncotarget 7:34453-71
Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8

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