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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG031782-06A1
Application #
8739817
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-09-15
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Bejarano, Eloy; Murray, John W; Wang, Xintao et al. (2018) Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell :e12777
Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647
Dowling, Samuel D; Macian, Fernando (2018) Autophagy and T cell metabolism. Cancer Lett 419:20-26
Caballero, Benjamin; Wang, Yipeng; Diaz, Antonio et al. (2018) Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell 17:
Toledo, Miriam; Batista-Gonzalez, Ana; Merheb, Emilio et al. (2018) Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1. Cell Metab 28:268-281.e4
Walters, Ryan O; Arias, Esperanza; Diaz, Antonio et al. (2018) Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans. Cell Rep 25:663-676.e6
Mocholi, Enric; Dowling, Samuel D; Botbol, Yair et al. (2018) Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy. Cell Rep 24:1136-1150
Rodriguez-Muela, Natalia; Parkhitko, Andrey; Grass, Tobias et al. (2018) Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest 128:3008-3023
Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424
Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12

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