This proposal focuses on chaperone-mediated autophagy (CMA), a catabolic pathway that mediates the selective degradation of cytosolic proteins in lysosomes. CMA contributes to the maintenance of cellular homeostasis by participating in cellular quality control. We have previously found that CMA activity decreases with age and that restoration of proper CMA activity in livers of old rodents prevents organ deterioration and preserves organ function. We propose that failure of CMA contributes to the functional decline characteristic of old organisms and aggravates the course of age-related diseases. The overall goal of this proposal is 1) to identify the causes behind the functional failure of CMA with age, 2) to understand the consequences of the decrease in CMA activity with age in different organs and 3) to explore alternative interventions to the genetic manipulation to enhance CMA activity in aging organisms. With this purpose, during the next period of funding we intend to: 1) determine the contribution of lysosomal chaperones and co-chaperones to the lysosomal internalization of substrate proteins through the CMA translocation complex;2) elucidate the contribution of CMA to the regulation of cellular lipid metabolism through maintenance of endoplasmic reticulum and lipid droplet homeostasis and 3) analyze the systemic and organ-specific consequences of the decrease in CMA activity with age in relation to the function of this pathway in cellular quality control and in the regulation of the metabolic balance. Significance: This study will elucidate how functional decline of CMA contributes to aging and could help identifying new approaches to correct defective CMA in old organisms and prevent the alterations in cellular and organ homeostasis characteristics of aging

Public Health Relevance

Cellular and organ deterioration in old organisms results, at least in part, from a failure of the systems responsible for the maintenance of cellular quality control. Malfunctioning of these surveillance systems also underlies the basis of severe diseases associated with aging such as neurodegeneration, metabolic disorders or muscle weakness. This proposal focuses on one of the mechanisms that contribute to cellular cleaning whose activity is severely compromised with age. Understanding the reasons for the failure of this system in old organisms and the impact that the decline in its activity has on different aged organs should aid in the development of interventions based on the modulation of this system to slow down the aging process and to delay the onset or reduce the severity of different age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AG021904-11S1
Application #
8710830
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2003-04-15
Project End
2015-03-31
Budget Start
2013-09-15
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$69,485
Indirect Cost
$27,877
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8
Pampliega, Olatz; Cuervo, Ana Maria (2016) Autophagy and primary cilia: dual interplay. Curr Opin Cell Biol 39:1-7
Madrigal-Matute, Julio; Cuervo, Ana Maria (2016) Regulation of Liver Metabolism by Autophagy. Gastroenterology 150:328-39
Tasset, Inmaculada; Cuervo, Ana Maria (2016) Role of chaperone-mediated autophagy in metabolism. FEBS J 283:2403-13
Arias, Esperanza; Koga, Hiroshi; Diaz, Antonio et al. (2015) Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. Mol Cell 59:270-84
Moller, David E; Cuervo, Ana Maria; Gordon, Jeffrey et al. (2015) Reflections on the field of metabolism. Cell Metab 21:505-6
Park, Caroline; Suh, Yousin; Cuervo, Ana Maria (2015) Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun 6:6823
Schneider, Jaime L; Villarroya, Joan; Diaz-Carretero, Antonio et al. (2015) Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Aging Cell 14:249-64
Kaushik, Susmita; Cuervo, Ana Maria (2015) Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol 17:759-70
Patel, Bindi; Cuervo, Ana Maria (2015) Methods to study chaperone-mediated autophagy. Methods 75:133-40

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