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Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function

Nature Medicine volume 14, pages 959965 (2008) | Download Citation

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Abstract

Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems1,2. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age3, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.

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Acknowledgements

We are grateful to S. Kaushik and A.C. Massey for assistance in the preparation of this manuscript. The pUHD10-3 plasmid and the Alb-tTA mice were generous gifts from H. Bujard (University of Heidelberg) and the antibody to the asialoglycoprotein receptor was kindly supplied by A. Wolkoff (Albert Einstein College of Medicine). This work was supported in part by US National Institutes of Health National Institute on Aging grants AG021904 and AG19834, National Institute of Diabetes and Digestive and Kidney Diseases DK041918, an Ellison Medical Foundation Award and a Glenn Foundation Award.

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Affiliations

  1. Department of Developmental and Molecular Biology and Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center and Institute for Aging Research, 1300 Morris Park Avenue, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    • Cong Zhang
    •  & Ana Maria Cuervo

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Contributions

C.Z. performed all the experiments in this study. A.M.C. conceived, designed and directed the study.

Corresponding author

Correspondence to Ana Maria Cuervo.

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DOI

https://doi.org/10.1038/nm.1851

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