Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature Medicine volume 14, pages 959–965 (2008)Cite this article

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CMA activity is preserved in livers of aged Alb-Tet-off-L2A mice.
Figure 2: Livers of aged Alb-Tet-off-L2A mice accumulate fewer damaged proteins.
Figure 3: Improved cellular homeostasis in livers of aged Alb-Tet-off-LAMP-2A mice.
Figure 4: Livers of aged Alb-Tet-off-L2A mice show lower levels of cellular damage and improved organ function.

References

  1. Dice, J.F. Chaperone-mediated autophagy. Autophagy 3, 295–299 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Massey, A.C., Zhang, C. & Cuervo, A.M. Chaperone-mediated autophagy in aging and disease. Curr. Top. Dev. Biol. 73, 205–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Cuervo, A.M. & Dice, J.F. Age-related decline in chaperone-mediated autophagy. J. Biol. Chem. 275, 31505–31513 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Mizushima, N., Levine, B., Cuervo, A. & Klionsky, D. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cuervo, A.M. et al. Autophagy and aging: the importance of maintaining 'clean' cells. Autophagy 1, 131–140 (2005).

    Article  PubMed  Google Scholar 

  6. Cuervo, A.M. Autophagy: in sickness and in health. Trends Cell Biol. 14, 70–77 (2004).

    Article  PubMed  Google Scholar 

  7. Chiang, H.L., Terlecky, S.R., Plant, C.P. & Dice, J.F. A role for a 70 kDa heat shock protein in lysosomal degradation of intracellular protein. Science 246, 382–385 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Cuervo, A.M. & Dice, J.F. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501–503 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Salvador, N., Aguado, C., Horst, M. & Knecht, E. Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J. Biol. Chem. 275, 27447–27456 (2000).

    CAS  PubMed  Google Scholar 

  10. Agarraberes, F.A., Terlecky, S.R. & Dice, J.F. An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J. Cell Biol. 137, 825–834 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T.J. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Kiffin, R. et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J. Cell Sci. 120, 782–791 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Kiffin, R., Bandyopadhyay, U. & Cuervo, A.M. Oxidative stress and autophagy. Antioxid. Redox Signal. 8, 152–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Finn, P.F. & Dice, J.F. Ketone bodies stimulate chaperone-mediated autophagy. J. Biol. Chem. 280, 25864–25870 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Schmucker, D.L. Age-related changes in liver structure and function: Implications for disease? Exp. Gerontol. 40, 650–659 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Cavallini, G., Donati, A., Taddei, M. & Bergamini, E. Evidence for selective mitochondrial autophagy and failure in aging. Autophagy 3, 26–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Terman, A. The effect of age on formation an elimination of autophagic vacuoles in mouse hepatocyte. Gerontology 41, 319–325 (1995).

    Article  PubMed  Google Scholar 

  18. Brunk, U.T. & Terman, A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic. Biol. Med. 33, 611–619 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Tanaka, K., Nanbara, S., Tanaka, T., Koide, H. & Hayashi, T. Aminotransferase activity in the liver of diabetic mice. Diabetes Res. Clin. Pract. 5, 71–75 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Higami, Y. et al. Aging accelerates but life-long dietary restriction suppresses apoptosis-related Fas expression on hepatocytes. Am. J. Pathol. 151, 659–663 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pappas, P., Stephanou, P., Vasiliou, V. & Marselos, M. Zoxazolamine-induced paralysis in two rat substrains: differences in hepatic drug metabolism. Eur. J. Drug Metab. Pharmacokinet. 23, 461–467 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Massey, A.C., Kaushik, S., Sovak, G., Kiffin, R. & Cuervo, A.M. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl. Acad. Sci. USA 103, 5805–5810 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wattiaux, R., Wattiaux-De Coninck, S., Ronveaux-Dupal, M. & Dubois, F. Isolation of rat liver lysosomes by isopycnic centrifugation in a metrizamide gradient. J. Cell Biol. 78, 349–368 (1978).

    Article  CAS  PubMed  Google Scholar 

  24. Storrie, B. & Madden, E.A. Isolation of subcellular organelles. Methods Enzymol. 182, 203–225 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Agarraberes, F.A., Terlecky, S.R. & Dice, J.F. An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J. Cell Biol. 137, 825–834 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jentoft, N. & Dearborn, D. Protein labeling by reductive alkylation. Methods Enzymol. 91, 570–579 (1983).

    Article  CAS  PubMed  Google Scholar 

  27. Lowry, O.H., Rosebrough, N.J., Farr, A.L. & Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275 (1951).

    CAS  PubMed  Google Scholar 

  28. Barret, A. Handbook of Proteolytic Enzymes (eds. Barrett, A.J., Rawlings, N.D. & Woessner, J.F.) 850–862 (Academic Press, San Diego, 1998).

    Google Scholar 

Download references

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.

Author information

Authors and 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, 10461, New York, USA

    Cong Zhang & Ana Maria Cuervo

Authors
  1. Cong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Maria Cuervo
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–11 and Supplementary Discussion (PDF 2215 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhang, C., Cuervo, A. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14, 959–965 (2008). https://doi.org/10.1038/nm.1851

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing