Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function
Open accessAbstract
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 systems. 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 age, 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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Livers of mice with preserved CMA function show better cellular homeostasis, improved ability to respond to cell damage induced by different stressors, and liver function comparable to that of young mice.
“Livers of mice with preserved CMA function show better cellular homeostasis, improved ability to respond to the cell damage induced by different stressors and their liver function is comparable to that of young mice (Zhang and Cuervo, 2008).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Zhang and Cuervo, 2008
The age-dependent decrease of CMA in mouse liver has been prevented through genetic manipulations.
“our laboratory has recently prevented the age-dependent decrease of CMA in liver through genetic manipulations in mice (Zhang and Cuervo, 2008)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Zhang and Cuervo, 2008
The activity of other quality control mechanisms, such as macroautophagy and the UPS, is also improved in mice with preserved CMA function.
“the activity of other quality control mechanisms, such as macroautophagy and the UPS, is also improved in these animals (Zhang and Cuervo, 2008)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Zhang and Cuervo, 2008
Activation of an exogenously added copy of the CMA receptor in transgenic mice when its endogenous levels start to decrease prevents the decline in CMA activity in old animals.
“Activation of an exogenously added copy of the CMA receptor in transgenic mice when its endogenous levels start to decrease prevents the decline in CMA activity in the old animals.”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Zhang and Cuervo, 2008
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- Authors
- Zhang, C., & Cuervo, A. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- ORCID
- Zhang, Cong
- Venue
- Nature Medicine
- Published
- 2008-08-10
- Volume
- 14
- Issue
- 9
- Pages
- 959-965
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2722716
- OpenAlex
- W2051429808
- Cited by
- 520
- References
- 4
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 21 · 2023: 28 · 2022: 17 · 2021: 32 · 2020: 18 · 2019: 30 · 2018: 39 · 2017: 31 · 2016: 27 · 2015: 33 · 2014: 34 · 2013: 33 · 2012: 30
- FWCI
- 27.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- Glenn Foundation for Medical Research
- National Institutes of Health
- National Institute on Aging (R03AG019834, R01AG021904, AG19834, R37AG021904, AG-021904)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK041918, P01DK041918)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- chaperone-mediated autophagy, aging, liver, lysosomal degradation, protein quality control, transgenic mice, liver function
- MeSH terms
- Aging, Animals, Autophagy, Gene Expression Regulation, Humans, Liver, Lysosomes, Proteins, Zoxazolamine, Molecular Chaperones, Microscopy, Electron, Transmission, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2
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