Age-related decline in chaperone-mediated autophagy
Open accessAbstract
Intracellular protein degradation rates decrease with age in many tissues and organs. In cultured cells, chaperone-mediated autophagy, which is responsible for the selective degradation of cytosolic proteins in lysosomes, decreases with age. In this work we use lysosomes isolated from rat liver to analyze age-related changes in the levels and activities of the main components of chaperone-mediated autophagy. Lysosomes from "old" (22-month-old) rats show lower rates of chaperone-mediated autophagy, and both substrate binding to the lysosomal membrane and transport into lysosomes decline with age. A progressive age-related decrease in the levels of the lysosome-associated membrane protein type 2a that acts as a receptor for chaperone-mediated autophagy was responsible for decreased substrate binding in lysosomes from old rats as well as from late passage human fibroblasts. The cytosolic levels and activity of the 73-kDa heat-shock cognate protein required for substrate targeting to lysosomes were unchanged with age. The levels of lysosome-associated hsc73 were increased only in the oldest rats. This increase may be an attempt to compensate for reduced activity of the pathway with age.
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The activity of chaperone-mediated autophagy decreases in almost all tissues of old rodents and in senescent human fibroblasts in culture.
“we have found that the activity of this autophagic pathway decreases in almost all tissues of old rodents and in senescent human fibroblasts in culture (Cuervo and Dice, 2000; Dice, 1982)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Cuervo and Dice, 2000
The Introduction says chaperone-mediated autophagy decreases in most tissues of old organisms, and the Discussion reports a decrease in senescent human fibroblasts in culture. The paper's own rodent results concern rat liver; it does not establish a decrease in almost all tissues of old rodents. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA step-by-step comparative analysis of CMA in livers of young and old rodents revealed a decrease with age in binding and lysosomal translocation of substrate proteins, due to progressively lower levels of the CMA receptor at the lysosomal membrane with age.
“A step-by-step comparative analysis of CMA in livers of young and old rodents revealed a decrease with age in binding and lysosomal translocation of the substrate proteins, due to progressively lower levels of the CMA receptor at the lysosomal membrane with age (Cuervo and Dice, 2000).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Cuervo and Dice, 2000
Animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.
“and animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.40–42”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [41]
The Results discuss lysosomes from young and old rat livers, and the Experimental Procedures mention a cathepsin D antibody; neither addresses mutant mice or demyelination. Searches for VAMP7, lysosomal exocytosis, cathepsin D mutant mice, and demyelination found no passage supporting the claim. Page numbers were unavailable in our copy. (LLM, conf=0.78)
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- Authors
- Cuervo, A. M., & Dice, J. F.
- Affiliations
- Tufts University (US)
- Corresponding author
- Dice, J. Fred
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 40
- Pages
- 31505-31513
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2124165909
- Cited by
- 665
- References
- 1
- Citations by year
- 2026: 20 · 2025: 21 · 2024: 26 · 2023: 24 · 2022: 25 · 2021: 36 · 2020: 32 · 2019: 40 · 2018: 36 · 2017: 34 · 2016: 45 · 2015: 37 · 2014: 31 · 2013: 31 · 2012: 39
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG00829, AG-06116)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- chaperone-mediated autophagy, aging, lysosomes, Hsc70, substrate binding, selective protein degradation, lysosomal membrane, liver lysosomes, human fibroblasts, age-related decline
- MeSH terms
- Age Factors, Aging, Animals, Cytosol, Dose-Response Relationship, Drug, Fibroblasts, Heat-Shock Proteins, Humans, Immunohistochemistry, Kinetics, Liver, Lysosomes, Male, Membrane Glycoproteins, Microscopy, Electron, Proteins, Rats, Inbred F344, Subcellular Fractions, Time Factors, Antigens, CD, Molecular Chaperones, HSP70 Heat-Shock Proteins, HSC70 Heat-Shock Proteins, Rats, Lysosomal Membrane Proteins
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