Decreased Proteasomal Activity Causes Age-Related Phenotypes and Promotes the Development of Metabolic Abnormalities
Open accessAbstract
The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis.
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Recent studies report age-dependent deficits in the activities of both the autophagy-lysosomal and ubiquitin-proteasome systems.
“Recent studies have reported age-dependent deficits in the activities of both the autophagy-lysosomal and the ubiquitin-proteasome systems, which represent the principal proteolytic systems implicated in protein quality control74,75.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [75]
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“On the contrary, decreased proteasome activity in flies and mice has been reported to be associated with a shorter lifespan (Tonoki et al., 2009; Tomaru et al., 2012).”
Background
- Authors
- Tomaru, U., Takahashi, S., Ishizu, A., Miyatake, Y., Gohda, A., Suzuki, S., Ono, A., Ohara, J., Baba, T., Murata, S., Tanaka, K., & Kasahara, M.
- Affiliations
- Hokkaido University (JP)
- Kanazawa University (JP)
- The University of Tokyo (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Tomaru, Utano
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 180
- Issue
- 3
- Pages
- 963-972
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2067224531
- Cited by
- 185
- References
- 41
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 20 · 2020: 24 · 2019: 25 · 2018: 15 · 2017: 10 · 2016: 10 · 2015: 16 · 2014: 19 · 2013: 8 · 2012: 4
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- proteasome, aging, longevity, obesity, hepatic steatosis, high-fat diet, transgenic mouse model, ubiquitination, protein oxidation, Bcl-xL, RNase L, ADRP, lipid droplet formation
- MeSH terms
- Perilipin-2, Adipose Tissue, Aging, Animals, Cells, Cultured, Endoribonucleases, Fatty Liver, Insulin, Liver, Longevity, Male, Membrane Proteins, Metabolic Diseases, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Phenotype, Weight Loss, Leptin, Polyubiquitin, Proteasome Endopeptidase Complex, bcl-X Protein, Mice, Diet, High-Fat
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