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CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control
Open accessAbstract
During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP-/- mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP-/- mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.
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“studies in CHIP defective mice also support an important role for the UPS in longevity and health-span (Min et al., 2008)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Min et al., 2008
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“Also, mutant mice deficient in a co-chaperone of the heat-shock family exhibit accelerated-aging phenotypes, whereas long-lived mouse strains show a marked up-regulation of some heat-shock proteins (Min et al., 2008; Swindell et al., 2009).”
From The Hallmarks of Aging (2013) · cites this paper as Min et al., 2008
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Metadata
- Authors
- Min, J.-N., Whaley, R. A., Sharpless, N. E., Lockyer, P., Portbury, A. L., & Patterson, C.
- Affiliations
- Carolina Cardiovascular Biology Center
- UNC Lineberger Comprehensive Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Patterson, Cam
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-06-01
- Volume
- 28
- Issue
- 12
- Pages
- 4018-4025
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2423116
- OpenAlex
- W2143659623
- Cited by
- 256
- References
- 49
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 8 · 2021: 16 · 2020: 20 · 2019: 14 · 2018: 18 · 2017: 19 · 2016: 17 · 2015: 11 · 2014: 22 · 2013: 19 · 2012: 14
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- American Heart Association
- National Institutes of Health (5r01gm061728-12)
- National Institute on Aging (AG 024282, P01 AG 024282)
- National Heart, Lung, and Blood Institute (HL 65619, R01HL065619, R37HL065619)
- National Institute of General Medical Sciences (GM-61728, R01-GM061728)
- 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 › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CHIP, protein quality control, aging, longevity, accelerated aging, cellular senescence, proteasome activity, ubiquitin-proteasome system, oxidative stress, protein aggregation, proteostasis
- MeSH terms
- Aging, Animals, Brain, Cytoplasm, Lipids, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Oxygen, Phenotype, Cellular Senescence, Molecular Chaperones, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Mice
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