Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis
Abstract
Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that plays an important role in detoxification of oxidative damage to membrane lipids. Because oxidative stress is proposed to play a causal role in aging, we compared the life spans of Gpx4 heterozygous knockout mice (Gpx4(+/-) mice) and wild-type mice (WT mice). To our surprise, the median life span of Gpx4(+/-) mice (1029 days) was significantly longer than that of WT mice (963 days) even though the expression of Gpx4 was reduced approximately 50% in all tissues of Gpx4(+/-) mice. Pathological analysis revealed that Gpx4(+/-) mice showed a delayed occurrence of fatal tumor lymphoma and a reduced severity of glomerulonephritis. Compared to WT mice, Gpx4(+/-) mice showed significantly increased sensitivity to oxidative stress-induced apoptosis. Our data indicate that lifelong reduction in Gpx4 increased life span and reduced/retarded age-related pathology most likely through alterations in sensitivity of tissues to apoptosis.
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Mice heterozygous for mitochondrial glutathione peroxidase 4 or the ubiquinone biosynthesis protein CLK1 display high levels of mitochondrial oxidative stress, yet live longer than their wild-type counterparts.
“Mice heterozygous for the mitochondrial glutathione peroxidase 4 or the ubiquinone biosynthesis protein CLK1 display high levels of mitochondrial oxidative stress, yet live longer than their wild-type counterparts 93, 94.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [93]
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- Authors
- Ran, Q., Liang, H., Ikeno, Y., Qi, W., Prolla, T. A., Roberts, L. J., Wolf, N., VanRemmen, H., & Richardson, A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Wisconsin–Madison (US)
- Vanderbilt University (US)
- University of Washington (US)
- South Texas Veterans Health Care System (US)
- Corresponding author
- Ran, Q.
- Venue
- The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-01
- Volume
- 62
- Issue
- 9
- Pages
- 932-942
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- OpenAlex
- W2141897277
- Cited by
- 195
- References
- 64
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 14 · 2017: 10 · 2016: 7 · 2015: 12 · 2014: 14 · 2013: 9 · 2012: 12
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P30AG13319, P01 AG19316, P01AG020591, P01AG019316, P30AG013319)
- National Institute of General Medical Sciences (R37 GM42056, R37GM042056)
- 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 › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- GPX4, lifespan, aging, apoptosis sensitivity, oxidative stress, lipid peroxidation, antioxidant defense, lymphoma, glomerulonephritis, age-related diseases
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Aging, Animals, Antioxidants, Glomerulonephritis, Glutathione Peroxidase, Heterozygote, Longevity, Male, Mice, Inbred C57BL, Lipid Peroxidation, Gene Expression, Apoptosis, Mice, Knockout, Oxidative Stress, Mice
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