Reduction in Glutathione Peroxidase 4 Increases Life Span Through Increased Sensitivity to Apoptosis

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) an...

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Bibliographic Details
Published in:The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2007-09, Vol.62 (9), p.932-942
Main Authors: Ran, Qitao, Liang, Hanyu, Ikeno, Yuji, Qi, Wenbo, Prolla, Tomas A., Roberts, L. Jackson, Wolf, Norman, VanRemmen, Holly, Richardson, Arlan
Format: Article
Language:English
Subjects:
Age
Aging
Aging - genetics
Aging - metabolism
Aging - pathology
Animals
Antioxidants - metabolism
Apoptosis
Apoptosis - genetics
Apoptosis - physiology
Fatty acids
Gene Expression
Glomerulonephritis - genetics
Glomerulonephritis - metabolism
Glutathione Peroxidase - deficiency
Glutathione Peroxidase - genetics
Glutathione Peroxidase - metabolism
Heterozygote
Lipid Peroxidation
Lipids
Longevity - genetics
Longevity - physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Proteins
Rodents
Studies
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Summary: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.
ISSN:1079-5006
1758-535X
DOI:10.1093/gerona/62.9.932