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) 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.
Ran
Qitao
Q
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USA.
Liang
Hanyu
H
Ikeno
Yuji
Y
Qi
Wenbo
W
Prolla
Tomas A
TA
Roberts
L Jackson
LJ
Wolf
Norman
N
Van Remmen
Holly
H
VanRemmen
Holly
H
Richardson
Arlan
A
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D005921:Glomerulonephritis / Q000235:genetics / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D015227:Lipid Peroxidation; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase
D000975:Antioxidants; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase