Ran Qitao, Liang Hanyu, Ikeno Yuji, Qi Wenbo, Prolla Tomas A, Roberts L Jackson, Wolf Norman, Van Remmen Holly, Richardson Arlan
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USA.
J Gerontol A Biol Sci Med Sci. 2007 Sep;62(9):932-42. doi: 10.1093/gerona/62.9.932.
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.
谷胱甘肽过氧化物酶4（Gpx4）是一种抗氧化防御酶，在膜脂氧化损伤的解毒过程中发挥重要作用。由于氧化应激被认为在衰老过程中起因果作用，我们比较了Gpx4杂合敲除小鼠（Gpx4(+/-)小鼠）和野生型小鼠（WT小鼠）的寿命。令我们惊讶的是，Gpx4(+/-)小鼠的中位寿命（1029天）显著长于WT小鼠（963天），尽管Gpx4(+/-)小鼠所有组织中的Gpx4表达降低了约50%。病理分析显示，Gpx4(+/-)小鼠致命性肿瘤淋巴瘤的发生延迟，肾小球肾炎的严重程度降低。与WT小鼠相比，Gpx4(+/-)小鼠对氧化应激诱导的细胞凋亡敏感性显著增加。我们的数据表明，Gpx4的终身减少增加了寿命，并最有可能通过改变组织对细胞凋亡的敏感性来减少/延缓与年龄相关的病理变化。
