Linking oxidative stress and genetics of aging with p66Shc signaling and forkhead transcription factors

被引:41
作者
Purdom, S
Chen, QM
机构
[1] Univ Arizona, Interdisciplinary Grad Program Genet & Genom, Tucson, AZ 85724 USA
[2] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA
关键词
antioxidant enzymes; apoptosis; caloric restriction; longevity; invertebrate models; signal transduction; transgenic mice;
D O I
10.1023/A:1025123413403
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Genetics versus oxidative stress have been long-standing points of contention among theories seeking to explain the root of aging. Because aging is the highest risk factor for many diseases, it is to our advantage to better understand the biological mechanisms of this process. Caloric restriction has been the only reliable means of extending lifespan in mammalian models until recently. The discovery of mutant strains of mice with increased longevity could be a significant contributor to our understanding of the genetic and molecular basis of human aging. One genetic approach that increases the longevity of mice is the removal of the p66Shc gene, which encodes a protein belonging to a family of adaptors for signal transduction in mitogenic and apoptotic responses. Normally, p66Shc is tyrosine phosphorylated ( activated) by various extracellular signals including EGF and insulin. However, serine phosphorylation of p66Shc can occur after oxidative stress either in association with or independently of tyrosine phosphorylation. p66Shc serine phosphorylation has been linked to inactivation of members of forkhead transcription factors, resulting in increased intracellular oxidant levels and increased sensitivity to apoptosis. Knocking out p66Shc allows moderately elevated activity of forkhead transcription factors and better-equipped antioxidant defenses at the cellular level. Recent reports have suggested that methylation of the p66Shc promoter has important implications in its expression regulation. This leads us to hypothesize that the methylation status of the p66Shc promoter may differ between individuals and therefore contribute to variations of longevity. We present evidence arguing that decreasing oxidative stress or increasing resistance to oxidative damage as a result of genetic variation or p66Shc knockout is likely contributing to individual differences in longevity.
引用
收藏
页码:181 / 191
页数:11
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