The common germline Arg72Pro polymorphism of p53 and increased longevity in humans

Abstract

More than ten million single nucleotide polymorphisms (SNPs) have been identified in humans; however, the importance of most SNPs for health and disease is not understood. Most SNPs are indeed unimportant and because of often inadequately powered studies, many observations on SNP effects can not be repeated by other researchers. SNPs are at best shown to influence protein function or level, rarely to influence risk of disease, and almost never to influence total mortality, the ultimate endpoint. A wellknown functional SNP in the tumor suppressor TP53 gene leads to increased longevity: in the Danish general population (n = 9219) homozygotes for the minor allele versus homozygotes for the major allele had an increase in median survival of 3 years. This is partly explained by increased survival after development of cancer or other diseases, in accordance with the observation that this Arg72Pro substitution in the p53 protein has important influence on cell death via increased apoptosis. Thus, the increased longevity may be due to a generally increased robustness after a diagnosis of any life-threatening disease. In contrast to widespread skepticism on the importance of SNPs in humans, this gain-of-function p53 SNP of importance for cell repair mechanisms has a profound influence on longevity.