6 p53, Cancer, and Longevity

Abstract

Cancer is a pathology directly linked to the aging process (Campisi 2000; Balducci and Beghe 2001). Cancer incidence in the human population increases in an almost geometric fashion with age. Cancer is also a genetic disease, as it arises due in large part to an accumulation of mutations in critical genes that maintain normal cellular division, growth, and homeostasis (Vogelstein and Kinzler 2004). One group of genes that have evolved to minimize the frequency of these mutations and their effects are the tumor suppressor genes. The hundreds of tumor suppressor genes in our genome prevent early cancers from arising by maintaining genomic stability and by eliminating genomically unstable cells before they can become cancer cells. By preventing these early cancers, they are also longevity assurance genes. Vogelstein and Kinzler (1997) have categorized tumor suppressor genes as either “caretakers” or “gatekeepers.” The caretakers are a first line of defense against cancer in that they prevent the genome from acquiring new, potentially oncogenic mutations. The gatekeepers are a second line of defense in that they eliminate or arrest those cells that do acquire oncogenic mutations, preventing the emergence of a cancer. The primary mechanisms by which the gatekeepers suppress cancers are apoptosis (programmed cell death) and senescence (irreversible cell cycle arrest) (Campisi 2003). Rodent cancer models in particular have been instrumental in showing that nascent tumors are arrested or eliminated by both apoptosis and senescence (Fig. 1) (Schmitt 2003; Lowe et al. 2004). Mutation or loss of these gatekeeper tumor suppressors almost...