Are somatic cells inherently deficient in methylation metabolism? A proposed mechanism for DNA methylation loss, senescence and aging

Abstract

A mechanism of aging is proposed for mammals and other vertebrates. In this mechanism, most somatic cells have inherent deficiencies in methylation metabolism with respect to their capacity to methylate DNA. This leads to incomplete DNA methylation in each cell cycle which, accumulated over many cell cycles, contributes to genetic instability, senescence and cancer. These proposed metabolic deficiencies are present from the time somatic cells are young, yet it is only after many cell divisions that deleterious effects are realized. In nature, most animals have reproduced or have been killed by predators or other environmental hazards before they can be greatly affected by these deficiencies. These deficiencies evolved in animals eating a balance of nutrients from nature. Evidence from the literature is reviewed which establishes that methylation is lost from the DNA of many mammalian somatic cells as they age both in vivo and in vitro, and that DNA methylation levels are influenced by factors, such as diet, that affect methylation metabolism. Partially correcting the proposed deficiencies is considered as a possible molecular mechanism by which caloric restriction extends lifespan. Other possible dietary and transgenic means to correct the proposed deficiencies and extend lifespan are discussed.