The evolutionary tangle of aging, sex, and reproduction and an experimental approach to its molecular dissection

Exchange of genetic materials by two individual members of the same species is considered to be the origin of primitive sex. During evolution, this primitive form of molecular sex has been transformed into a complex biological function involving specialized sexual structures and multiple hormonal interactions. Development and maintenance of these reproductive structures are also dependent on hormones and hormone receptors. Furthermore, reproductive specialization in higher forms of life has led to customized species-specific rates of aging and life-span potentials that are commensurate with the reproductive needs of the particular type of organism. Because of this reproductive imposition on aging of the organism, temporal regulation of the hormone response is a significant component of the genetics of aging. We have observed a marked age-dependent alteration in the hepatic expression of the rat androgen receptor (rAR) gene. Among the large number of transcription factors that control the rAR gene, at least three appear to participate in its age-dependent regulation. Two of these are positively acting and yet/to be characterized transcription factors, while the third is a negative regulator the nuclear factor κB (NF-κB). NF-κB is the major trans-regulator for genes involved in the immune response, inflammation, and oxidative stress. Involvement of NF-κB in the modulation of both oxidative stress and sex function provides the first example of a common molecular link between sex and aging.