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 sp ecies is considered to be the origin of primitive sex. During evolutio n, this primitive form of molecular sex has been transformed into a co mplex biological function involving specialized sexual structures and multiple hormonal interactions. Development and maintenance of these r eproductive structures are also dependent on hormones and hormone rece ptors. Furthermore, reproductive specialization in higher forms of lif e has led to customized species specific rates of aging and life-span potentials that are commensurate with the reproductive needs of the pa rticular 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 m arked age-dependent alteration in the hepatic expression of the rat an drogen receptor (rAR) gene. Among the large number of transcription fa ctors that control the rAR gene, at least three appear to participate in its age-dependent regulation. Two of these are positively acting an d yet/to be characterized transcription factors, while the third is a negative regulator the nuclear factor kappa B (NF-kappa B). NF-kappa B is the major tr ans-regulator for genes involved in the immune respon se, inflammation, and oxidative stress. Involvement of NF-kappa B in t he modulation of both oxidative stress and sex function provides the f irst example of a common molecular link between sex and aging.