Antioxidant genes, hormesis, and demographic longevity

Mortality rates have been observed to slow down or even decline in late life such that a small subset of the population has a significantly longer survival than does the remainder of its cohort. The mechanism for this phenomenon of "demographic longevity" has been attributed either to epigenetic effects occurring in a genetically homogenous population or to differential mortality occurring in a genetically heterogenous population. However, neither of these alternative mechanisms is sufficient to fully explain the data. In this article, we review the theoretical arguments and empirical data bearing on this question. We propose that exposure to a wide variety of environmental stressors will hormetically raise the transient basal level of expression of the antioxidant defense system (ADS) genes and, probably to a lesser extent, the heat shock protein (hsp) genes in the long-lived subset of the exposed population. The enhanced protection from oxidative damage provided by elevated levels of ADS gene products would reduce the functional genetic damage associated with aging. This resultant reduced level of genetic damage in the long-lived subset provides a mechanism for the phenomenon of demographic longevity. We further propose that this epigenetic response to environmental variation, acting at the gene expression level, would have associated Darwinian fitness costs for the whole population that outweigh the fitness benefits conferred to the smaller long-lived subset. Thus, hormetically elevated levels of ADS gene expression would be restricted to this smaller long-lived subset of the population. Our hypothesis also predicts that spontaneous DNA damage occurring in the long-lived cohort would be more efficiently removed by the hormetically elevated levels of DNA repair enzymes, thus reducing the age-dependent genetic variance in this smaller subset. Since accumulated somatic mutation may lead to functional damage in critical cell or tissue systems, this mechanism would result in a reduced late-life mortality for the hormetically induced cohort, Our hypothesis provides additional predictions that may be tested empirically.