Antioxidant genes, hormesis, and demographic longevity

Mortality rates have been observed to slow down or even decline in late lif e such that a small subset of the population has a significantly longer sur vival than does the remainder of its cohort. The mechanism for this phenome non of "demographic longevity" has been attributed either to epigenetic eff ects occurring in a genetically homogenous population or to differential mo rtality occurring in a genetically heterogenous population. However, neithe r of these alternative mechanisms is sufficient to fully explain the data. In this article, we review the theoretical arguments and empirical data bea ring on this question. We propose that exposure to a wide variety of enviro nmental stressors will hormetically raise the transient basal level of expr ession of the antioxidant defense system (ADS) genes and, probably to a les ser extent, the heat shock protein (hsp) genes in the long-lived subset of the exposed population. The enhanced protection from oxidative damage provi ded by elevated levels of ADS gene products would reduce the functional gen etic 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 as sociated Darwinian fitness costs for the whole population that outweigh the fitness benefits conferred to the smaller long-lived subset. Thus, hormeti cally elevated levels of ADS gene expression would be restricted to this sm aller long-lived subset of the population. Our hypothesis also predicts tha t spontaneous DNA damage occurring in the long-lived cohort would be more e fficiently removed by the hormetically elevated levels of DNA repair enzyme s, thus reducing the age-dependent genetic variance in this smaller subset. Since accumulated somatic mutation may lead to functional damage in critic al cell or tissue systems, this mechanism would result in a reduced late-li fe mortality for the hormetically induced cohort, Our hypothesis provides a dditional predictions that may be tested empirically.