Detoxification reactions: relevance to aging.

It is widely (although not universally) accepted that organismal aging is the result of two opposing forces: (i) processes that destabilize the organism and increase the probability of death, and (ii) longevity assurance mechanisms that prevent, repair, or contain damage. Processes of the first group are often chemical and physico-chemical in nature, and are either inevitable or only under marginal biological control. In contrast, protective mechanisms are genetically determined and are subject to natural selection. Life span is therefore largely dependent on the investment into protective mechanisms which evolve to optimize reproductive fitness. Recent data indicate that toxicants, both environmental and generated endogenously by metabolism, are major contributors to macromolecular damage and physiological dysregulation that contribute to aging; electrophilic carbonyl compounds derived from lipid peroxidation appear to be particularly important. As a consequence, detoxification mechanisms, including the removal of electrophiles by glutathione transferase-catalyzed conjugation, are major longevity assurance mechanisms. The expression of multiple detoxification enzymes, each with a significant but relatively modest effect on longevity, is coordinately regulated by signaling pathways such as insulin/insulin-like signaling, explaining the large effect of such pathways on life span. The major aging-related toxicants and their cognate detoxification systems are discussed in this review.