CR mimetics have been proposed that target a number of pathways related to energy metabolism such as glycolysis inhibitors, antioxidants, sirtuin regulators, and insulin sensitizers. As summarized previously, inhibition of glycolysis remains a promising target despite our disappointing results with 2DG. Given the popularity and general acceptance of the Free Radical Theory of Aging, antioxidants have been the focus of many studies in biogerontology (15).
Treatment with antioxidants has occasionally been shown to lead to an increase in average lifespan; however, reproducible increases in both average and maximal lifespan in mammals have not been observed.
Sirtuins serve as gene silencers, and emerging evidence supports a possible role in aging and lifespan extension in short-lived organisms (16). Insulin sen-sitizers may also act to mimic CR, because an increase in insulin sensitivity is among the most rapid and robust response to this nutritional intervention. In vitro studies have shown that phenformin, a treatment for diabetes, suppresses calcium responses of hippocampal neurons to glutamate and decreases their vulnerability to excitotoxicity (17). Studies of phenformin treatment in vivo on markers related to CR and lifespan have been inconclusive. However, at least one study has shown that phenformin reduced reactive oxygen species (18).
Given the redundancy of metabolic pathways and their sometimes differing regulation in different tissues, it seems unlikely that a CR mimetic targeting a single pathway will produce all of the beneficial effects of CR. It may be necessary to target, for instance, both glucose and lipid metabolic pathways to achieve the full benefit of CR without reducing food intake. Thus, it is conceivable that "cocktails," containing various combinations of candidate "segmental" CR mimetics, might be devised to more completely duplicate the effects of CR (19).
Beyond the obvious potential benefits of CR mimetics on lifespan and aging, this approach provides additional opportunities to probe aging at the molecular level. The utility of CR as such a probe is limited by the fact that it requires energy restriction at the level of the whole organism from which tissues can then be harvested for study. Given this constraint, certain types of molecular studies are challenging at best or at worst not possible. If further validated, this approach has obvious benefit in that it provides molecular gerontologists with additional tools to probe biological processes of aging at the subcellular level, perhaps ultimately leading to the development of pharmaceuticals that may also mimic CR.
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