We first proposed the idea of CR mimetics in 1998 (10) and further expanded on this potential approach in a subsequent article in Scientific American (11). In our initial study, we reported that disruption of cellular glucose metabolism (e.g., glycolysis) using the glucose analogue 2-deoxy-D-glucose (2DG) fed in the diet to rats lowered body temperature and fasting insulin levels without significantly reducing food intake over a 6-mo period at the selected dose (10). The 6-mo duration of this study was insufficient to assess indices of biological aging or longevity, but did validate that it may be possible to "mimic" metabolic effects of CR without reducing food intake. A follow-up survival study in rats unfortunately indicated that the window between efficacy and toxicity was too narrow to make this particular compound useful. The concept of CR mimetics has been further validated in other experiments. For example, similarly to CR, 2DG has been shown to be neuroprotective in rodent models of neurotoxicity and ischemia (12,13), and disruption of a different enzyme in glycolysis by iodoacetate protects neurons from glutamate toxicity (14). Thus, it is possible to mimic metabolic and protective effects of CR without reducing normal food intake.
Use of the term CR mimetics is becoming increasingly commonplace in the gerontological literature, with CR mimetics often loosely defined as any intervention, genetic or otherwise, that results in lifespan extension in a fashion similar to CR. In many cases, it is not understood whether food or energy intake were reduced by the intervention being tested, making it impossible to determine whether any effects observed mimicked CR or were in fact due to an actual reduction in energy intake (i.e., CR). In our view, a CR mimetic must have limited, if any, effects on food intake and must specifically target energy metabolism, because it is well established that energy is the nutritional factor responsible for the diverse and beneficial effects of CR. Another critical point is that to mimic CR effectively and to have a potential impact on fundamental processes of aging, candidate mimetics must increase both average and maximal lifespan. These important points are raised not in an attempt to limit the scope of possible CR mimetic approaches, but to ensure that candidate CR mimetics are appropriately focused and evaluated.
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