For this reason, we have undertaken a search for CR mimetics, agents that can exert the same biological effects as CR, but without reducing food consumption. One promising class of candidate compounds are those which affect glycolysis and/or glucoregulation. Initial studies with 2-deoxyglucose (2DG) have demonstrated the feasibility of this approach. Rats fed 2DG exhibit lower body temperature and plasma insulin (as well as lower plasma glucose under some conditions), and a trend toward greater survival during the mid-portion of the lifespan, while maintaining essentially ad libitum food intake. Unfortunately, 2DG has a very narrow window between efficacy and toxicity, which is reduced further by exposure time, and will probably render this compound impractical for human application. However, two "anti-diabetic" agents, phenformin and metformin, appear to mimic some of the bioeffects of 2DG without apparent toxicity. Preliminary experiments suggest that the latter can increase median and maximal survival of rats to the same extent as 30% CR.
Clearly, additional studies will be necessary to refine our approach and determine an optimal intervention protocol. However, taken together, the above results support the possibility of identifying agents that regulate glucose metabolism, without reducing caloric intake, as possible CR mimetics for eventual human use.
Key words:
CR mimetics, aging
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