Caloric Restriction and CR Mimetics: Possible Relevance to Humans
George S. Roth, Donald K. Ingram, and Mark A. Lane
National Institute on Aging, Baltimore, ND 21224
Dietary caloric restriction (CR) is the only intervantion
conclusively shown to slow aging, extend lifespan, and maintain health
and vitality in mammals. Our group at the NIA has expanded on nearly
70 years of work in rodents and lower animals by demonstrating similar
beneficial effects of CR in primates. In addition, biomarkers of the
CR state, including lower body temprature and circulating insulin
levels as well as higher levels of dehydroepiandrosterone sulfate
(DHEAS), correlate with extended longevity in humans. Nevertheless,
most people would be unwilling to maintain a 30-40% reduced food
intake over the bulk of their adult lifespan.
We have therefore initiated research into the area of CR mimetics;
compounds which may exert the same anti-aging and anti-disease effects
as CR, but without the necessity of reducing energy consumption. The
lead compound in this work has been 2-deoxyglucose (2DG), a structural
analog of glucose, which competitively inhibits glycolytic enzymes to
reduce energy flow within cells. 2DG elicits many of the same
biological effects as CR, including reduced tumorigenesis, increased
neuroprotection, and elevation of stress hormones. A preliminary
study in rats demonstrated lower insulin and body temperature, but no
appetite suppression or reduction in food intake by 2DG.
Unfortunately, the window between efficacy and toxicity for this agent
is rather narrow, rendering possibilities for long-term use in humans
slim at best. However, other naturally occurring substances with
negligable side effects are currently being evaluated for eventual
human application. Thus, it may eventually be possible to obtain the
beneficial effects of CR without actually reducing food consumption.
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