The role of metabolism in aging.

Metabolism appears to play a significant role in determining the rate of aging. Long-lived mutants and selected stocks of model experimental organisms exhibit characteristic changes in life history and physiological features consistent with altered metabolism. Specifically, these include the accumulation of metabolite pools of glycogen, lipid and polyhedric alcohols, suggesting that prolonged life is associated with restriction of the flow of carbon through glycolysis. Limiting carbon flow by reducing caloric intake is well known to extend life. Studies examining the mRNA expression pattern of functional gene groups generally indicate that nutrient restriction does affect metabolism. One study of Drosophila melanogaster has demonstrated that the flux of carbon through glycolysis is reduced in larvae of selected long-lived populations. Here we propose a new hypothesis describing the interaction between the glycation process, glucose level, damage by free oxygen radicals and chaperonin proteins. Intermediate steps of the Maillard Reaction produce free radicals, similar to those produced during respiration, that also damage lipids, proteins and DNA. Antioxidant enzymes themselves can be inactivated by glycation. This establishes a positive feed-back between the rate of metabolism, glucose availability and damage by free oxygen radicals. The high levels of available glucose in ad libitum feeding should add to production of radicals, reduce levels of protective antioxidants and proportionally increase damage by free radicals. Thus, caloric restriction should lower available glucose, increase the level of antioxidants and thereby slow the rate of aging. Chaperonins act to block glycation, reducing its negative effect on antioxidant enzymes release and contribution of free radicals.