Hyperinsulinemia: The missing link among oxidative stress and age-related diseases?

Mounting evidence supports Harman's hypothesis that aging is caused by free radicals and oxidative stress. Although it is known that oxidant species a re produced during metabolic reactions, it is largely unknown which factor( s), of physiological or pathophysioiogical significance, modulate their pro duction in vivo. In this hypothesis paper, it is postulated that hyperinsul inemia may have such function and therefore promote aging, independently of elevations of glycemia. Hyperinsulinemia is secondary to impaired insulin stimulated glucose metabolism at the level of skeletal muscle (insulin resi stance) and is seen in about one third of glucose tolerant humans following dietary carbohydrate intake. If other insulin-stimulated (or inhibited) pa thways retain normal sensitivity to the hormone, hyperinsulinemia could, by its effects on antioxidative enzymes and on free radical generators, enhan ce oxidative stress. Other proaging effects of insulin involve the inhibiti on of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) s ynthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia acc elerates aging also offers a metabolic explanation for the Life-prolonging effect of calorie restriction and of mutations decreasing the overall activ ity of insulin-like receptors in the nematode Caenorhabditis elegans. (C) 2 000 Elsevier Science Inc.