Aberrant Insulin Receptor Signaling and Amino Acid Homeostasis as a Major Cause of Oxidative Stress in Aging

Abstract

The mechanisms leading to the increase in free radical-derived oxidative stress in "normal aging" remains obscure. Here we present our perspective on studies from different fields that reveal a previously unnoticed vicious cycle of oxidative stress. The plasma cysteine concentrations during starvation in the night and early morning hours (the postabsorptive state) decreases with age. This decrease is associated with a decrease in tissue concentrations of the cysteine derivative and quantitatively important antioxidant glutathione. The decrease in cysteine reflects changes in the autophagic protein catabolism that normally ensures free amino acid homeostasis during starvation. Autophagy is negatively regulated by the insulin receptor signaling cascade that is enhanced by oxidative stress in the absence of insulin. This synopsis of seemingly unrelated processes reveals a novel mechanism of progressive oxidative stress in which decreasing antioxidant concentrations and increasing basal (postabsorptive) insulin receptor signaling activity compromise not only the autophagic protein catabolism but also the activity of FOXO transcription factors (i.e., two functions that were found to have an impact on lifespan in several animal models of aging). In addition, the aging-related decrease in glutathione levels is likely to facilitate certain "secondary" disease-related mechanisms of oxidative stress. Studies on cysteine supplementation show therapeutic promise.