NADPH: new oxygen for the ROS theory of aging.

Abstract

First stated in 1950 by Dentham Harman, the free radical theory of aging hypothesized that free radicals oxidize macromolecules, creating a cumulative damage that acts as a key driver of aging. Although it enjoyed wide acceptance for many years, this proposal has been challenged by many different observations. Studies on the biological roles of reactive oxygen species (ROS) have uncovered beneficial signaling functions of these highly reactive molecules; treatment of animal models and humans with antioxidant products have failed to protect against age-induced pathologies; and overexpression of most antioxidant enzymes in animal models have not increased lifespan nor protected from aging. All these findings have led to the discredit of the free radical theory of aging in academia. A recent report by us [1] adds fresh support to the free radical theory of aging. We focused our attention on a molecule that had remained relatively unnoticed in the aging field: nicotinamide adenine dinucleotide phosphate, or NADP. Its reduced form, NADPH, is the donor of reductive potential to glutathione and thioredoxins, which in turn are used (directly or indirectly) by glutaredoxins, peroxiredoxins and glutathione peroxidases to neutralize ROS (see Figure 1). Thus, NADPH serves as the ultimate donor of reductive power for the large majority of ROSdetoxifying enzymes. NADPH can be generated by several metabolic pathways, including the reactions catalyzed by the malic enzymes, isocitrate dehydrogenases and folate dehydrogenases; but the main source of cellular NADPH are two enzymes of the oxidative branch of the Editorial