Tissue-specific modulation of NADH consumption as an anti-aging intervention in Drosophila.

Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD) or reduced (NADH) states, which together form a key NADH/NAD redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD ratio. Here, we created transgenic expressing a genetically encoded xenotopic tool NOX to directly manipulate the cellular NADH/NAD ratio. We found that NOX expression in impacts both NAD(H) and NADP(H) metabolites in a sex-specific manner. NOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the eye, a widely used system to study reductive stress. Utilizing NOX, we demonstrate that targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of NOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, we used xenotopic tool NOX to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials.