Fig. 3

Boosting NAD⁺ levels is beneficial for health and lifespan. NAD⁺ is a rate-limiting cofactor for the enzymatic activity of sirtuins. Boosting intracellular NAD⁺ levels by physiological (e.g. exercise, calorie restriction, fasting) or pharmacological [e.g. resveratrol, sirtuin activating compounds (STACs)] interventions, and inducing NAD⁺ biosynthesis through supplementation with precursors (e.g. NA, NAM, NR) or inhibition of NAD⁺ consuming enzymes (e.g. PARP-1, CD38) leads to activation of sirtuins (e.g. SIRT1, SIRT3). SIRT1 deacetylates and activates transcriptional regulators (e.g. PGC-1α, FOXO1), whereas SIRT3 deacetylates and activates multiple metabolic gene targets (e.g. succinate dehydrogenase, superoxide dismutase 2), which in turn regulate mitochondrial biogenesis and function. Supplementation with NR or PARP inhibitors extends lifespan in worms by inducing the UPR^mt stress signaling response via Sir-2.1 activation, which then triggers an adaptive mitohormetic response to stimulate mitochondrial function and biogenesis. Improved mitochondrial function associated with mitohormesis or metabolic adaptation can attenuate the impact of mitochondrial diseases, aging as well as age-related metabolic and neurodegenerative disorders. The physiological and pharmacological interventions that boost NAD⁺ levels are highlighted in yellow and pink respectively whereas the pathways that produce and consume/decrease NAD⁺ levels are highlighted in green and red respectively