The autophagy–NAD axis in longevity and disease

NAD and autophagy are vital regulators of metabolic homeostasis that are required for the alleviation of cellular stress.Both NAD levels and autophagy activity decline with age, and genetically or pharmacologically boosting either promotes lifespan extension and attenuates age-related pathology in laboratory animals.Research over the past decade has revealed that NAD+‐consuming enzymes (NADases) can directly regulate autophagy in cells, from early transcription events to late-stage autophagosome–lysosome fusion.It was recently shown that autophagy deficiency induces fatal depletion of NAD+/NADH, that is rescuable by NAD precursor supplementation, suggesting a role of autophagy in NAD maintenance.Therefore, NAD and autophagy form a bidirectional feedback relationship which may be linked to longevity and age-related disease, and could represent a target for therapeutic intervention. Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.