Age-related NAD⁺ decline

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite that is reported to decline in concentration in tissues of aged animals. Strategies to increase NAD⁺ availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD⁺ metabolism remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD⁺, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD⁺ and changes in the composition of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD⁺ content of specific cells and subcellular compartments as well as determining the threshold levels at which NAD⁺ depletion triggers physiological consequences in different tissues. Understanding how NAD⁺ metabolism changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clinical trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD⁺ availability can impact human physiology. Thus, it is an exciting time for NAD⁺ research, with much remaining to be learned in terms of both basic biology and potential therapeutic applications.