Age-related NAD+ decline

Abstract

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.

Figure 1:. NAD⁺ as a redox cofactor and cosubstrate for signaling enzymes.

NAD⁺ (center) can accept electrons (in the form of a hydride anion, H⁻), converting the cofactor to its reduced form, NADH, and facilitating the oxidation of substrates. Subsequently, the electrons can be donated to facilitate reduction reactions with concomitant oxidation of NADH back to NAD⁺. This process is critical to hundreds of reactions, including those of central carbon metabolism, driving energy production (i.e., glycolysis, the TCA cycle and oxidative phosphorylation). NAD⁺ also serves as a co-substrate for several families of enzymes that regulate key biological processes via changes in protein modification or the generation of signaling molecules (e.g., Sirtuins, PARPs and CD38/CD157).

Figure 2:. Potential mechanisms resulting in lower tissue NAD⁺ concentrations with age.

Schematic illustrating distinct scenarios that could result in lower measured NAD⁺ in extracts of tissues from aged animals. Uniform loss involves all cells experiencing a similar NAD⁺ deficit. Heterogenous loss suggests local defects resulting in impaired synthesis or excess consumption that could affect a subset of cells disproportionately. Tissue composition may also change with age, resulting in decreased cellularity or the appearance of cells with less NAD⁺ (e.g., adipocytes). A shift in the redox balance could lower NAD⁺ without any change in the total (NAD⁺ + NADH) pool. A decrease in the number of mitochondria (or other NAD⁺-rich organelles) could decrease the whole-tissue NAD⁺ concentration and apparent redox state (i.e., whole tissue NAD⁺:NADH ratio) without actually changing NAD⁺ concentration or redox state in any given compartment.