Age-Dependent Decline of NAD-Universal Truth or Confounded Consensus?

Nicotinamide adenine dinucleotide (NAD) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD-dependent enzymes. In the early 2000s, reports that NAD declines with aging introduced the notion that NAD metabolism is globally and progressively impaired with age. Since then, NAD became an attractive target for potential pharmacological therapies aiming to increase NAD levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD with aging in different species (i.e., yeast, , rat, mouse, monkey, and human), to determine whether the notion that overall NAD levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.