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, C. elegans, 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.