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

Abstract

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 time. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to boost 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 it 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 aimed to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD+ during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

Tissue‐specific effects of exercise as NAD+‐boosting strategy: Current knowledge and future perspectives

“…Although promising as such, a recent review of studies on this topic concluded that despite overall claims of NAD + decline with age the scientific evidence is rather limited and often restricted to certain tissue types. Additionally, the authors highlight the potential selection bias attached to narrative literature reviews and shed light on the importance of unbiased longitudinal studies to establish an evidence‐based foundation for the abovementioned claims 30 . Hence, while the exact impact of aging on tissue NAD + content remains unclear (especially in humans), tissue‐specific alterations of NAD + homeostasis are frequently reported in disease settings, 31 making tissue‐specific approaches indispensable when investigating NAD + ‐modifying interventions.…”