NAD+

What Is NAD+?

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme present in every cell, and the central electron carrier of cellular metabolism, not a peptide. Every step of converting nutrients into ATP through the Krebs cycle and oxidative phosphorylation requires NAD+ as a substrate. It is also the obligate substrate for two enzyme families implicated in ageing: the sirtuins (SIRT1 to SIRT7, which regulate DNA repair, mitochondrial biogenesis, and stress response) and the PARPs (poly-ADP-ribose polymerases, which repair DNA strand breaks and consume large amounts of NAD+ in doing so).

Tissue NAD+ levels decline by 50% or more between ages 20 and 60, a change associated with mitochondrial dysfunction, slower DNA repair, and reduced sirtuin activity. Raising intracellular NAD+, whether through direct administration or through the precursors NMN, NR, and niacin, reactivates these pathways in the published models. The central mechanistic debate concerns cellular entry. Charles Brenner's work argues that intact NAD+ cannot cross the cell membrane because of its size and phosphate groups, and is instead degraded extracellularly to nicotinamide riboside or nicotinamide before re-entry and resynthesis. David Sinclair's group argues that the practical outcome, elevated intracellular NAD+, is what matters regardless of the conversion route. The bulk of human randomised trial evidence concerns oral NR and NMN; injectable NAD+ has decades of clinic use and emerging trial data but no large Phase 3 study.