NAD+: what the literature documents about this central cofactor of cellular metabolism
An obligatory substrate for sirtuins and PARPs, NAD+ declines with age: a review of the research literature on this central coenzyme of energy metabolism.
NAD+ (Nicotinamide Adenine Dinucleotide) is one of the most extensively studied cofactors in cell biochemistry, and the literature devoted to its role in cellular aging has grown considerably over the past decade.
A redox cofactor, substrate for three enzyme families
NAD+ first acts as a cofactor in cellular oxidation-reduction reactions. But recent literature is mainly interested in its role as an obligatory substrate for three enzyme families: sirtuins (SIRT1 to 7), PARPs (Poly-ADP-ribose polymerases, involved in DNA repair) and CD38, a membrane enzyme that consumes NAD+.
A documented decline with age
Several studies (PMC10692436, PMC9512238, PMID 37971292) describe a progressive decrease in intracellular NAD+ levels with age, correlated with a decline in mitochondrial function and DNA repair capacity. This observation is at the core of the fundamental literature's interest in strategies for restoring NAD+ levels in vitro.
SIRT3, PGC-1α and mitochondrial biogenesis
Elevating NAD+ levels in vitro restores the activity of SIRT3, a mitochondrial sirtuin involved in the deacetylation of respiratory chain proteins. Studies describe an improvement in fatty acid β-oxidation and a stimulation of mitochondrial biogenesis via the PGC-1α pathway — a central transcriptional regulator of mitochondrial function.
Insulin sensitivity and the kynurenine pathway
At the metabolic level, the literature reports an improvement in insulin sensitivity associated with elevated NAD+, as well as a modulation of tryptophan metabolism via the kynurenine pathway — a metabolic axis increasingly studied in connection with chronic low-grade inflammation.
Cellular senescence and autophagy
Reported effects also include a reduction in cellular senescence markers (p16, p21) and an increase in autophagy — the cellular recycling mechanism for damaged organelles — in the studied models.
A central cofactor, not a single-target molecule
Unlike peptides with a single receptor target, NAD+ acts as a transversal metabolic hub, which explains the breadth of the spectrum of mechanisms documented in the literature — from DNA repair to mitochondrial function to cellular senescence.