NAD+ occupies an unusual position: the basic biology is genuinely compelling, the animal data is solid, and the human clinical evidence is thinner than the marketing suggests. All three of those statements are true simultaneously.
What NAD+ does
Nicotinamide adenine dinucleotide is a coenzyme present in every cell, required for the electron transfers that convert food into ATP. Without it, oxidative metabolism stops. This part is not controversial — it is textbook biochemistry.
It is also the required substrate for two families of enzymes that matter in aging biology: sirtuins, which regulate gene expression and mitochondrial function, and PARPs, which repair DNA damage. Both consume NAD+ to work.
The decline is real and measurable
Tissue NAD+ falls substantially with age across multiple species, including humans. Several mechanisms contribute: increased consumption by PARPs responding to accumulated DNA damage, rising activity of the NAD+-consuming enzyme CD38, and reduced salvage-pathway efficiency.
The consequence is a resource constraint. Sirtuins and PARPs compete for a shrinking pool, which means DNA repair and metabolic regulation increasingly trade off against each other.
Where the evidence gets thin
Restoring NAD+ in aged mice improves mitochondrial function, exercise capacity and several markers of tissue health. These results are reproducible and come from good laboratories.
Human trials are a different picture. Studies of oral precursors — nicotinamide riboside and NMN — reliably show that blood NAD+ levels rise. What they have not consistently shown is that the functional outcomes people care about improve as a result. Trials have been small, short, and have used heterogeneous endpoints.
Why delivery route matters
Oral precursors face substantial first-pass metabolism. A meaningful fraction of an oral dose is converted or cleared before reaching systemic circulation, which is part of why effective oral doses are measured in hundreds of milligrams while subcutaneous NAD+ protocols use a fraction of that.
How we think about prescribing it
- Reasonable for persistent fatigue after a standard workup is unremarkable.
- Reasonable as one component of a broader protocol with measured endpoints.
- Not a substitute for fixing sleep, glucose regulation or thyroid status.
- Worth re-measuring at 90 days rather than continuing on faith.