NAD+ research gets awkward

NAD+ and aging: CD38 consumes the supply

Aging is the obvious starting point for NAD+ research, but the CD38 experiment in mice is more interesting than the slogan about declining levels. CD38 is an enzyme that consumes NAD+. Its activity rose as the mice aged; tissue NAD+ and mitochondrial function fell. Mice lacking CD38 were protected against that decline.

CD38’s absence makes this experiment persuasive to me. It does more than notice a lower number: it changes one part of the system and observes what follows. The SIRT3 review examines another part, an NAD+-dependent enzyme in mitochondria, the cell's energy-producing compartments. That review’s footing is largely mouse and mechanistic evidence. Its human clinical implications await testing.

The 2025 human-evidence review adds an unwelcome qualification: age-related NAD+ decline has been consistently observed in only a limited number of human studies, and tissue-specific data remain sparse. NAD+ decline seemed a settled human premise to me. That review leaves me less willing to treat every older body as the same replenishment problem.

NMN trial: muscle insulin sensitivity

In the NMN trial in prediabetic, postmenopausal women, participants received 250 mg/day orally for ten weeks. Muscle became more responsive to insulin, meaning insulin helped it take up glucose more effectively. Body composition and HbA1c, a measure of longer-term blood sugar, did not change.

The unchanged findings sharpen the result. Muscle insulin sensitivity is a particular observation in a particular population. The scope is muscle glucose handling; a diabetes treatment or a general energy boost would need separate human findings.

Earlier work in mice with diet- and age-induced diabetes found restored NAD+ in liver and muscle and improved glucose handling. That makes a coherent biological lead. It does not enlarge the human trial's result to cover everyone who hears about NAD+ benefits.

Glaucoma prevention in mice: 93% of eyes

The number in Williams and colleagues’ glaucoma study is striking: at the highest tested amount of nicotinamide, 93% of eyes did not develop glaucoma. Those eyes belonged to glaucoma-prone mice. Retinal NAD+ had fallen with age, and vitamin B3 was protective in this animal model.

Those mouse eyes account for the appeal to me: a memorable number, an identifiable organ and an outcome more tangible than a metabolite. The species is essential to that percentage: the intervention was tested in glaucoma-prone mice, and efficacy in people remains unestablished.

Drug-resistant melanoma in cell lines and mice

In drug-resistant melanoma cell lines and mouse xenografts, resistant cancer cells increased NAMPT, an enzyme involved in rebuilding NAD+. Inhibiting that enzyme depleted NAD+ and ATP, the cells' usable energy currency, and improved survival in the mice carrying the tumors. Their intervention attacked the cancer's NAD+ rebuilding machinery.

Set that beside the review linking NAD+ deficits with aging and cancer. A depleted supply can be associated with harmful processes; a thriving cancer can also depend on making more. Neither paper makes NAD+ a cancer treatment or proves that a precursor supplement feeds cancer in people.

The melanoma work dismantled my first, simpler picture of replenishment. A molecule cannot distinguish a cell I want protected from one I want stopped. Universal replenishment is a position I cannot defend from these papers.

Human evidence on NAD+ and visible aging

No human trial in this record shows NAD+ or its precursors reversing visible aging. The review of human precursor supplementation finds limited efficacy and inconsistent translation from higher blood NAD+ to clinical outcomes. The NMN walking trial returns to a much narrower result: distance walked during a test.

My patience now hinges on a trial that connects the tissue, the change in NAD+ and a meaningful human outcome in the same experiment. Another raised blood number would be useful chemistry. It would leave the larger argument where it is.