NAD+ consumption and replacement

Deleting CD38 in mice

The NAD+ story gets more interesting for me when CD38 enters it. This enzyme consumes NAD+, and its activity rose with age in the mouse research. Mice without CD38 retained more NAD+ and better mitochondrial function. SIRT3, another protein dependent on NAD+, helped explain the connection to the mitochondria, the cell's energy-producing machinery.

That is an alteration of a system's demand for a molecule. A genetic deletion in a mouse is a very particular intervention; swallowing a precursor introduces a different intervention into a different organism. The consumption experiment gives a reason to investigate the system, while leaving human treatment to human trials.

I had expected replenishment to be the whole plot. CD38 makes the plot less comfortable and more useful: how fast a cell spends NAD+ can matter alongside how it makes it.

Energy chemistry and cellular repair

NAD+ is a coenzyme, a molecule that helps enzymes carry out their chemistry. It cycles between oxidised and reduced forms while cells extract usable energy from food. Other enzymes consume it during signalling and DNA repair. The review of NAD+ metabolism during ageing describes these overlapping demands on a shared resource.

NR and NMN are precursors from which the body can make NAD+. Each has its own route through metabolism. Direct NAD+, oral NR and oral NMN therefore arrive with different chemical and delivery questions.

One reason I distrust the broad phrase “NAD+ treatment” is that it hides those distinctions. An experiment can establish a useful fact about a precursor, a tissue or an enzyme while leaving the other versions largely unexplored.

The heart experiment and HMGCS2

A study using human heart tissue and a mouse model of heart failure examined the heart's capacity to make ketones. NAD+ repletion restored activity of HMGCS2, increased fatty-acid oxidation and improved cardiac function in the mice. When HMGCS2 was knocked down in heart muscle cells, the functional rescue was lost.

I appreciate that second manipulation. It gives the apparent benefit a condition: the relevant metabolic machinery had to remain available. “More NAD+” alone tells too little of the experiment.

The human part involved heart tissue; the improvement in cardiac function came from the mouse model. Whether a treatment improves symptoms or lasting outcomes in people with heart failure remains a clinical question.

Precursor trials

In healthy overweight adults, an 8-week trial of oral NR raised whole-blood NAD+ in a dose-dependent fashion. Adverse events did not differ significantly from placebo, and flushing was not reported. The blood finding is well defined; the trial did not establish longer life.

An NMN trial in middle-aged adults reported higher blood NAD+, improved walking distance and better quality-of-life scores over 60 days. A separate 10-week NMN trial in prediabetic, postmenopausal women found improved muscle insulin sensitivity. Body composition and HbA1c, a measure of average blood sugar, were unchanged in that study.

Those are different populations and outcomes. The precision of the NMN muscle finding impressed me. It would be excessive to award it the rest of healthy ageing as well.

The 2025 review of human precursor supplementation describes limited efficacy, sparse measurements inside tissues and age-related NAD+ decline consistently observed in only a limited number of human studies. The widespread mouse finding has a thinner human foundation than the replenishment story often suggests.

Safety and the NMN supplement dispute

Tolerability under trial supervision covers the ingredient and circumstances tested. The controlled evidence for direct intravenous NAD+ wellness treatments is weak in this record, and compounded injectable preparations carry contamination and unwanted-substance risks. Supplement contents can vary as well.

NAD+ supports cellular growth and metabolism, which raises a theoretical concern about supporting existing cancers. The research used here supplies no rate of cancer harm from supplementation. Both an automatic reassurance and an invented risk percentage would run ahead of the evidence.

NMN's status as a dietary supplement has been contested, while compounded NAD+ injections are not FDA-approved. The dispute about supplement sales leaves a separate question from whether a particular trial showed a useful health outcome. I want the prescribing responsibility made explicit here: Promise Peptides requires a licensed U.S. clinician's prescription for NAD+ treatment through mypromise.com.

More informative work would connect tissue measurements with repeatable functional gains in the same human population.