Why NAD+ Supplements Are a Waste of Money

Your NAD+ levels are not low because your body forgot how to make it.

That assumption is what the entire NAD+ supplement industry is built on, and it is wrong in a way that costs people real money for real years while the actual problem gets worse underneath.

To understand why, you need the full picture first.

Your cells run on something called NAD+, which is a molecule your body uses to transfer energy and run the repair enzymes that keep your DNA and mitochondria functional. When you are young, NAD+ levels stay relatively stable because the amount being made roughly matches the amount being used. As you get older, that balance collapses, and most research confirms that NAD+ drops significantly in tissues across the body by middle age and beyond. That much of the popular story is accurate.

Where the story goes wrong is the explanation for why.

The supplement industry frames this as a production problem, so they sell you precursors like NMN and NR that your body can use to synthesize more NAD+. The logic sounds reasonable. If levels are low, give the body more raw material. But a study published in Cell Metabolism found something that breaks that logic entirely. When researchers looked at aged tissue, CD38 activity, where CD38 is an enzyme that consumes NAD+ to produce immune signaling molecules, had increased two to three fold compared to young tissue. And the correlation between CD38 activity and NAD+ levels was nearly perfect in the inverse direction. More CD38, less NAD+. Every time, across every tissue they measured.

Then they did the definitive experiment. They bred mice that had no CD38 enzyme at all, and those mice maintained NAD+ levels at every age, levels that looked indistinguishable from young mice, without any supplementation. The body was not making less. Something was eating it.

That something has a clear upstream cause. A 2020 paper in Nature Metabolism traced the chain all the way back. As you age, you accumulate what are called senescent cells, which are damaged cells that stopped dividing but did not die the way they were supposed to. These cells put out a steady stream of inflammatory signals, and those signals cause a specific type of immune cell called a macrophage to massively upregulate CD38 expression. The researchers measured this directly and found that CD38 expression in macrophages exposed to senescent cell signals increased up to 600 fold. Not a modest increase. Six hundred times.

So the chain looks like this. Damaged cells accumulate, they signal inflammation, that inflammation trains immune cells to express enormous amounts of CD38, and CD38 burns through NAD+ to fuel the immune response to all that damage.

There is a second drain running in parallel. Damaged mitochondria activate a family of enzymes called PARPs, which stands for poly ADP-ribose polymerases, and PARPs use NAD+ as the raw material to build the molecular tags they attach to damaged DNA as part of the repair process. More mitochondrial damage means more PARP activity means more NAD+ consumed. So you have CD38 burning from one side and PARPs burning from the other, and both are being driven by accumulated cellular damage.

Now you can see exactly why pouring in more precursor does not work. The drain is open. You are not filling the tub, you are just running the faucet faster. And a 2023 review in Science Advances that examined 25 human trials on NR supplementation concluded there is an unfortunate tendency in the literature to exaggerate the importance and robustness of the reported effects, which is a polite way of saying the human data does not back the marketing.

There is also a delivery problem on top of the consumption problem. Research published in FEBS Letters found that gut bacteria convert NMN into niacin before it ever gets absorbed, meaning most of what you take as a premium NAD+ precursor arrives at your cells as plain niacin, which costs a fraction of a cent per dose. A separate enterohepatic circulation study confirmed the same thing for NR. The gut microbiome is deamidating these molecules and routing them through the niacin pathway regardless of what the label says.

So what actually addresses the drain rather than fighting it?

Exercise does something that no supplement has cleanly replicated, which is increasing NAMPT expression. NAMPT is an enzyme that recycles NAD+ by salvaging used pieces back into the active molecule, and a 2023 meta-analysis of exercise training studies found that consistent training increases intracellular NAMPT expression by over 127 percent, with a large effect size. That is not a small signal.

For the mitochondrial side, a peptide called SS-31 targets the inner mitochondrial membrane directly and helps restore function at the site where PARP activation is being triggered. A 2020 study in Aging Cell showed that neither SS-31 nor NMN alone significantly raised NAD levels in aged mouse hearts, but the combination did, producing results that most closely matched young tissue. That finding matters because it tells you the mitochondrial repair has to happen before the precursor support does anything meaningful.

For the senescent cell side, a peptide called FOXO4-DRI was developed to selectively trigger apoptosis in senescent cells by interfering with the survival mechanism those cells use to avoid dying. If you remove the senescent cells, you remove the signal that is driving the 600-fold CD38 upregulation in the first place. That is where the drain gets closed, not partially reduced, actually closed.

If after doing all of that you want to add a NAD+ precursor, niacin works, absorbs cleanly, bypasses the gut conversion problem, and costs almost nothing.

The real insight here is not just that you should take different supplements. It is that your body's declining NAD+ is a symptom of accumulated cellular damage, not a nutrient deficiency, and treating it like a deficiency is the same logic as refilling a car's oil every week without ever fixing the leak. The oil is low because something is wrong. The question was never how to add more.

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References

1. Camacho-Pereira J, Tarrago MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metabolism. 2016;236:1127-1139. Finding: CD38 activity increases 2-3 fold with age across all tissues, with near-perfect inverse correlation to NAD+ levels. CD38 knockout mice maintained NAD+ at all ages. Source
2. Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nature Metabolism. 2020;211:1265-1283. Finding: Senescent cells secrete inflammatory cytokines that cause macrophages to upregulate CD38 expression up to 600-fold, establishing the causal chain from cellular senescence to NAD+ decline. Source
3. Kim LJ, Chalmers TJ, Madawala R, et al. Host-microbiome interactions in nicotinamide mononucleotide NMN deamidation. FEBS Letters. 2023;59717:2196-2207. Finding: Gut bacteria deamidate NMN before absorption, converting it to nicotinic acid niacin. Ablation of microbiome with antibiotics increased direct NMN uptake, confirming gut conversion. Source
4. Science Advances enterohepatic circulation study. Finding: NMN and NR facilitate NAD+ synthesis primarily through conversion to niacin-pathway metabolites in the gut, confirming that most oral precursors become niacin before absorption. Source
5. Sun X, Su L, Bu T, Zhang Y. Exercise training upregulates intracellular nicotinamide phosphoribosyltransferase expression in humans: a systematic review with meta-analysis. Frontiers in Public Health. 2023;11:1287421. Finding: Exercise training increases NAMPT expression by over 127% with a large effect size Cohen's d = 0.81. Source
6. Whitson JA, Martin SS, Zhang H, et al. SS-31 and NMN: Two paths to improve metabolism and function in aged hearts. Aging Cell. 2020;1910:e13213. Finding: Neither SS-31 nor NMN alone significantly increased resting NADH levels in aged mouse hearts. Only the combination did, best recapitulating the young state. Source
7. Brakedal B, Doring A, Riber C, et al. What is really known about the effects of nicotinamide riboside supplementation in humans. Science Advances. 2023;929:eadi4862. Finding: Review of 25 NR human studies concluded there is "an unfortunate tendency in the literature to exaggerate" the importance and robustness of reported effects. Source

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