Why NAD+ Supplements Are a Waste of Money

Your NAD+ levels are not low because your body forgot how to make it. They are low because something is consuming it faster than it can be replaced, and that distinction changes everything about how you should approach the problem.

Start with the big picture. Your body runs on NAD+, which is a molecule that acts as an electron carrier in cellular energy production and also serves as fuel for a class of repair and signaling enzymes. When you are young, your body makes enough of it and recycles enough of it to keep pace with demand. As you age, that balance breaks down. The standard explanation in supplement marketing is that production falls off, so you should take more. The research tells a different story.

Here is the full chain. As cells accumulate damage over decades, some of them stop dividing but refuse to die. Those are what we call senescent cells, which are essentially cells that have exited the normal lifecycle but remain metabolically active and inflammatory. They secrete a cocktail of inflammatory signals into surrounding tissue. Those signals activate immune cells called macrophages, and those macrophages respond by dramatically upregulating an enzyme called CD38, which is an enzyme whose job is to break down NAD+ to produce the signaling molecules the immune system needs to coordinate its response to damage. The more senescent cells you accumulate, the more inflammatory signaling, the more CD38 activity, the more NAD+ gets consumed. That is the drain.

The data on this is not subtle. A 2016 paper published in Cell Metabolism found that CD38 activity increases two to three fold across all tissues as mice age, and that this increase correlates almost perfectly with the decline in NAD+ levels. When researchers eliminated CD38 entirely, NAD+ levels stayed constant regardless of age. The animals aged, but their NAD+ did not fall. That finding tells you something important: the production machinery is largely intact. The problem is consumption.

A 2020 paper in Nature Metabolism took this further by establishing the causal chain more precisely. Senescent cells secrete inflammatory cytokines that cause macrophages to upregulate CD38 expression by up to 600 fold. That is not a modest effect. That is a near complete reorientation of how your immune cells handle NAD+ in the presence of tissue damage.

Now layer in the second drain. Damaged mitochondria trigger their own repair response through enzymes called PARPs, which stands for poly ADP-ribose polymerases, and these are enzymes that detect DNA strand breaks and coordinate repair by consuming NAD+ as their energy source. When mitochondria are functioning poorly, the damage signals are constant, the PARPs stay active, and NAD+ gets pulled into repair mode continuously. So you have CD38 burning through your NAD+ on the immune side, and PARPs burning through it on the repair side, and both problems trace back to accumulated cellular and mitochondrial damage rather than any failure of production.

This is where the supplement framing breaks down. If you take NMN or NR, you are adding substrate to a system with an open drain. There is also evidence from gut microbiome research suggesting that a significant portion of oral NMN gets converted to niacin by gut bacteria before it is even absorbed, meaning what you are actually getting may be functionally similar to taking plain niacin, which costs a fraction of the price. A 2023 paper in FEBS Letters confirmed that ablating the gut microbiome with antibiotics meaningfully increased direct NMN uptake, which implies that intact gut bacteria are intercepting and converting most of it. A review of 25 human studies on nicotinamide riboside published in Science Advances in 2023 concluded there is an unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects. The supplement industry has moved faster than the evidence.

So what actually addresses the drain rather than just adding more to the bucket.

Exercise consistently and specifically. A 2023 systematic review with meta-analysis published in Frontiers in Public Health found that exercise training increases expression of NAMPT by over 127%, with a large effect size of Cohen's d of 0.81. NAMPT is the rate-limiting enzyme in NAD+ recycling, meaning it is the bottleneck that determines how efficiently your body recaptures and reuses NAD+ rather than losing it. Exercise does not just burn calories, it upregulates the machinery that keeps NAD+ circulating.

Address the mitochondrial damage that keeps PARPs active. This is where a peptide called SS-31 becomes relevant. SS-31 targets the inner mitochondrial membrane specifically, where it reduces oxidative damage and helps restore normal mitochondrial function. A 2020 paper in Aging Cell found that neither SS-31 nor NMN alone significantly increased resting NAD levels in aged mouse hearts, but the combination did, producing results that best recapitulated the young state. That finding suggests that fixing the underlying mitochondrial damage changes how the system responds to precursor support.

Address the senescent cells that are driving the CD38 upregulation in the first place. A peptide called FOXO4-DRI works by disrupting the mechanism senescent cells use to evade programmed cell death, which allows the body to clear them through a process called apoptosis. Clearing senescent cells removes the inflammatory signal that tells macrophages to upregulate CD38, which addresses the primary NAD+ drain at its source rather than downstream.

Once those two drains are reduced, if you want additional precursor support, plain niacin accomplishes the same conversion that expensive NMN and NR supplements do after gut processing, at a fraction of the cost.

The deeper point is this. Your body is not broken in the way the supplement industry needs it to be broken in order to sell you the solution. Production is mostly intact. What has changed is the demand side, driven by damage accumulation that your biology was not designed to manage at scale over a 70 or 80 year lifespan. Pouring more precursor into that system without addressing the damage is treating a symptom of aging with a product sized to match your wallet, not the actual problem.

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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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