NAD+ Injections, Aging Mitochondria, and What the Research Shows

Our clinic takes its name from the mitochondrion, so it's no surprise that patients ask me about NAD+ almost every week, often after a friend paid for an infusion at a wellness lounge and came home feeling ten years younger. The biology is sound and the mouse experiments are striking, yet the human evidence, especially for NAD+ given by needle, is far thinner than the people selling it admit.

What NAD+ does

NAD+, short for nicotinamide adenine dinucleotide, is the coenzyme that carries electrons stripped from your food into the mitochondrial machinery that makes ATP, your cells' fuel. It hands those electrons to the electron transport chain, where coenzyme Q10, the subject of our post on statins and mitochondria, carries them onward. A second group of enzymes consumes NAD+ outright, among them the sirtuins, which regulate metabolism and gene expression, and the PARPs, or poly-ADP-ribose polymerases, which repair damaged DNA [1]. This means a cell short on NAD+ loses capacity to make energy and capacity to repair itself at the same time. Your body builds NAD+ from vitamin B3 and from the amino acid tryptophan, then recycles it through a salvage pathway whose rate-limiting enzyme is called NAMPT.

NAD+ falls with age in people, not only in mice

Massudi and colleagues, in a 2012 study in PLoS One, measured NAD+ in pelvic skin samples from 49 people, newborns through age 77, and found that NAD+ fell with age in both men and women while DNA damage climbed [2]. In 2015, Zhu and colleagues used high-field magnetic resonance spectroscopy to measure NAD inside the brains of healthy volunteers, which I find more persuasive than skin, and they reported age-dependent declines in NAD+, in total NAD, and in the balance between NAD+ and NADH, the form that carries the electrons [3]. Both studies are cross-sectional, comparing younger people with older ones instead of following anyone over time, so neither can tell us whether the decline drives aging or accompanies it.

Why it falls

The leading explanation is that aging tissue destroys NAD+ faster, not that it makes less. Camacho-Pereira and colleagues, in a 2016 mouse study in Cell Metabolism, demonstrated that the expression and activity of CD38, an enzyme that breaks down NAD+, rise with age, and that CD38 is required for both the age-related NAD decline and the mitochondrial dysfunction that comes with it [4]. A 2020 paper in Nature Metabolism connected CD38 to inflammation, showing that pro-inflammatory macrophages, a type of immune cell, accumulate in visceral fat and liver during aging, carry high levels of CD38, and lower the NAD in the tissue around them [5]. I find that second result more useful clinically, because you can change visceral fat and chronic inflammation, and both travel with the insulin resistance I described in our post on mitochondrial dysfunction and type 2 diabetes.

What restoring NAD+ does in mice

Gomes and colleagues, in a 2013 paper in Cell, showed that as NAD+ declines in the nucleus of aging mouse cells, the nucleus and the mitochondria stop coordinating, and the mitochondria lose components of oxidative phosphorylation, the process that makes ATP. Raising NAD+ in old mice restored their mitochondrial function to that of a young mouse [6]. I think that result, more than any other, launched the NAD+ industry, though I've watched enough promising rodent findings fail in human trials to hold it loosely.

Oral precursors raise NAD+, with mixed clinical results

Most human research uses oral precursors, smaller molecules the body converts into NAD+, chiefly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), and they reliably raise NAD+ in blood. In a randomized, placebo-controlled crossover trial with two six-week periods, Martens and colleagues found that NR was well tolerated and stimulated NAD+ metabolism in healthy middle-aged and older adults, with hints of lower blood pressure and arterial stiffness that the authors said future trials should test [7].

Does a higher blood level change anything you'd feel or measure? Yoshino and colleagues, in a 10-week randomized trial in Science in 2021, gave NMN or placebo to postmenopausal women with prediabetes who were overweight or obese. Muscle insulin sensitivity, measured with the hyperinsulinemic-euglycemic clamp, improved on NMN and didn't change on placebo [8]. Dollerup and colleagues ran a similar experiment with NR, randomizing 40 obese, insulin-resistant men to 2,000 mg a day or placebo for 12 weeks, and found no improvement in insulin sensitivity, glucose metabolism, or body composition [9]. A 2026 systematic review of 33 human intervention studies found the same split, with oral NR and NMN consistently raising NAD-related metabolites while their effects on functional, metabolic, and vascular outcomes were heterogeneous and often null [10].

Injected NAD+ has almost no trial evidence

The product on our formulary is NAD+ itself, compounded for injection at 200 mg per mL, and I can't point you to a randomized trial showing that injected or infused NAD+ improves any clinical outcome. The same 2026 systematic review found no eligible outcomes trial of intravenous or intramuscular NAD+ for anti-aging or wellness [10]. Compounded NAD+ isn't FDA-approved, and no FDA-approved NAD+ product exists.

The closest thing we have is a pharmacokinetic pilot, in which Grant and colleagues infused NAD+ intravenously at 3 micromoles per minute for six hours and tracked it in blood and urine. Plasma NAD+ and its metabolites didn't rise for the first two hours, which the authors interpreted as rapid and complete removal from the plasma, and the metabolites that appeared later were consistent with enzymes cleaving the NAD+ apart [11]. Nikiforov and colleagues, working with cultured human cells in 2011, found that only nicotinamide, nicotinic acid, and their nucleosides such as NR readily entered cells, while NAD and NMN had to be degraded outside the cell into those smaller precursors first [12]. If the same holds in a living person, my read is that injected NAD+ works, to whatever extent it works, by delivering precursors.

The fairest argument for the needle comes from mice, in which intravenous NR and NMN reached multiple tissues intact while the same molecules given by mouth were converted to nicotinamide in the liver [1]. No one has tested whether that difference matters in humans, or compared injected NAD+ against an oral precursor on any outcome.

Side effects, and who should skip it

The main safety signal is how unpleasant a fast infusion feels. In a 2026 retrospective review written by employees of a commercial wellness chain, clients who received 500 mg of intravenous NAD+ on four consecutive days reported moderate to severe gastrointestinal symptoms, a faster heart rate, and chest pressure during the infusions. The symptoms resolved when the infusion ended, but they lengthened the NAD+ infusions to an average of 97 minutes, against 37 minutes for NR [13]. I know of no published tolerability data for subcutaneous or intramuscular NAD+. I'd steer away anyone who's pregnant, breastfeeding, or under treatment for cancer, since no study has established safety in those groups. If you compete in a drug-tested sport, clear any injection or infusion with your anti-doping authority first.

What to do

The habits that support your own NAD+ cost little and carry better evidence than the injection.

• Do both aerobic and resistance exercise. de Guia and colleagues found that NAMPT in skeletal muscle declined with age across 57 people, and that 12 weeks of aerobic training raised it by 12 percent in young adults and 28 percent in older adults, while resistance training raised it by 25 and 30 percent [14].
• Eat niacin-rich animal foods. Liver, beef, poultry, and fish supply vitamin B3 along with tryptophan, and I've made the broader case for liver in our post on organ meats.
• Avoid chronic alcohol excess. Your liver spends NAD+ at both steps of breaking down ethanol, so heavy drinking drains the pool you're trying to fill.
• Protect your sleep and keep a regular schedule, for the reasons I gave in our post on sleep, ATP, and the mitochondria.
• Lose visceral fat and lower chronic inflammation, since inflamed tissue carries more of the CD38 that destroys NAD+ [5].

If you still want to try NAD+ once those basics are in place, we'll treat it as an experiment. Decide in advance what you expect to feel or measure, give it a defined trial, and stop paying for it if nothing changes.

Ask a provider about NAD+

References

1. Liu L, Su X, Quinn WJ 3rd, et al. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab. 2018. PMID: 29685734
2. Massudi H, Grant R, Braidy N, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012. PMID: 22848760
3. Zhu XH, Lu M, Lee BY, et al. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015. PMID: 25730862
4. Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016. PMID: 27304511
5. Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat Metab. 2020. PMID: 33199924
6. Gomes AP, Price NL, Ling AJ, et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013. PMID: 24360282
7. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018. PMID: 29599478
8. Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021. PMID: 33888596
9. Dollerup OL, Christensen B, Svart M, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018. PMID: 29992272
10. Gallagher C, Emmanuel OO. NAD+ supplementation for anti-aging and wellness: A PRISMA-guided systematic review of preclinical and clinical evidence. Ageing Res Rev. 2026. PMID: 41655607
11. Grant R, Berg J, Mestayer R, et al. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. Front Aging Neurosci. 2019. PMID: 31572171
12. Nikiforov A, Dölle C, Niere M, et al. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J Biol Chem. 2011. PMID: 21504897
13. Reyna K, Heinzen G, Patel N, et al. Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. Front Aging. 2026. PMID: 41704678
14. de Guia RM, Agerholm M, Nielsen TS, et al. Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep. 2019. PMID: 31207144