NAD+ precursors: blood levels rise, outcomes have not followed

NAD+ is a molecule mitochondria use in the core reactions that produce ATP, and its levels in several tissues decline with age in animal studies. That single fact supports a large market: intravenous NAD+ infusions at clinics, and oral precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), sold as supplements. The human trial record is now large enough to summarize.

What the trials did and found

Nicotinamide riboside. In the first placebo-controlled human trial, published in 2018, 30 healthy adults aged 55 to 79 were randomized to NR 500 mg twice a day or placebo in a six-week crossover design, and 24 completed it [1]. NR raised blood NAD+ by about 60 percent and was well tolerated. In an exploratory analysis, systolic blood pressure and arterial stiffness were lower on NR in the 13 participants who started with elevated blood pressure or stage 1 hypertension. The authors described the study as a pilot and said a larger trial was needed before any claim about blood pressure could be made [1]. A second six-week crossover trial, published in 2020, gave NR 1000 mg a day to 13 adults with overweight or obesity and measured insulin sensitivity by clamp, muscle mitochondrial function from biopsies, liver and muscle fat, cardiac function, and ambulatory blood pressure. Muscle acetylcarnitine rose, and nothing else changed: no improvement in insulin sensitivity, mitochondrial function, blood pressure, or inflammation markers [2].

NMN. In a 10-week randomized trial published in 2021, 25 postmenopausal women with prediabetes and overweight or obesity took NMN 250 mg a day (n = 13) or placebo (n = 12). Insulin-stimulated glucose disposal in muscle, measured by clamp, improved with NMN, along with muscle insulin signaling markers. Blood glucose, blood pressure, lipids, liver insulin sensitivity, liver fat, and inflammation markers did not change [3]. It remains one of the few positive functional findings in the precursor literature, in a small and specific population, and one of the authors is an inventor on a patent application related to NMN.

Newer trials and pooled analyses. Trials since 2022 have added functional endpoints and have mostly come back null. A 24-week placebo-controlled trial in 14 men aged 65 and older with diabetes and reduced grip strength or walking speed found no improvement in either measure with NMN 250 mg a day [4]. A 12-week industry-funded trial in healthy older men reported nominal gains in gait speed and left-hand grip strength that the authors said needed validation in larger studies [5]. A 2025 meta-analysis of randomized trials of NMN or NR in adults with a mean age of 60 or older found no effect on muscle mass, handgrip strength, gait speed, or chair-stand time, with one exception: a longer six-minute walk distance with NR in people with peripheral artery disease [6]. A 2024 meta-analysis of eight NMN trials (342 adults, 14 days to 12 weeks) found no benefit on fasting glucose, insulin, HbA1c, insulin resistance, or lipids [7].

Lifespan data. In mice, the National Institute on Aging's Interventions Testing Program, which runs lifespan studies in genetically heterogeneous mice, found no lifespan extension from NR in either sex [8]. No human trial of any precursor has reported lifespan, healthspan, dementia, or cardiovascular events as an endpoint.

The measurement gap

Two structural problems run through this literature. First, there is no validated clinical test of tissue NAD+ status. Blood levels respond to supplementation, but blood is not the tissue of interest, and no trial has shown that a blood level predicts a clinical outcome. A 2026 study of seven cohorts (303 participants) that used a pre-validated mass spectrometry assay found that whole-blood NAD+ did not vary with age or with exercise and diet interventions, and that measured levels were highly sensitive to how samples were stored and handled; the authors attributed much of the earlier conflicting literature to those handling artifacts [9]. The National Institute on Aging has an open funding call for standardized methods to measure NAD+ in clinical trials, which is a plain statement that none exists yet.

Second, infused NAD+ does not reach cells as NAD+. Cell-surface enzymes (CD38, CD157, CD73, NPP1) break extracellular NAD+ down into nicotinamide, NMN, and NR, and it is those breakdown products that cells take up and use to rebuild NAD+ inside [10]. Cell culture work with isotope-labeled compounds showed that NMN itself is converted to NR outside the cell before uptake [11]. The infusion therefore delivers the same building blocks the oral precursors do, at infusion prices.

Interpretation

Precursors reliably move a blood number. Across trials, they have not reliably moved strength, walking speed, aerobic capacity, insulin sensitivity in general populations, or any hard endpoint, and the one positive insulin finding sits in a single 25-person trial in one defined group. A real biochemical effect without demonstrated clinical benefit is the profile of an unproven product, and when time and money are limited, interventions with outcome data come first.

Sources

1. Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 2018. https://doi.org/10.1038/s41467-018-03421-7
2. Remie CME, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. American Journal of Clinical Nutrition, 2020;112(2):413-426. https://doi.org/10.1093/ajcn/nqaa072
3. Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 2021;372:1224-1229. https://doi.org/10.1126/science.abe9985
4. Akasaka H, et al. Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance. Geriatrics & Gerontology International, 2023;23(1):38-43. https://pubmed.ncbi.nlm.nih.gov/36443648/
5. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging, 2022. https://doi.org/10.1038/s41514-022-00084-z
6. Prokopidis K, et al. The effect of nicotinamide mononucleotide and riboside on skeletal muscle mass and function: a systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, 2025;16(3):e13799. https://doi.org/10.1002/jcsm.13799
7. Chen F, et al. Effects of nicotinamide mononucleotide on glucose and lipid metabolism in adults: a systematic review and meta-analysis of randomised controlled trials. Current Diabetes Reports, 2024. https://doi.org/10.1007/s11892-024-01557-z
8. Harrison DE, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell, 2021;20(5):e13328. https://doi.org/10.1111/acel.13328
9. Trętowicz et al. Human whole-blood NAD+ levels do not vary with age or lifestyle interventions. Nature Metabolism, 2026. https://doi.org/10.1038/s42255-026-01537-5
10. Enzymology of extracellular NAD metabolism. Cellular and Molecular Life Sciences, 2021. https://doi.org/10.1007/s00018-020-03742-1
11. Ratajczak J, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature Communications, 2016;7:13103. https://doi.org/10.1038/ncomms13103