Nicotinamide adenine dinucleotide, NAD+, is a coenzyme present in every cell in the body and is central to energy metabolism, serving as an electron carrier in the mitochondrial respiratory chain. Beyond energy production, NAD+ is required by sirtuins, a family of proteins involved in DNA repair, gene expression regulation, and stress responses that are associated with longevity in animal models. It is also consumed by PARP enzymes, which repair DNA strand breaks. NAD+ levels decline by approximately 50 percent between the ages of 20 and 50 in humans, and this decline has been proposed as a significant contributor to the metabolic and functional changes of ageing.
Precursor Supplementation: NMN and NR
Direct NAD+ supplementation is poorly absorbed. The more effective approach is supplementing with NAD+ precursors that are efficiently taken up by cells and converted to NAD+. The two most studied precursors are nicotinamide mononucleotide and nicotinamide riboside. Both have been shown in human clinical trials to raise blood NAD+ levels significantly. A trial by Yoshino et al. at Washington University found that NMN supplementation of 250mg per day for 10 weeks improved muscle insulin sensitivity and raised skeletal muscle NAD+ metabolite levels in overweight postmenopausal women with prediabetes. A separate trial by Trammell et al. demonstrated that NR supplementation dose-dependently raised whole blood NAD+ in healthy adults.
Human Trial Evidence for Functional Outcomes
Beyond raising NAD+ levels, the question is whether this produces meaningful functional outcomes. A 2020 trial by Martens et al. in older adults found that NR supplementation of 1000mg per day for six weeks reduced blood pressure and aortic stiffness compared to placebo. A Japanese trial by Igarashi et al. found that NMN supplementation improved physical performance, specifically walking speed and grip strength, and self-reported fatigue in older men. The field is at an early but accelerating stage: the human trial evidence is promising but not yet definitive for longevity outcomes specifically.
Practical Considerations
The doses used in published trials range from 250mg to 1000mg per day for NMN, and similar doses for NR. Both are generally well-tolerated. NMN is more expensive and has fewer published human trials than NR, though both raise NAD+ effectively. Some longevity clinicians combine either NMN or NR with resveratrol and quercetin, polyphenols that activate sirtuins and are proposed to work synergistically with elevated NAD+. This combination has not been trialled in controlled human studies and represents a reasonable hypothesis rather than established evidence.
- NR or NMN supplementation raises NAD+ levels in humans: this is established in multiple trials
- Functional benefits in human trials include improved insulin sensitivity, reduced arterial stiffness, and improved physical performance in older adults
- Doses of 250 to 500mg per day are within the range studied in published trials
- Exercise independently raises NAD+ through increased NAMPT expression: it is not a substitute for supplementation but they are complementary
- The longevity implications require longer-term human trial data that is not yet available
Sources
- Yoshino, M., et al. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229.
- Martens, C.R., et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286.