Everything you need to know about Nicotinamide Adenine Dinucleotide (NAD+) and NAD+ precursors, Nicotinamide Riboside and Nicotinamide Mononucleotide (NR, NMN)
- ryansboltonmd
- Mar 19
- 4 min read
Updated: Mar 25
While research is still ongoing, dozens of companies have been selling NR and NMN supplements for almost a decade and countless IV clinics have provided NAD+ drips to celebrities like the Kardashians and Haley Bieber for hundreds of dollars an infusion.
With all this hype, it's worth asking, is NAD+ actually worth the price? What have human studies suggested? Do any studies suggest that supplemented animals live longer? If a patient should take it, how much should they be taking and how often? How can they know if it's working? What biomarkers can be tracked? Are there any risks?
Research has found that NAD+ levels decline with aging, which is believed to contribute to age-related decline in cellular function across basically all tissues and organs throughout the body.
NAD+ is a crucial coenzyme found in all living cells, and it plays a vital role in numerous cellular processes.
Some of the major functions include:
Energy Production:
NAD+ is essential for cellular respiration, the process by which cells convert nutrients into ATP
It acts as an electron carrier in the electron transport chain within mitochondria, facilitating ATP production.
DNA Repair:
NAD+ is a substrate for enzymes like PARPs (poly ADP-ribose polymerases), which are involved in DNA repair
Gene Expression:
NAD+ is involved in regulating gene expression through its interaction with sirtuins, a family of proteins involved with aging and metabolism
Cell Signaling:
NAD+ is involved in various cell signaling pathways, influencing processes like calcium signaling and immune responses.
Mitochondrial Function:
NAD+ is critical for optimal mitochondrial function, including maintaining mitochondrial health and biogenesis (the creation of new mitochondria).
Because NAD+ levels decline with age, up to 50% in some tissues, and NAD+ is a critical molecule in cellular metabolism, molecules that increase NAD+ levels have emerged as a potential therapeutic strategy for increasing lifespan/healthspan.
Both oral NAD+ precursors, Nicotinamide Riboside and Nicotinamide Mononucleotide (NR, NMN) are shown in studies to boost blood levels and cellular levels of NAD+ effectively. It's unclear how well NAD+ infusions boost intracellular levels. Oral bioavailability could vary based on a patients gastrointestinal health, etc. but the overall consensus seems to be that there is not a significant advantage to IV administration of NAD+.
There are several non-human animal studies that suggest possible beneficial neurological, cardiovascular and anti-inflammatory effects.
There is conflicting data in animal studies on whether increasing NAD+ increases lifespan. Many studies, including the Interventions Testing Program studies on NR, have found no significant increase in lifespan.
One study has suggested that long term NMN supplementation (13 months of supplementation, lifespan ~ 24 months) resulted in a longer median lifespan (~8.5%) in female mice.
Another shorter term (6 week) study on NR supplementation started late in life may also extend mean mouse lifespan by around 5%.
There are a few human studies but the clinical endpoints they use (telomere elongation, changes in DNA methylation in tissue samples) are controversial biomarkers for aging.
Here's a breakdown of a few of these human studies from a meta-analysis on NAD+.
Study Sample Intervention Endpoint
Eight healthy men 45–60 years old | Oral NMN (300 mg/day) after 30 min of breakfast for 90 days | Elongating telomere length in peripheral blood mononuclear cells (PBMC) |
Humans 10 twin pairs | Escalating dose of NR supplementation (250 to 1000 mg/day) for 5 months | DNA methylation and modulation epigenetic control of gene expression in muscle and adipose tissue. |
These human studies could be extrapolated to suggest a dose and frequency for patients.
Telomere length and epigenetic changes could be tracked as biomarkers if a patient wanted, but they have not been validated a causal biomarkers of aging. There is also commercially available testing to track NAD+ blood levels for around $200 a test to see if a patient's NAD+ levels are increasing.
It's unclear from current research what blood level of NAD+ a patient should aim for.
In one study from China, whole blood NAD+ levels (for 1,500 healthy patients with mean age of 43) were 34.5 ± 5.4 μmol/L for men and 31.3 ± 5.2 μmol/L for women. https://pubmed.ncbi.nlm.nih.gov/35388296/
There also seems to be a more consistent decline in blood levels of NAD+ with aging for men compared to women in this and other studies.
One study showed age‐related NAD+ decline is more severe for males with the average NAD+ level from blood fingerstick decreasing from 44.2 ± 18.9 μM in males 20 to 50 to 25.9 ± 9.8 μM in males 50 to 80.
Another interesting thing this study noted was a number of outlier patients with very high blood levels of NAD+ that may suggest metabolic and genetic variants. This study also examined both 500 mg and 1000 mg per day of oral NMN supplementation effects on blood NAD+ levels. The 1000 mg group had large variations in the response to NMN suggesting additional phenotypic variation for pathways around NAD+. Research on NAD+ genotypes and phenotypes is ongoing, and may further stratify individuals who may benefit from NAD+ increases.
There is a theoretical risk of fueling a malignant tumor by increasing NAD+ levels, however there isn't clear data that this happens from any of the human studies so far. Most reported adverse effects have been small - headaches, gastrointestinal distress, sleep disturbance, liver enzyme elevation.
Key take-aways:
NAD+ boosting supplements are likely safe (unless a patient has cancer - although mice studies have not found increased tumor burden), but the benefits of increasing NAD+ levels in humans are uncertain.
Most human studies have been done on oral NR and NMN supplements, which have been shown to increase NAD+ levels. It is unclear that there is any clinical benefit to doing expensive NAD+ IV drips, which may be even less effective at restoring intracellular levels.
Changes in DNA methylation could suggest there is an anti-aging effect, however we don't know enough about the causal significance of these epigenetic changes to assert this.
Overall, there are no published human studies so far, that strongly support its use as a general longevity supplement.
When tested in the Interventions Testing Program, NAD+ failed to extend lifespan in mice. A few other mice studies have shown modest life extension. Animal studies, mostly in mice models of neurological and cardiovascular disease suggest possible benefits from NAD+ supplementation that could provide a basis for investigation in humans.
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