Few supplements have drawn as much longevity-community attention as nicotinamide riboside (NR), a form of vitamin B3 that the body can convert into NAD+. A 2018 randomized, double-blind, placebo-controlled crossover trial in Nature Communications remains one of the most cited human studies of the compound. It asked a narrow, practical question: if healthy middle-aged and older adults take NR every day for six weeks, is it safe, and does it raise NAD+?
The answer to both was yes. The trial also left some tantalizing, unproven hints about blood pressure and arterial stiffness.
Why NAD+ Matters, and Why It Drops With Age
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme found in every cell. It is central to energy metabolism, and it is also a required co-substrate for enzymes involved in DNA repair, stress responses and cellular signaling, including the sirtuin family. Sirtuins have been linked in preclinical research to some of the benefits of calorie restriction on healthspan.
In animal studies and some human tissue data, NAD+ availability appears to fall with age. Proposed contributors include increased consumption by NAD-degrading enzymes, such as CD38 and PARPs, and changes in how efficiently cells recycle and make NAD+. The precise human picture is still being worked out, and the extent of the decline varies by tissue. Still, the logic that motivated this trial is straightforward: if NAD+ bioavailability is limiting in older tissues, giving the body more precursor might help. NR is one such precursor.
The Dose and Trial Design
The study, led by researchers at the University of Colorado Boulder and collaborators, used a 2 × 6-week crossover design (NCT02921659). Each participant took both NR and placebo, in randomized order, so each served as their own control. That design is well suited to small physiology studies because it reduces person-to-person variability.
- Population: healthy, lean middle-aged and older adults (recruited ages 55–79; average BMI around 24)
- Intervention: nicotinamide riboside 500 mg twice daily, 1,000 mg/day in total
- Comparator: matched placebo
- Duration: six weeks per period
- Blinding: double-blind
The 1,000 mg/day split dose is notably higher than the amounts used in many early human pharmacokinetic studies, which is part of why this trial is often cited as a reference point for chronic dosing.
The Headline Result: About 60% Higher NAD+
The main finding was that NR supplementation was well tolerated and effectively stimulated NAD+ metabolism. NAD+ in peripheral blood mononuclear cells (PBMCs), the immune cells isolated from a blood draw, was elevated by roughly 60% compared with placebo.
Two points deserve emphasis:
- PBMCs are a proxy. They are accessible, but they are not muscle, heart, brain or liver. A rise in blood-cell NAD+ shows the precursor is absorbed and used. It does not prove that NAD+ rose in other tissues, or that any such rise would be functionally meaningful.
- The result is biochemical. An increase in an NAD+ metabolite is evidence of target engagement. It is not evidence of clinical benefit.
On safety, the researchers reported that chronic supplementation at this dose was well tolerated in this group, which was the trial's central practical contribution.
The Blood Pressure and Arterial Stiffness Signal
Beyond NAD+ metabolism, the investigators looked at physiological function. This is where the paper's cardiovascular-aging motivation shows. Large-artery stiffening and rising systolic blood pressure are hallmarks of vascular aging and major risk factors for cardiovascular disease.
The authors reported initial signals worth following up, including trends toward lower blood pressure and lower carotid-femoral pulse wave velocity (PWV), a standard measure of aortic stiffness. They framed these carefully. The trial was not designed or powered to prove a vascular benefit, and the authors explicitly said future clinical trials should further assess NR for reducing blood pressure and arterial stiffness in this population.
That distinction matters. A trend in a small secondary analysis is a reason to design a better trial, not a reason to claim a treatment effect.
Practical Takeaways
- Biochemically, it works as intended. At 1,000 mg/day, NR raised PBMC NAD+ by about 60% over placebo in healthy older adults.
- Short-term tolerability looked good. Six weeks of 500 mg twice daily was well tolerated in this healthy group.
- Don't generalize the dose. The findings apply to the studied product, dose and population. They do not establish what's best for anyone with a medical condition, who is on medication, or who is pregnant. Talk to a clinician before supplementing.
- Treat vascular effects as a hypothesis. The BP and PWV findings are suggestions for follow-up.
- Check product quality. Supplement purity and dosing vary, and trial material is not necessarily what's on a store shelf. Also check the paper's funding and conflict disclosures when weighing industry-linked supplement research.
Limitations
This was a relatively small, physiology-focused trial. Its primary readouts were metabolic and tolerability measures, not hard clinical endpoints such as heart attacks, strokes, disability or mortality. Participants were healthy and lean, so results may not carry over to people with obesity, diabetes, hypertension, kidney disease or other conditions. Six weeks also says nothing about multi-year safety or durability of effect.
It is also worth being clear about what this study does not show: it does not show that raising NAD+ slows aging, extends lifespan or prevents disease. NR is not an anti-aging cure, and this paper doesn't claim it is.
Bottom Line
The 2018 Nature Communications trial is a solid early step: a clean, randomized, placebo-controlled demonstration that 1,000 mg/day of NR raises NAD+ in blood cells of healthy older adults and appears safe over six weeks. Whether that translates into better blood pressure, more flexible arteries or any lasting health benefit is the question for larger, longer trials in the populations most likely to benefit.
