Key Points:
- Most of the upcoming human trials involving NAD+ supplementation revolve around neurodegenerative disorders like Alzheimer’s and Parkinson’s disease.
- There is also a handful of trials testing the effects of boosting NAD+ on obesity and type 2 diabetes.
- Whether healthy and fit individuals will benefit from NAD+ may be answered with a new and upcoming trial.
In today’s media landscape, it can be difficult to trust influencers, even when they are scientists. Within the health and longevity space, many are guilty of overhyping scientific results to make the supplement they are pushing more alluring. These scientific results are often from animal studies, which do not always translate to humans.
Animal studies are designed to inform human studies by, for example, determining which treatments are worth spending the time, money, and effort on testing. More often than not, the results discovered in animals are not replicated in humans. Thus, the most informed consumer will be aware of the latest and ongoing clinical studies concerning a compound of interest.
With that being said, an international team of scientists has gathered the latest and ongoing clinical trials involving NAD+ treatments that target aging and age-related conditions. The following will describe these trials to give an overall sense of whether supplementing with NAD+ may be beneficial to aging individuals.
Neurodegenerative Conditions
Mounting evidence suggests that nervous system degeneration is largely caused by deficits in energy metabolism, which NAD+ enhances. As such, most of the ongoing trials testing the effects of NAD+ precursors on human subjects involve neurodegenerative conditions.
Alzheimer’s Disease (AD)
AD is the most common neurodegenerative disease, yet there is no well-established treatment, leading researchers to look for alternatives to drugs that target amyloid plaques and tau tangles. Considering that higher niacin intake from food is associated with a reduced risk of AD and age-associated cognitive decline, this NAD+ precursor is being tested on AD patients. In addition to assessing safety, the study will determine whether 500 mg of niacin raises NAD+ levels in the cerebrospinal fluid, confirming that it affects the brain.
In another study, researchers will assess whether 1 g of the more popular NAD+ precursor, NR (nicotinamide riboside), can improve cognition in AD patients and subjects with mild cognitive impairment. The researchers will also assess whether NR improves energy metabolism by measuring mitochondrial health and oxidative stress levels. Additionally, in a derivative study, sleep efficiency, gait speed, and circadian rhythms will be assessed in some of the same participants.
Using a sophisticated technique called 31P-MRS, researchers will determine the optimal dose of NR necessary to raise brain NAD+ levels. In this study, AD patients will be given 1 g of NR, followed by 2 g, and then 3 g. Cognitive performance will be measured to determine the optimal dose for combating the cognitive deficits associated with AD. Moreover, a dose-dependent assessment of aging hallmarks, such as autophagy and inflammation, will also be made.
Notably, a previous study showed that combining 1 g of NR with other metabolic activators (2.55 g of N-acetyl-L-cysteine, 3.73 g of L-carnitine tartrate, and 12.35 g of L-serine) improves memory and reverses neurodegeneration in AD patients. However, another previous study showed that 1 g of NR did not alter the cognition of individuals with mild cognitive impairment. This could mean that combining NAD+ supplements with other metabolic activators is necessary to reverse brain aging.
Parkinson’s Disease (PD)
PD is the second most common neurodegenerative disease, affecting a region of the brain that modulates fine motor skills. The clinical severity of PD will be measured in response to 1 g of NR in an ongoing study, and the optimal dose (1, 2, or 3 g) for raising brain NAD+ levels will be tested. This latter study builds on a smaller study that demonstrated NR increases brain NAD+ levels, which was associated with clinical improvements in PD, and the induction of markers associated with mitochondrial health and autophagy. Furthermore, previous studies have shown that the intravenous injections of NAD+ alleviate the symptoms of PD.
Amyotrophic lateral sclerosis (ALS)
ALS, also known as Lou Gehrig’s disease, is characterized by the degeneration of neurons that innervate muscles and control movement. In a study that is now recruiting, researchers will test whether the combination of NR and a polyphenol called pterostilbene can slow the progression of ALS and improve the survival of subjects. The same Norwegian scientists will determine which dose of NR/pterostilbene (1.5 g/ 300 mg or 1 g/ 200 mg) is optimal. The NR/pterostilbene combo has previously been shown to slow disease progression in ALS patients, improving lung function and muscular strength.
Obesity and Diabetes
Chronically consuming excess calories, especially in the form of refined sugars and saturated fats, can alter our physiology in ways that resemble advanced age. One consequence of consuming these types of excess calories is insulin resistance, where our cells stop taking in glucose due to desensitization to insulin. Moreover, both insulin resistance and obesity increase the risk of developing type 2 diabetes.
In obese, insulin-resistant men, 2 g of NR supplementation failed to improve insulin sensitivity or body composition, the insulin-secreting function of the pancreas, or mitochondrial health. In healthy, obese men and women, 1 g of NR also did not improve insulin sensitivity or mitochondrial health. Additionally, NR did not improve liver and muscle fat accumulation, heart function, blood pressure, or inflammation. However, NR was shown to provide minor improvements in body composition and metabolic rate during sleep.
In contrast to NR, the NAD+ precursor NMN (nicotinamide mononucleotide) was shown to improve insulin sensitivity in postmenopausal women. Considering that NMN has been shown to prolong the lifespan of female but not male mice, these studies point to the sex-specific efficacy of NAD+ supplements, especially when it comes to metabolic health and alleviating insulin resistance. A recently completed, but not yet published, study may clear this up, as it will assess the effect of 450 mg of NMN on insulin sensitivity.
In people with prediabetes, a metabolic state between insulin resistance and type 2 diabetes, the safety and tolerability of slow-release niacin will be tested. This particular form of niacin is designed to be delivered to the lower gastrointestinal tract with the intention of targeting gut bacteria, primarily found in the colon. The dose will start at 100 mg and escalate to 200 mg, 500 mg, 1 g, and finally 2 g of niacin. This study may lead to further studies exploring the role of NAD+ and the gut microbiome.
Both diabetes and obesity significantly increase the risk of liver disease. To address this, a study currently recruiting participants is testing the effect of the NAD+ precursor nicotinamide on obese people with type 2 diabetes and liver disease. Another recruiting study sponsored by the Mayo Clinic will test the effect of intravenous niacin on free fatty acid levels in obese and overweight individuals. By doing so, this study will explore whether NAD+ supplementation promotes “fat burning.”
Healthy Individuals and Other Conditions
For healthy individuals looking to enhance their cardiovascular performance or who wish to prevent age-related conditions while still relatively young, an upcoming study will test the effect of 1 g of NMN on aerobic capacity. One concern is that healthy and fit individuals already have sufficient NAD+ levels and that boosting NAD+ will have little to no beneficial effects. This study explores this, helping to determine whether NAD+ supplementation is necessary for healthy individuals.
Ongoing clinical trials will also be testing the effects of NAD+ precursor supplementation on cardiovascular-related conditions like heart failure. One such study will test the effect of 250 mg of NR on heart failure patients. Other conditions that may potentially be treated by NAD+ supplementation in upcoming clinical trials include long COVID, multiple sclerosis, and breast cancer. Most of the clinical trials mentioned will be completed before 2028, except for the breast cancer study, which is expected to be completed in 2035.
Important Considerations
It is important to consider that many clinical trials do not account for the diet and exercise routine of participants. Foods high in NAD+ precursors, such as meat, legumes, and grains, can raise cellular NAD+ levels. Additionally, consuming excess calories can lower NAD+ levels. Moreover, exercise can improve NAD+ homeostasis. Thus, individuals who consume a healthy diet and exercise regularly may not have low NAD+ levels, potentially rendering NAD+ supplements ineffective.
With that said, supplementing with NAD+ precursors may be most beneficial for those who already suffer from age-related metabolic dysfunction, such as neurodegenerative diseases, type 2 diabetes, and obesity. Some estimates suggest that NAD+ supplements should not be taken before the age of 32, but this likely depends on the health status of the individual. Many individuals tend to become more sedentary and consume more calories with age due to various lifestyle factors. However, for those who live an active lifestyle later in life, taking NAD+ supplements may be unnecessary.
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