How To Best Increase NAD+ Levels

Nicotinamide adenine dinucleotide (NAD+) is at the core of a multitude of biological processes critical for human health and longevity. But with age, your NAD+ levels begin to drop, and aberrant NAD+ production is observed in many diseases, particularly those that are age-related like cardiovascular and neurodegenerative diseases (Hong et al., 2020).

So, it’s not surprising that there’s a lot of interest in figuring out how to boost NAD+ levels. There are various ways you can increase NAD+ levels naturally. This includes:

• Calorie restriction
• Regular exercise
• Cutting out sun-tanning
• Drinking less alcohol

But, perhaps the easiest way to see increased NAD+ levels is through consumption of NAD+ precursors. You can do this through some different approaches:

• Vitamin B3 (niacin, nicotinamide, and nicotinamide riboside)
• Foods rich in NAD+ precursors
• NAD+ boosting supplements

In human cells and those of other mammals, NAD+ is synthesized mostly through the precursor nicotinamide mononucleotide (NMN) (Yoshino et al., 2018). This direct NAD+ precursor gets synthesized from other vitamin B3 compounds called nicotinamide riboside (NR) and nicotinamide (NAM). You can get a fix of all three of these compounds — NMN, NR, and NAM — from food.

NMN, for example, is found in various types of natural foods (Mills et al., 2016):

But these amounts of NMN are generally considered to be way below the amounts needed to move the needle on NAD+ levels, which is thought to be in the hundreds of milligrams to grams range. To get NAD+ levels to rebound or reach new heights likely means moving into the realm of NMN supplementation.

Recent preclinical studies — those in animal models and cells cultured in lab dishes — have demonstrated that the administration of NMN could compensate for the deficiency of NAD+. NMN has also shown convincing effective and beneficial results in several animal models of human disease, so researchers have launched several clinical trials on NMN supplementation to investigate its clinical potential in humans.

NMN Supplement Research

In 2016, an international collaborative team between Keio University School of Medicine in Tokyo and Washington University School of Medicine in St Louis started a phase I human clinical study evaluating the safety and accessibility of NMN ( UMIN000021309 ) (Tsubota 2016). The clinical trial also was designed to evaluate the effect of NMN on metabolic-syndrome-related parameters. To learn how NMN behaves in the human body, this trial recruited 10 healthy volunteers, who were evaluated for safety and the time course of blood NMN concentrations (Irie et al., 2020).

A single oral administration of NMN up to 500 mg was found to be safe and effectively consumed in healthy subjects without causing severe adverse effects. They found that five hours after NMN administration, the major final metabolites of NMN were significantly increased by NMN administration in a dose-dependent manner — the higher the dose, the greater the effects. However, in this study, the team failed to detect NMN in samples of plasma — the liquid component of blood without cells.

In 2017, a phase II study ( UMIN000030609 ) assessing the safety of long-term NMN in healthy subjects was also launched in Japan. Additionally, a study ( UMIN000025739 ) opened at Hiroshima University, Institute of Biomedical and Health Sciences in 2017 evaluating the effect of long-term oral NMN administration on various hormones, mitochondria, and enzymes dependent on NAD+ implicated in healthy biological aging called sirtuins in healthy volunteers.

In 2019, a new clinical study ( UMIN000036321 ) was initiated at the University of Tokyo Hospital to evaluate the effect of oral NMN administration on the body composition in elderly persons. Other clinical trials of NMN are ongoing at Washington University to examine the effect of NMN on insulin sensitivity, blood lipids, and body fat as well as several disease markers of metabolic and cardiovascular health ( NCT03151239 ) (Okabe et al., 2019).

NMN as a Nutraceutical

Although these studies have led to the approval of some capsule formulations of NMN being approved that have been put on the market as health supplements, the safety and effect on human health and longevity remain unclear. But it needs to be noted that these clinical trials were not planned to develop pharmaceuticals. Rather, these studies were designed to evaluate NMN as a nutraceutical. That’s because, although NMN can be potentially developed as a pharmaceutical, drug development for disease treatment or prevention takes heaps of time and money because of rigorous regulations and strict clinical trial adherence.

Developing NMN as a nutraceutical may have several advantages, such as saving time and costs, which would accelerate future clinical applications. The clinical studies covered here on NMN aim to set the necessary scientific foundation for the diligent development of NMN as a nutraceutical that promotes healthy aging and longevity.

How Does NMN Compare With Other NAD+ Precursors?

Among various NAD+ precursors, NMN and nicotinamide riboside (NR) seem to increase NAD+ levels more effectively than other precursors, such as nicotinamide (NAM) and niacin, in rodents. It is difficult to compare NMN with NR, both of which are quickly metabolized and converted to other NAD+ intermediates before being taken up by cells in animals and humans. However, NR, instead of NMN, is unstable and quickly converted into NAM in mouse plasma.

NAM, which is a precursor to NMN, is safe for long-term dietary intake at 500 to 1000 mg per day (Hwang and Song, 2020). Although headache, dizziness, and vomiting occurred in healthy humans when NAM at doses up to 6000 mg were ingested on an empty stomach, these adverse effects were minor and resolved upon termination. Adverse effects of NAM reported for humans are limited to several organs, namely the liver, kidney, and pancreas. There is also an increased risk for low platelets — the cells responsible for blood clotting.

High doses of niacin, a common form of vitamin B3, between 2000 and 6000 mg can have several side effects. These include severe skin flushing combined with dizziness, rapid heartbeat, itching, nausea and vomiting, abdominal pain, diarrhea, gout, liver damage, and diabetes (Mayo Clinic 2020). Taking niacin also might worsen allergies, gallbladder disease, and symptoms of certain thyroid disorders. Niacin can interfere with blood glucose control, which would be detrimental for people with diabetes.

The Future of NAD+ Supplement Research

Despite the growing research efforts aimed at making the most of the therapeutic potential of NAD+ precursors to treat metabolic and aging-related diseases, the clinical evidence on its safety and effectiveness is insufficient to support its utility as a pharmaceutical.

We need more research to increase the prospects of developing drugs based on NAD+ precursors, such as NMN. For example, the efficiency and long-term safety of NMN need to be examined in further animal studies and human trials. Getting a better handle on how NMN is processed by humans could help determine the optimal concentration for administration in different bodily regions and facilitate understanding how it exerts its health- and longevity-related effect.

Nevertheless, the clinical application of research on biological aging and age-related diseases is now on the horizon worldwide. The intervention with natural compounds, such as NMN, can be a promising strategy, and enthusiasm continues to blossom in the field of biological aging and longevity.

NMN.com is an online resource covering news related to nicotinamide mononucleotide
(NMN), a precursor to the vital molecule nicotinamide adenine dinucleotide (NAD+).
NAD+ plays essential roles in cellular energy production and functions as a coenzyme for
proteins that promote healthy metabolism and maintain DNA integrity. Cellular NAD+
levels diminish as we age, and studies suggest that NMN supplementation restores
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