NR Supplement and NMN Effectiveness: Do These Compounds Work for Human Longevity

Could a simple pill be the solution to our aging problems? Is an NR supplement the breakthrough in anti-aging we've been searching for?

With the rise of Nicotinamide Adenine Dinucleotide (NAD+) boosters, the interest in supplements like Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) has skyrocketed. [1]

Questions like "Does NMN work?" and comparisons of "NMN vs NR" dominate the conversation about these longevity supplements—while promising in preclinical studies, the real test for NMN and NR supplements lies in human research. Clinical trials establish whether these supplements are effective anti-aging solutions or if concerns like whether NMN is a scam hold merit.

With multiple clinical studies already published or underway, let’s dive into the current research in humans.

Critical findings on NAD+, aging, and NMN/NR supplements

• Declining NAD+ levels are a hallmark of aging.
• Two NAD+ precursors —NR and NMN— have been more extensively studied than others.
• NMN + NR supplementation extends life in organisms like yeast, worms, and mice and improves metabolic function in animals.
• Human studies show NR supplements are safe for short-term use, effectively boosting NAD+ levels.
• NR may improve blood pressure, reduce aortic stiffness, benefit skeletal muscle, and offer anti-inflammatory effects.
• NR hasn't been effective in improving glucose or insulin sensitivity.
• Elysium's combination of NR + pterostilbene could be a helpful measure in ALS treatment.
• The first human study on NMN published recently indicates tolerability of doses up to 500mg.
• Further research is needed to fully understand the effects of elevated NAD+ levels via supplementation in humans.

» Uncover the science behind anti-aging supplements, vitamins, and pills

Tackling aging with NMN and NR supplements: Boosting low NAD+ levels

To fully understand the science, we must start with the star of the show, NAD+. NAD+ is a molecule that acts as a coenzyme in many critical processes in our body, including:

• Cellular energy production
• DNA repair
• Sirtuin activity (enzymes involved in aging)

Without NAD+ acting as a coenzyme, these processes simply can't occur, and life wouldn't exist. Interestingly, mounting evidence suggests that NAD+ levels decline with age—a change scientists now consider a hallmark of aging. Lower NAD+ levels are also responsible for many age-related conditions like cardiovascular disease, neurodegenerative diseases, and cancer. [2]

Can we boost NAD+ levels by taking NAD+ supplements?

Not quite. NAD+ in supplemental form has very poor bioavailability, meaning it doesn't have much effect when introduced to the body. However, NAD+ has several molecules that transform into NAD+ through enzymatic reactions.

Scientists have studied two such intermediates more extensively than others:

• Nicotinamide riboside (NR)
• Nicotinamide mononucleotide (NMN)

Several studies indicate that supplementing with these precursors can increase NAD+ levels and prolong the lifespan of yeast, worms, and mice. [3-5] Furthermore, other animal studies show that boosting NAD+ can also improve muscle generation, cardiovascular function, and glucose metabolism. [5-7]



Figure 1. Proposed uptakes of NR and NMN Reprinted from "NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR,” Yoshino, Jen, et al. 2018, Cell metabolism vol. 27,3. Copyright 2017 by Elsevier Inc.

So far, in human studies, research is much farther along for NR supplementation compared to NMN. One reason could be how the body converts these intermediates to NAD+ (see Figure 1).

Research suggests that cells can uptake NR directly from the blood, where it is then converted to NMN and then NAD+. However, there are two proposed mechanisms for the uptake of NMN in living organisms: [2]

1. NMN must first convert to NR to enter cells, then change back to NMN and subsequently into NAD+. [3]
2. NMN may enter cells directly through an unknown transporter. [2]

More research is needed to fully understand these mechanisms, especially in humans. 

NR: Results from human studies

2016: Let the clinical trials begin

Clinical research examining the bioavailability of NR in supplemental form began in 2016. ChromaDex, a company that produces the NR supplement NIAGEN®, sponsored the first published study conducted in humans.

In this small crossover study, twelve healthy individuals were given three doses of NR. Each subject completed each dose (100mg, 300mg, and 1,000mg) with a 7-day washout period between each one.

2017: Consistent results continue

More than a year later, two additional studies on humans were published:

1. In November 2017, a self-funded study by supplement company Elysium Health, Inc. examining the safety and sustainability of Basis, its own supplement. Basis is a combination of NR and pterostilbene (PT), a polyphenol found in blueberries linked to anti-aging.

The randomized, double-blind trial included 120 healthy subjects between 60-80 years old. They were assigned to one of three groups in which each completed eight weeks of daily supplementation:

• A placebo group
• A dose of 250 mg NR + 50 mg PT
• A dose of 500 mg NR + 100mg PT



Figure 2. Change from baseline NAD+ concentration across different study groups.

Reprinted from "Repeat dose NRPT increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study," by Dellinger, R.W. et al. 2017, npj Aging Mech Dis3, 17. Copyright 2017 by Springer Nature.

2. In December 2017, a much smaller study showed similar results. Eight subjects took increasing doses of NR for eight days. Doses started at 250mg of NR on days one and two, then doubled every two days, ending with 2,000mg on days seven and eight.

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2018: Disappointing results on metabolic function

In March 2018, a randomized crossover trial examined the tolerability of NR supplementation in healthy adults and multiple secondary outcomes. ChromaDex also partially funded the study and provided the study pills.

The study included 24 lean and healthy men and women between the ages of 55 and 79. Half of them were placed in Group A, where they received a placebo for six weeks before crossing over to receive 1,000mg of NR capsules for the remaining six weeks.

Subjects in Group B received the NR supplementation first, followed by the placebo. NR supplementation raised levels of NAD+ by ~60% compared to the placebo. Furthermore, people with lower blood cellular levels experienced a more significant increase in NAD+ levels.

Other secondary outcomes didn't improve, including:

• Physical activity
• Body fat
• Markers of exercise performance
• Glucose and insulin regulation

In August 2018, a study explored NR’s effect on insulin sensitivity and other metabolic parameters in obese, insulin-resistant men. Forty men aged 40-70 were randomized into two groups. The experimental group received 2,000mg of NR daily for 12 weeks, while the control group received a placebo.

No changes in insulin sensitivity or glucose metabolism occurred. There were also no differences in secondary outcomes observed, including:

• Resting energy expenditure
• Lipid metabolism
• Body composition

2019: Breakthroughs in ALS research and skeletal muscle

Researchers used Elysium Health’s drug EH301 (a clinical name for Basis) to test its efficacy on the progression of ALS. In this randomized control trial, 32 participants with ALS were given 1200mg of EH301 or a placebo for four months and encouraged to follow a Mediterranean-style diet.

The group taking EH301 showed significant improvements in:

• ALS symptoms
• Pulmonary function
• Muscular strength
• Muscle-to-fat weight ratio

The researchers concluded that EH301 significantly slowed the progression of ALS and improved other health outcomes associated with ALS.

Elysium Health, Inc. has announced the initiation of several more clinical trials, including the effects of Basis on:

• Fatty liver
• Muscle metabolism
• Exercise performance
• Preventing Acute Kidney Illness



The conclusion on NR supplement safety and efficacy in humans

Based on this research, we can conclude that NR supplements are generally safe to take and will most likely increase your NAD+ levels, but the effects of increased NAD+ remain unclear.

Furthermore, the study periods were short, so we still don't know the long-term effects of NR supplementation. With that said, many more studies with NR are underway—Chromadex alone claims to have over 100 preclinical trials in the works. For more information on current studies, search “nicotinamide ribose” at clinicaltrials.gov.

NMN supplement research is still in its infancy

NMN has gained a lot of attention lately, especially after the release of David Sinclair’s book Lifespan. Here, the longevity scientist discusses his research examining NMN, particularly in mice. He has been very open about taking NMN but has also made it clear that he has no opinion on whether anyone else should take the supplement.

Similar to NR, the research in animal studies looks promising, but the first study in humans was only published in 2020. Phase I of this study merely assessed the safety of NMN supplementation; therefore, NAD+ levels were not even measured.

Ten healthy Japanese men received a single dose of 100mg, 250mg, and 500mg of NMN on separate occasions. All quantities were tolerated without adverse side effects. The authors concluded that up to 500mg of NMN is safe in healthy men. For phase II, researchers will reportedly examine the efficacy of NMN, as well as appropriate dosage and frequency; however, it remains unclear if this study has started.

» Check out this study on how NMN supplementation improves endurance capacity

The future of anti-aging supplements: promising results and ongoing research

In conclusion, NR and NMN supplements have shown promising results in preclinical studies and early human trials. While more research is needed to fully understand the potential benefits of these supplements, it's clear that NAD+ is a critical molecule for healthy aging.

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References:

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342515/

[2] Yoshino, Jun, et al. “NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR.” Cell metabolism vol. 27,3 (2018): 513-528. doi:10.1016/j.cmet.2017.11.002

[3] https://www.ncbi.nlm.nih.gov/pubmed/17482543

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753670/

[5] https://www.ncbi.nlm.nih.gov/pubmed/27127236

[6] https://www.ncbi.nlm.nih.gov/pubmed/26970090

[7] https://www.ncbi.nlm.nih.gov/pubmed/21982712

[8] https://rally.partners.org/study/mib1b

[9] https://clinicaltrials.gov/ct2/show/NCT03151239