Our Apeiron Life Scientific Advisory Board members review each perspective post.
What it is:
Vitamin B3 (Vit. B3) also goes by the scientific name Nicotinamide. NAD, NMN, and NR all contain Vitamin B3 in their molecular structure. This crossover is why you may have heard discussions regarding one or all of these molecules, especially regarding longevity.
NAD = Nicotinamide Adenine Dinucleotide (The bioactive natural form in foods.)
Nicotinamide = Vit. B3
Dinucleotide = Two Sugar molecules + two phosphates
NMN = Nicotinamide Mononucleotide
Nicotinamide = Vit. B3
Nucleotide = Sugar molecule + a phosphate
NR = Nicotinamide riboside
Nicotinamide = Vit. B3
Riboside = Sugar molecule
NAD (B3 + Sugar + Phosphate) assists many processes in the body and is called a coenzyme due to its ability to “help.” The NAD component assists in a wide array of chemical reactions, including:
Energy production (ATP) - leads to muscle contraction, protein communication, and DNA repair. ATP (adenosine triphosphate) is our body's fuel. When broken down, it activates muscle contraction and creates energy. However, it is stored in limited supply and must be continuously synthesized.
Protection such as the activation of the protective enzymes called Sirtuins. NAD is necessary for activating Sirtuin proteins which defend our cells and repair damage.
Researchers are just starting to piece together how it all functions, with a long way to go.
The supplements NMN and NR are precursors to NAD formation. They have recently gained traction due to their potential benefits in longevity, revitalizing cells, relieving metabolic disorders, and increasing overall health.
What has NAD got to do with longevity? NAD levels tend to decline as we age, with difficulty repairing damaged cells. We, therefore, have an accumulation of damaged cells and a lower capacity to restore them.
Why not just supplement Vitamin B3? Supplementing Vitamin B3 (Nicatinomide) lacks the sugar and phosphate that NMN contains, which our cells require to form NAD. It can be toxic to other areas of the body, especially the liver, and it has not shown increased NAD levels. NR lacks the phosphate leading the studies to be less promising so far.
Purported claims:
The researchers at the forefront of the NAD+ precursor experiments include Dr. David Sinclair and Dr. Matt Kaeberlein. They have chosen to focus on separate precursors to NAD. This area of research is new, and therefore, there are many factors to explore with many theories yet scarce human studies to base claims upon.
NMN and Sinclair
Dr. David Sinclair is a prominent advocate for increasing NAD, specifically with NMN supplements. A Professor of Genetics at Harvard Medical School and an expert in the field of longevity. Sinclair explains that over time (aging), our DNA replication systems malfunction leading to altered cell activity. Over time our NAD levels also lower, meaning lower Sirtuin repair activity and therefore deteriorating cellular health (aging). This is why Sirtuin pathways are stated to be longevity genes, as they keep your body ticking along at a youthful level. Sirtuins only like to activate when the body is under adversity (exercise, cold), but if they think times are “good,” such as when surrounded by copious fat cells (obesity), they don’t switch on.
Resveratrol also impacts the Sirtuin gene pathways alongside NAD. Sinclair states that resveratrol is like a car, and NAD is the fuel; you’re not accelerating anywhere without both of them. There are a few other Sirtuin activating compounds, but resveratrol got the most hype due to its existence in red wine. It also exists in whole foods such as cocoa, grapes, and berries, so eating a wide variety of whole foods is essential.
NMN is the precursor to NAD, which Sinclair focuses on in his research. In previous studies, supplementing with NAD did not increase NAD levels; the body is quite clever at regulating its intake. However, supplementing with NMN did show an increase in NAD levels in new, small-scale studies. Sinclair’s unpublished clinical trials show that you may double your NAD levels if you take NMN for two weeks. However, just because NAD increases does not necessarily mean it is effective for longevity.
NR supplementation has been around for longer and is one of the more highly studied molecules, but research shows no increase in NAD levels nor longevity in mice. It is prolific as it is cheaper to produce (without the phosphate NMN carries). It is considered a safe substance, but this doesn’t necessarily mean it is effective.
For NR, a rigorous new 2021 study by the Interventions Testing Program (ITP) did not show a significant increase in the lifespan of mice.
Rapamycin and Kaeberlein
Dr. Matt Kaeberlein is a Professor of Pathology and Genome Sciences at the University of Washington. His research focuses on rapamycin, the immunosuppressant drug currently being tested in dogs.
Kaeberlein previously worked on Resveratrol research but was unable to replicate Sinclair’s findings.
His opinion on the longevity supplements such as NMN, NR, Resveratrol, and others is that they may tweak the Sirtuin network and affect longevity pathways. However, the human clinical data does not show it occurs in an impactful or compelling way.
Resveratrol and NAD precursors have high biochemical activity. So they have an effect on Sirtuins but also on a wide range of other chemical reactions all over the body. You can’t consume these supplements and expect them to spot work on only the longevity reactions.
Rapamycin, on the other hand, he is hopeful will prove effective through the inhibition of mTOR pathways, which may improve cell and organ lifespan.
To learn more check, out Dr. Dev Mishra, Medical Director of Apeiron Life’s blog post on Rapamycin.
What the science says:
The science is limited, but a plethora of new human studies are being conducted for future information.
The claims made by NMN and NR are that they restore NAD levels, leading to enhanced insulin sensitivity, less frailty, better blood flow, better mitochondrial function, active, energetic, and overall healthier (mice).
However, these claims are limited to mice and yeast cells. There is not enough information to claim the effects on humans or the possible long-term consequences.
When viewing smaller studies, NR increased NAD blood levels; however, this does not mean it is necessarily absorbed into cells and is adequate for longevity purposes.
The claim made by Rapamycin is that it inhibits mTOR, which may lead to cell and organ immunity rejuvenation.
Previous Rapamycin research has evidence of extending lifespan in yeast, worms, flies, and mice.
NAD IV drips are offered in the United States alongside disclaimers that they are neither medically advised nor approved by the FDA. They’ve made claims to treat everything from hangovers to addiction, but this is not regulated nor backed by research.
Our take:
Increasing or maintaining NAD levels is important. However, the best way to go about this has not been scientifically proven yet. Lifestyle approaches that may preserve or increase NAD levels include exercise, maintaining muscle mass, healthy eating patterns, and adequate sleep. Also, avoid cell damage or stress through sunburn, smoking, alcohol, or other harmful practices.
Remember, nutrition is individualized, and so are supplementation needs. Sinclair constantly monitors himself to see how his body reacts explicitly to these unregulated supplements. His medical history, microbiome, medications, and lifestyle habits are specific to him. If you wish to follow his protocol, you must recognize that he admits he is experimenting on himself as a subject. Human trials show NMN as safe but not necessarily effective. If you wish to partake in this or any other longevity supplement, be aware of any changes in your body, good or bad.
Sourcing where you get your supplements from is crucial. Please speak to your Client Advocate about our Apeiron Life Supplementation program.
Will this benefit you?
Possibly, there is not enough research on NAD precursor supplementation. We do not know the long-term effects of any of these items. The short-term information does show NMN and NR supplementation to be safe.
The science is limited in NMN, but we know that so far, the research is promising in mice, yeast cells, and in small group, short-term settings. There needs to be more research into the combinations of molecules (such as NMN and Resveratrol) and studies in humans.
Still curious to try it? If you do, here’s what to keep an eye on:
Published research does not yet show that supplementing NMN or NR molecules in humans works as it does in mice. These studies are cutting edge and therefore do not have the luxury of time to back up the proposed information.
Sinclair and other longevity scientists depend on hype, leading to further funding for their work. This means any new information is released immediately, even if the impact is minor or not yet duplicated and therefore unsupported by other experiments. None of them are entirely independent from the benefits of people purchasing their supplements or even requesting more information on their specific research.
Should we be concerned about boosting cancerous cells? There is a difference between causing cancer and increasing cancer cell growth. In one study where the mice were predisposed to pancreatic cancer, there was an increase in the cancerous cells. However, in healthy mice, NAD did not create cancerous cells. So fueling your healthy cells with NAD in this scenario may mean you're also feeding cancerous cells if they exist.
“None of this is ready for prime time. The bottom line is I don’t try any of these things,” stated the director of the National Institue of Aging at NIH, Felipe Sierra.
References and additional reading:
Mahan, L K, and Raymond, J L. Krause's Food & the Nutrition Care Process. Elsevier Inc, 2017. Print.
NMN Studies in Mice
NMN Studies in Humans
NR Studies in Mice
NR Studies in Humans
NR Studies in Yeast Cells
Rapamycin
Berberine
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