Do the NAD Precursors NMN and NR Work?
If all those acronyms are greek to you, get ready for an update on what are among the most promising, off-the-shelf anti-aging supplements.
Let's start with what is NAD (Nicotinamide Adenine Dinucleotide), often referred to as "NAD+" to denote the oxidized form of NAD. [1]
NAD+ is a coenzyme that living things -- like us -- cannot survive without. It's critical for everything from energy and metabolism to sleep. Unfortunately, levels of NAD+ naturally decline as we get older. In experiments with old mice, when their NAD+ is boosted, they grow denser fur, run longer and faster, and develop various biomarkers associated with youthfulness, such as restored muscle function, enhanced regeneration of the brain and protection against the metabolic effects of high-fat diets. [2]
Given that NAD+ is so important for robust life and that it declines as we age, the natural question is:
"What can we do to increase NAD+ as we get older?"
This is where those two other acronyms come into play, as they represent two molecules that act as NAD+ precursors; meaning, that NAD+ can be synthesized (made) by NMN and NR. [3]
NMN stands for Nicotinamide Mononucleotide and NR is short for Nicotinamide Riboside. They are both molecules that act as precursors to NAD+, meaning that they become NAD+ through a series of chemical transformations, thereby increasing its level in the body. NMN is similar to NR, the basic difference being that it has an extra molecule attached -- a phosphate. In the case of NR, NAD+ has been increased in both human and mouse studies, and NMN has boosted NAD+ in mouse studies. (Human trials are underway for NMN and its ability to boost NAD, but have not yet been finished.)
Before I get into specifics, I can suspend the suspense and answer the question posed by the title of this article: Yes, the NAD+ precursors NMN and NR do work to boost NAD. Scientific studies of mice demonstrate that these NAD+ precursors not only increase NAD, but also reduce their biological age. [4]
The very few human trials on NR show that it boosts NAD+ levels in us as well, but it's uncertain if this confers similar anti-aging benefits that accrue to mice. [5] NMN is undergoing human trials now, but the results have not been published. [6] Most scientists who study NMN, such as Dr. Shin-ichiro Imai, are confident that NMN, like NR, does increase NAD+ levels in humans. Both NAD+ precursors are available without prescription as a supplement and are considered safe.
The Best NMN Precursors: Molecule Size Doesn't Matter Anymore
The answer to which molecule, NMN or NR, bests makes NAD+ is not straightforward, because new scientific studies reveal certain complexities. For instance, a 2016 study that mapped the NMN and NR conversion path to become NAD+ made a conclusion that is no longer accurate:
NMN converts to NR, which then enters the cell for NAD+ synthesis. There is no signs of a direct NMN transport path into the cell.
One big reason it was thought that NMN needed to convert to NR in order to enter cells was due to the size of the NMN molecule; it's too big to enter cells easily, was the reasoning, given that it has that extra phosphate molecule attached that NR does not. Hence, until earlier this year (2019), much of the scientific community thought that NMN can not directly enter the cells of most tissues to boost NAD+ (NAD+ synthesis). But then a new study published in Nature Metabolism in 2019 discovered a new pathway for NMN to directly enter cells -- no conversion to NR needed.
Arm wrestling over whether NMN or NR is the better NAD+ precursor for humans will not result in a winner until the two molecules are studied side by side in humans. Until then we can make some observations.
As mentioned, the most salient difference between NMN and NR is molecular size. NMN is larger than NR, and thereby was thought to need to be broken down to fit into the cell. Now that a new "transporter" mechanism was discovered earlier this year and was shown to be able to shuttle NMN directly into some cells, molecule size is no longer a viable comparative distinction that favors NR.
Dr. Shin-ichiro Imai, mentioned earlier, is a professor of developmental biology at Washington University in St. Louis, and was the lead researcher in that 2019 study that identified a transporter that allows NMN to get into the cell without converting to NR. NR has been shown to enter cells in the liver, muscle, and brain tissue of mouse models. But again, the two have never been matched up against each other in a way that can truly identify one as superior to the other relative to NAD+ precursors.
Why Should You Care About NMN and NR? (The Story of Sirtuins)
Why does it matter that these two molecules get into your cells and how they do it, you wonder? I started to answer that question at the beginning of this piece, and now want to return to the healthspan-promoting value of boosting NAD+ through NMN and NR supplementation.
You know that NR and NMN are beneficial because they elevate levels of NAD, which decline with age, and that NAD+ is vital to metabolism, turning nutrients into energy. Supplementing NR and NMN could provide other myriad benefits as a result of boosting NAD. NR supplementation in mice, for example, has proven beneficial for things like mitochondrial function. NMN supplementation in mice has shown improved blood flow and endurance as well as other age-associated physiological decline like low energy, weight gain, among others.
What I now want to explore is how NAD+ activates sirtuins, a set of proteins that regulate longevity.
Sirtuins are a family of proteins that play a role in aging by regulating cellular health. They're responsible for critical biological functions like DNA expression and many aspects of aging. However, sirtuins can only function in the presence of NAD, nicotinamide adenine dinucleotide, which as mentioned, is a coenzyme found in all living cells. [7]
When you think of proteins you might think of an important macronutrient that we need in our diet along with fats and carbohydrates, but in this case I'm referring to molecules called proteins, which work throughout the body's cells in a number of different functions. Concerning sirtuin proteins, we can borrow an office analogy to explain how sirtuins work.
In this analogy, the proteins are the departments at a company, each one focusing on its own specific function while coordinating with other departments. Your body's cells are the office. In the office, there are many people working on various tasks performed to fulfill the mission of the company as efficiently and durably as possible. Just as priorities in the company change due to various internal and external factors, so do priorities in the cells. Someone has to run the office, regulating what gets done when, who's going to do it, and when to switch course when priorities change. In the office, that would be your CEO; in the body at the cellular level, it's your sirtuins.
Because they can only function with sufficient levels of NAD+, sirtuins become compromised as NAD+ declines. Back to our analogy: If sirtuins are a company's CEO, then NAD+ is the money that pays the salary of the CEO and employees, all while keeping the lights on and the office space rent paid. Simply put, sirtuins manage everything that happens in your cells in order to keep the body as productive as possible, but their functionality falters as the NAD+ they need declines.
The bottom line on sirtuins is that when activated they help keep you younger by slowing down the aging process, but to do that sirtuins need NAD+, and NAD+ needs a bioavailable precursor like NMN.
References:
- https://pediaa.com/difference-between-nad-and-nadh/
- https://endpoints.elysiumhealth.com/5-reasons-scientists-are-studying-nad-the-golden-nucleotide-11cd7bb7e6af
- https://www.right-of-assembly.org/nad-precursors
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668137/
- https://www.elysiumhealth.com/en-us/basis/human-clinical-trial-results
- https://www.nature.com/articles/npjamd201621
- https://www.prohealthlongevity.com/blogs/control-how-you-age/nad-sirtuin-activator-governs-aging
