NMN vs NR — David Sinclair version (2019)

Dr David Sinclair - I’ve got this subject on my mind today because, whenever a new study about boosting NAD hits the presses, my inbox explodes.

Take, for instance, what happened in the wake of some recent research out of Richard Goodman’s lab at Oregon Health & Science University. The paper, published in Proceedings of the National Academy of Sciences, provides evidence that a known NAD-booster, NMN, enhances the SARM1-mediated neurotoxicity of vincristine, a cancer chemotherapeutic agent.

In another paper, from researchers at the University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, one dose of NMN increased mitochondrial NAD+ in mouse brains for 24 hours, and raised chemical energy levels, too.

Sometimes, when papers like this are published, the reaction is:

HEY EVERYBODY! NMN HAS THIS SCARY EFFECT AND OH MY GOD IT’S GOING TO KILL US ALL AND WE SHOULD TAKE MORE NR INSTEAD!!!

Other times, the reaction is:

HEY EVERYBODY! NMN HAS THIS INCREDIBLE EFFECT AND LET’S ALL GO OUT AND BUY LOTS OF NMN INSTEAD OF NR!!!

My reaction?

“Hmmm. Interesting.”

Let me be clear here: I do get excited about results like those published in these papers. More knowledge is always better than none.

What I don’t do is make my decisions about the comparative efficacy of Nicotinamide mononucleotide or Nicotinamide riboside (or anything else) based on any one paper.

It’s no secret that I take NMN; I’ve been very up front about that. I would consider it to be an act of dishonesty to not disclose that fact. It also should not be a secret at this point that I have absolutely no opinion whatsoever on whether anyone else should take these supplements. I’m a professor and researcher, not a salesman or representative from an analytics company, so I’m unable to advise where to get it, how to take it, or whether or not you should give it to your pet chinchilla.

By the way, if you see my name on a product’s website, it is being used without my permission. I don’t sell supplements.

With 25 years of experience in this field, and having read thousands of papers on this subject, I can give you my interpretation of the scientific literature, and my thoughts on some of the politics surrounding these molecules.

Whenever you or I are seeking to interpret scientific studies — in a way, for instance, that allows us to make decisions about the difference between NMN and NR — we all need to remember that:

1. Cell culture results are trumped by mouse results.

2. Mouse results are trumped by human results.

3. Anecdotes and small human trial results, while certainly interesting and sometimes even exciting, are trumped by double-blind placebo controlled studies.

4. Approved drugs, of course, trump all of that — and even then we absolutely must push onward with more research, more research, and more research. Our jobs are never done. Our curiosity should never be satisfied.



With that in mind, what does the science show when it comes to NMN and NR?

Well, we know that NAD boosters have shown efficacy in plenty of cell cultures and in mouse models of human diseases. Both NR and NMN have been shown to benefit the health of elderly mice, and neither of these treatments show negative health effects, even in long-term mouse experiments—not in inflammation, senescence, or cancer models.

The side effect in a mouse? Slightly longer life, and even that’s debated.

In humans, research into the effects of NR vs NMN is still gaining traction — with a few small-scale registered clinical trials completed and multiple others underway. Ultimately, no mouse study is proof these molecules will work or will fail in humans to treat a disease or affect the lace of aging. We have to test them in people, in rigorous and independent scientific studies.

Most of what has been completed in humans so far helps us better understand NR.

For example:

1. A randomized, double-blind, three-arm crossover pharmacokinetic study in 12 human subjects showed that NR raises NAD+ by as much as 2.7-fold in human blood with a single oral dose of 1000 mg.

2. Researchers at the University of Washington have completed a clinical trial with 140 participants showing that orally administered NR gives a dose dependent increase in NAD+ from 250-1000 mg/d plateauing at a 2-fold increase in NAD+ at day nine.

3. Researchers have also reported positive effects of NR on vascular endothelial function in healthy middle-aged and older adults, with further investigations of motor and cognitive changes to come.

4. Recently, researchers have found that a resveratrol analog called pterostilbene combined with NR seemed to help ALS/Lou Gehrig’s patients.*

5. Most recently, a placebo-controlled study assessing 500 mg of NR, taken twice daily by 70- to 80-year olds, showed increases in NAD+ in blood (but not muscle.) Inflammation fell and, unexpectedly, mitochondrial activity did too.

6. Multiple other studies are now underway assessing the effects of NR on muscle mitochondrial function, cognition, immune function, kidney function, traumatic brain injury, brown fat activity, lipid accumulation, energy metabolism, cardiovascular risk, body composition, and acetylcarnitine levels.

When will we have human trial results for NMN? Likely very soon. Right now, for instance, we know that:

An international collaborative team including researchers from Keio University in Tokyo and Washington University School of Medicine in St. Louis is running a Phase I human clinical study of NMN in Japan.

Clinical trials examining the safety and efficacy of NMN are also currently being run at Washington University, investigating the effect on insulin sensitivity, endothelial function, lipids, body and liver fat and markers of cardiovascular and metabolic health.

It’s also worth noting that research and development is underway on novel NAD precursors, such as Metrobiotech’s MIB-626* which is being tested in clinical trials by an independent team at a hospital in Boston.

The bottom line, for now, is that the science is a bit further along when it comes to NR, but it is far too early to say which is better for humans. This is not a race. Science isn’t a contest between two competitors. (And there are many other approaches to raising NAD being investigated: other analogs of NMN and NR, CD38 inhibitors, PARP1 inhibitors, SARM1 inhibitors, ACMSD inhibitors, and more.)

Yes, there is rivalry between scientists. It’s usually (although not always) a friendly rivalry.

But ultimately what we do is collaborative. What scientists are learning about NR is helping the researchers in my lab who are focused on NMN and its analogs. What NMN-focused researchers are learning is helping our colleagues understand NR. And the things that all of us are learning are contributing to our understanding of the ultimate goal: treatments and therapies that slow, stop or reverse aging in humans, which treat major diseases of aging, and which are safe and effective at doing so — no matter what they’re called or who invented them.

About the Author: David Sinclair is a professor in the Department of Genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, where he and his colleagues study sirtuins—protein-modifying enzymes that respond to changing NAD+ levels and to caloric restriction—as well as chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, cancer, and cellular reprogramming.



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