Nicotinamide Riboside vs. Nicotinamide Mononucleotide - dosing and effects on NAD+ | David Sinclair
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Two NAD+ precursors, nicotinamide riboside and nicotinamide mononucleotide, have been shown to ameliorate age-associated diseases in animals. They are well-tolerated at high doses and effectively raise NAD+ levels. Evidence suggests that these molecules, often referred to as "NAD+ boosters," may increase levels of NAD+ in humans, too; however, the doses used in some of the studies equate to far less than what was provided in the rodent studies. Currently, only nicotinamide riboside has been shown to raise plasma NAD+ levels and may possibly have beneficial health effects in humans. Future research, focused on "super boosters," may have relevance for treating complex diseases such as diabetes, heart disease, cancer, and Alzheimer's. In this clip, Dr. David Sinclair discusses the current state of research on the NAD+ boosters nicotinamide riboside and nicotinamide mononucleotide.
Rhonda: So with the clinical studies, you know, I've seen a couple with nicotinamide riboside, but I guess the, you know, the question is with the nicotinamide riboside, there's been a little confusion about like, you know, whether or not nicotinamide riboside's even really getting converted into NAD inside cells and different organs other than the liver. This was this NAD flux paper that was done by Rabinowitz?
David: Rabinowitz?
Rhonda: Rabinowitz. Thank you. Yes, that study he recently published just a few months ago looking at nicotinamide riboside and how orally, at a dose half of what typically is used in all the other nicotinamide riboside animal studies. So typically, they do 400 milligrams per kilogram body weight per day. I don't remember how long, the duration they were doing it. But in the NAD flux study, he did 200 milligrams per kilogram body weight, which is significantly less than what all of these other studies like the one you mentioned with Alzheimer's disease and other studies that have shown improvements in mitochondrial function in mitochondrial mutator mice, and also muscular dystrophy, and all that. So...
David: Yeah, we use double that dose for a while.
Rhonda: Yeah, so maybe, you know, this NAD flux study that showed nicotinamide riboside given orally didn't form NAD in the muscle, but it did in the liver could have been a dose-dependent thing?
David: It would make sense because we've done a lot of this in mice and now in humans, and that there's a threshold that you need to cross, you need to take a certain amount to get over probably the body's clearance mechanisms and then you get up to a level that plateaus after about nine days. And they may have just been under that threshold, so the body was just clearing it out. But you have to seemingly overwhelm that clear-out system, so that's why we do at least 400 mgs per kilogram in mice.
Rhonda: And that's with nicotinamide riboside. The question is, I mean, that's like if you talk about a human equivalent dose for like a 180-pound man, that's like over two grams a day. And it kind of leads me to my next question, which was the most recent clinical study with nicotinamide riboside where they actually used a much higher dose than the original study that was done with Basis, the Elysium that had pterostilbene in it. This dose was like 1,000 milligrams a day and they looked at a variety of endpoints in addition to...I mean, they looked at endurance, looked at...
David: Right. It was Doug Seals' study.
Rhonda: Yes. And there was no statistical significance in anything. It raised NAD levels, but there was no statistical significance. There was trending improvement in the vascular system, but there was no effect on endurance. And I'm wondering again, well, if we go back to the human equivalent dose, what was given to the animals, that was still less than half. I mean, so the question becomes, is it not even making NAD in the muscle tissue at that dose or, you know, so...which brings me to the nicotinamide mononucleotide. You know, like now those studies have been done in animals at a much lower dose than 400 milligrams.
David: They have. Yeah. So we, in my lab, and at the company, Metro Biotech, we've been using a whole variety of different molecules and different... We're doing what's called pharmacokinetics. So there's a lot of literature that I could talk for another hour on. One of the big questions people ask me is, "Have you ever put NR and NMN head to head in a study?" And we need to do a lot more of those, typically they're not done. And I'm unaware of it being done in humans at this point. But in mice, what we see... And for all the NR folks out there, please don't be angry, this is just data. I don't run the experiments, I just deliver the message. That at the same dose, NMN will increase endurance. And I forget what that dose was. It might've been 200, 250.
Rhonda: Yeah, 200.
David: NMN didn't increase... Sorry, NR did not increase endurance, but NMN did. We do find that for some parameters, and Matt Kaeberlein, who I mentioned earlier who, he works on dog aging now after doing the SIR2 extension lifespan. So Matt also has published that, comparing NR and NMN, only NMN worked in his disease model, which was a mitochondrial disease where those animals really need a boost of NAD. So one of the issues could be that NMN is a better molecule in that regard. It could be that maybe the mice just worked better than humans and we need a bigger dose. But what I'm working on, which is not talked about a lot because it's in the commercial realm, is there's been a team of seven chemists working on much better molecules than any of these two that I'm talking about, super NAD boosters. And we have ones that work far better than NMN. And these are timed release. These are what we call prodrugs. And those are the ones that I'm really excited about for medicines of the future that don't just increase someone's endurance but could actually treat diabetes, and heart disease, and cancer, and Alzheimer's. That said, we are doing a clinical trial right now with a molecule called MIB 636. MIB is just Metro Biotech. And that's a couple of clinical trials that are being done at Brigham and Women's Hospital in Boston, separate group for me, it's all independent. And that's just a safety study. So when I come back on your show, if I come up back on your show, maybe I'll tell you if we see some actual efficacy, some results. We're going to be looking in the phase two study at strength and endurance in the muscle of people after some NMN dosing. So we're on the verge of knowing if this is real or not for people.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
An essential mineral present in many foods. Iron participates in many physiological functions and is a critical component of hemoglobin. Iron deficiency can cause anemia, fatigue, shortness of breath, and heart arrhythmias.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
A chemical that causes Parkinson's disease-like symptoms. MPTP undergoes enzymatic modification in the brain to form MPP+, a neurotoxic compound that interrupts the electron transport system of dopaminergic neurons. MPTP is chemically related to rotenone and paraquat, pesticides that can produce parkinsonian features in animals.
Dietary supplements that purportedly increase cellular levels of nicotinamide adenine dinucleotide (NAD+). Examples of potential NAD+ boosters include resveratrol (a plant-based dietary compound found in grapes), metformin (a type of diabetes medication), and nicotinamide mononucleotide (a derivative of niacin).
A coenzyme that is required for the production of energy in cells. NAD+ is synthesized from three major precursors: tryptophan, nicotinic acid (vitamin B3), and nicotinamide. It regulates the activity of several key enzymes including those involved in metabolism and repairing DNA damage. NAD+ levels rise during a fasted state. A group of enzymes called sirtuins, which are a type of histone deacetylase, use NAD+ to remove acetyl groups from proteins and are important mediators for the effects of fasting, caloric restriction, and the effects of the plant compound resveratrol, a so-called caloric restriction mimetic.
A precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a coenzyme that participates in the production of cellular energy and repair. NMN helps maintain cellular levels of NAD+, thereby facilitating NAD+-dependent cellular activities, such as mitochondrial metabolism, regulation of sirtuins, and PARP activity. Animal studies have demonstrated that NMN administration is effective in increasing NAD+ levels across multiple tissues while improving the outcome of a variety of age-related diseases. Although NMN administration has proven to be safe and to effectively increase NAD+ levels in rodents, the safety and efficacy of NMN supplementation in humans remain unknown. NMN is available in supplement form and is present in various types of food, including broccoli, avocado, and beef. It is also an intermediate compound in the NAD+ salvage pathway, the recycling of nicotinamide into NAD+.
A precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a coenzyme that participates in the production of cellular energy and repair. NMN helps maintain cellular levels of NAD+, thereby facilitating NAD+-dependent cellular activities, such as mitochondrial metabolism, regulation of sirtuins, and PARP activity. Animal studies have demonstrated that NMN administration is effective in increasing NAD+ levels across multiple tissues while improving the outcome of a variety of age-related diseases. Although NMN administration has proven to be safe and to effectively increase NAD+ levels in rodents, the safety and efficacy of NMN supplementation in humans remain unknown. NMN is available in supplement form and is present in various types of food, including broccoli, avocado, and beef. It is also an intermediate compound in the NAD+ salvage pathway, the recycling of nicotinamide into NAD+.
One of four nitrogen-containing molecules that comprise DNA. A nucleotide consists of one of four chemicals, called a “base,” plus one molecule of sugar and one molecule of phosphoric acid. Nucleotides are typically identified by the first letter of their base names: adenine (A), cytosine (C), guanine (G), and thymine (T). They form specific pairs (A with T, and G with C), and their bonds provide the helical structure of the DNA strand.
The movement of a drug or other xenobiotic substance into, through, and out of the body. Pharmacokinetics comprises absorption, distribution, metabolism, and excretion, often abbreviated "ADME." Many factors influence pharmacokinetics, including a person's age, gut health, and circadian rhythms, as well as the substance's bioavailability.
The highest level of intake of a given nutrient likely to pose no adverse health effects for nearly all healthy people. As intake increases above the upper intake level, the risk of adverse effects increases.
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
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