NAD+ boosters: NR, NMN, and how they affect sirtuins | David Sinclair
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Nicotinamide adenine dinucleotide, or NAD+, is a cofactor for multiple physiological processes in the body. NAD+ can be synthesized in the body in the NAD+ salvage pathway, or from two of its precursors, nicotinamide mononucleotide and nicotinamide riboside, often referred to as NAD+ "boosters." Boosting levels of NAD+ has been shown to improve lifespan and healthspan in animal models of premature aging and in humans. In this clip, Dr. David Sinclair describes the NAD+ salvage pathway and how boosting cellular NAD+ levels may be beneficial in slowing aging.
Rhonda: You've mentioned these NAD boosters and we probably should definitely get into that. But...
David: Well, they're central, too, because as I mentioned, the proteins, many of them like the sirtuins were moving around controlling the epigenome. You want to stabilize that as best you can. Animals like whales and naked mole rats have a very stable epigenome, so there's moving around of proteins and epigenomic noise accumulating. If we're exercising, we're taking NAD boosters, we do slow that process down, I believe.
Rhonda: Let's talk about what NAD boosters are, so the precursors for NAD. Right, we make NAD in our bodies, in our... So...
David: Yeah. We do. And so, NAD is recycled in the body because there's grams of it, you can't eat that much easily. And there's a cycle, it's called the salvage pathway of NAD. And it all starts with nicotinamide, which is a form of niacin, vitamin B3. But you can't just... Well, you can, but it's not very effective, just overdose on vitamin B3 because you need other things to make the big molecule, NAD. So NAD, the reason it's called nicotinamide adenine dinucleotide is that it's got these three main components, and the dinucleotide is related to DNA. But that's beside the point. It's a big molecule so that if you give a big molecule to cells, it doesn't get taken up. So we don't feed animals NAD. And we don't just feed them nicotinamide, which is the little end part of NAD because it's too small in that you need these other parts.
So NMN and NR are two molecules. So it stands for nicotinamide mononucleotide, which is essentially the precursor, the immediate precursor to NAD. If you'd give a cell NMN, it will be taken up by a transporter, which was just discovered by my buddy Shin Imai, we used to work together at MIT. Now he's at WashU. A few weeks ago, he wrote about it. I wrote about it, that there's a transporter that sucks up NMN, and the NMN is converted within one step to NAD in the cell, and now it's locked. It's a big molecule, it's locked inside the cell. And that step is carried out by an enzyme. It's got a name, it's called NAMPT. And that enzyme goes up under stress and calorie restriction. And in yeast, it's the same step. And so we showed years ago that that step of conversion of NMN to NAD or in yeast, what is it? Nicotinic acid to NAD is the critical step for boosting NAD when you're going through your circadian rhythms, when you exercise, when your cells are stressed. And without that step, you don't get the benefits of calorie restriction, your organs start to get old.
So what is NR? So NR is fairly popular, a lot of people have heard of it. It stands for nicotinamide riboside and all it is, it's just a smaller version of NMN without a phosphate on there. So there's no phosphorus on it. So if you take NR, your body has to first put on a phosphorus and then it has to basically link two of them together to make the NAD. So with all that said...
Rhonda: NR gets converted into NMN first and then into NAD?
David: Yes. Yes, it has to. Yeah. But NR and NMN have both been shown to raise the NAD levels in animals and in humans as well. And there's small nuances about the differences, but they both seem to be effective, not just in humans, actually, I should say, in mice. But in yeast, they work as well, which is nice.
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 80 percent of gene expression in mammals is under circadian control, including genes in the brain, liver, and muscle.[1] Consequently, circadian rhythmicity may have profound implications for human healthspan.
- ^ Dkhissi-Benyahya, Ouria; Chang, Max; Mure, Ludovic S; Benegiamo, Giorgia; Panda, Satchidananda; Le, Hiep D., et al. (2018). Diurnal Transcriptome Atlas Of A Primate Across Major Neural And Peripheral Tissues Science 359, 6381.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
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.
A class of enzymes that influence that influence aging and longevity through multiple molecular pathways. Sirtuins regulate a variety of metabolic processes, including release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. They also influence circadian clocks and mitochondrial biogenesis. Sirtuins are activated when NAD+ levels rise. The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or nicotinamide or a combination of these variables. There are seven known sirtuins, designated as Sirt1 to Sirt7.
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