NAD+ and resveratrol levels affect the aging process | David Sinclair
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NAD+ is a substrate for the sirtuin proteins, a family of enzymes involved in a variety of metabolic processes. Sirtuins utilize NAD+ to remove specific chemical structures called acetyl groups – a process called deacetylation – from cellular proteins to control transcriptional regulation, energy metabolism, circadian rhythms, DNA repair, and cell survival. In a simple analogy, NAD+ is the fuel in a car that the sirtuins are driving. To carry that analogy a bit further, resveratrol, a plant-based molecule found in red grapes and peanuts, acts as an accelerator to enhance the activity of the fuel – NAD+. In this clip, Dr. David Sinclair describes the links between NAD+, sirtuins, and resveratrol in the aging process.
Rhonda: So NAD levels decrease with age, and you think this is causal for...plays a causal role in the aging process?
David: Right, right. So why is NAD linked to sirtuins? So, sirtuins are enzymes.... And this is my picture of an enzyme, but think of like a Pac-Man that's chewing off chemical groups of other proteins, telling them what to do, like a traffic cop. And without NAD, they don't work. They're stuck shut. And so there's always NAD around, otherwise, you'll be dead. But if the levels go down as they do, as you get older, and I'm almost 50, so my levels probably are half what they were when I was 20, scary thought.
Rhonda: Wow.
David: So my sirtuins are working maybe half as well as they did telling the troops to go out and fix my body. So when I go for a run, I get less benefit from that. I feel tired, I don't make as much energy. Mitochondria are down. But by raising up the levels of NAD to when I was young, what I think is going on based on the animal work we've been doing for many years now is to trick the body into thinking that it's young again, or it's been exercising, or dieting, and that allows the sirtuins to do their job the way they once did.
Rhonda: By just having that level of NAD higher, like, it's basically like a signal.
David: It is. So I think of it as the fuel in a car if the sirtuins are driving. And then the resveratrol that we worked on years ago works on the same enzymes, but it's the accelerator pedal. So, it actually... The NAD is making it work, but resveratrol will come along and make it work even faster. So the combination of those two, we find, is even better than just one alone.
Rhonda: Cool.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
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.
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 polyphenolic compound produced in plants in response to injury or pathogenic attack from bacteria or fungi. Resveratrol exerts a diverse array of biological effects, including antitumor, antioxidant, antiviral, and hormonal activities. It activates sirtuin 1 (SIRT1), an enzyme that deacetylates proteins and contributes to cellular regulation (including autophagy). Dietary sources of resveratrol include grapes, blueberries, raspberries, and mulberries.
Resveratrol Autophagy ↑ Deacetylases (especially SIRT1) → ↓ Protein Acetylation → Autophagy
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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