The Metabolism-Aging Connection—and How to Master It
In 2004, Charles Brenner, a biochemist then working at Dartmouth College, discovered a form of vitamin B3 that could increase the lifespan of yeast cells. Fourteen years later, it’s being considered as a supplement in the perennial (human) quest to ward off aging. The form of B3 is called nicotinamide riboside (NR). What Brenner discovered was that the body can use NR to produce more of a coenzyme that’s critical to the healthy function and the metabolism of our cells throughout our lives. The coenzyme, which we also just discovered, is called nicotinamide adenine dinucleotide, or NAD. While NR exists as a vitamin in nature, Brenner says you’ll only find it in very small amounts in, for instance, milk. Today, Brenner’s work has been bottled into a dietary supplement, called Tru Niagen, and he now serves as Chief Scientific Advisor of the parent company, ChromaDex. (He’s also the Roy J. Carver Chair and Head of Biochemistry at the University of Iowa.)
We talked to him about all the possible ways to boost the body’s store of NAD and maintain healthy metabolism (which he explains encompasses more than we think), and all the things that can make this central system break down. Brenner isn’t one to tell you to give up something you enjoy (cheers), or lock yourself in a deprivation chamber, and he’s clear that the goal isn’t to stay young. The goal, he says, is age your best. Or, in our words, eat our cake and have it too.
A Q&A with Charles Brenner, Ph.D.
What can replenish NAD to keep up metabolism?
Tryptophan, an amino acid, in turkey, for example, is one precursor of NAD, but it’s a very inefficient building block. Tryptophan is also a building block for proteins and serotonins so it takes a lot tryptophan to make a very small amount of NAD.
Classic vitamin B3: Niacin & Nicotinamide
There are also three vitamin precursors of NAD—they’re all chemically similar but distinct compounds that we call “vitamin B3.” We’ve known about two forms of vitamin B3 since 1938, when niacin (also known as nicotinic acid) and nicotinamide were discovered by a biochemist in Madison, Wisconsin named Conrad Elvehjem. Around the same time, they realized that these vitamins were precursors of NAD, which was important to curing a horrible nutritional deficiency called pellagra that was endemic in the American South a hundred years ago. Pellagra is essentially the result of eating a diet of corn meal and lard, which is quite like shopping only in the aisles of the grocery store and not the perimeter where the whole foods are. It turns out that the diet of prisoners and hospital patients who were suffering from pellagra was deficient in NAD precursors. This is why flour is now fortified with niacin. This enrichment program has dealt with pellagra at a population scale—we don’t have huge deficiencies—but it hasn’t necessarily optimized health.
High doses of niacin can have amazing effects on our our plasma lipids, by lowering LDL cholesterol, our “bad cholesterol,” and elevating HDL cholesterol, the “good cholesterol.” The issue with high-dose therapeutic niacin, though, is that it causes flushing. So, if you take a gram of niacin, your skin is going to turn bright red and your ears are going to feel like they’re on fire. It’s fairly unpleasant.
Nicotinamide—the other classic NAD precursor vitamin—doesn’t have this same beneficial effect on plasma lipids. And high doses of nicotinamide, unfortunately, inhibit a family of enzymes called sirtuins, which are important metabolic regulators. They mediate some of the longevity-promoting effects of dietary restriction.
Newly Discovered vitamin B3: Nicotinamide Riboside (NR)
In 2004, when my lab was stationed at Dartmouth, we realized that there was another way that cells could make NAD, using a molecule called nicotinamide riboside (NR). NR turned out to be the most efficient precursor to NAD. We’ve done a comparison in mice: NR produces more NAD than equivalent doses of niacin or nicotinamide.
Can we get the NAD building blocks we need from food?
A good diet—made up of whole foods and minimally processed foods—helps support the body’s supply of NAD. If you’re eating vegetables, meat, fish—you’re eating cellular stuff, and you’re getting NAD, which is good. NAD breaks down to the vitamins and the vitamins get taken into cells to replenish NAD.
NR, in particular, is found in milk. But it would not make sense to drink milk for the NR—you’d have to drink hundreds of liters of milk to get the amount of NR contained in a supplement. So, some people choose to supplement with a compound like NR (ideally on top of eating a healthy diet), to replenish NAD and help cope with the inevitable stresses of life.
What are the most significant stressors?
Everyone has an idea of what stress looks like—maybe you picture sitting in traffic or your boss asking you to do something on a tight deadline. As a biologist, I think about stress as stuff that damages DNA and messes with bodily functions—that’s cellular and metabolic stress. Here’s what can contribute to it:
Overnutrition: When energy intake doesn’t match energy expenditure, we’re out of metabolic balance, which challenges our NAD metabolome (a measurement of all the NAD compounds). This is true of a mouse in a cage that is overfed and goes without exercise, which is not unlike a modern office worker who spends most hours sitting in a cube, eating processed foods.
Alcohol: Alcohol metabolism depends on NAD. It converts NAD to NADH, and then NADH is not in the form that helps us burn other foods.
“Frankly, we enjoy all of those things that are metabolic stressors. Who doesn’t enjoy hopping on a plane to go someplace? Having a big dinner and a couple glasses of wine?”
Time-zone disruption: In the last three months, I “hopped” on a plane to go to Hong Kong, Tokyo, and Singapore, which put my circadian rhythms upside down. Uncorrected, jet lag and shift work, makes your NAD peaking at all the wrong times with respect to cycles of wakefulness.
Free radicals: A lot of our metabolism happens in mitochondria, which are a really important organelle. They’re part of almost every cell and if you don’t have good mitochondrial function, you don’t have functioning metabolism. There’s a lot of oxygen in mitochondria, and because oxygen is the ultimate electron acceptor, it can pick up electrons to form reactive oxygen species, which are better known as free radicals. In excess, free radicals can cause damage to our cells. NADPH, one of the key NAD metabolites, is required for the mechanism by which our cells detoxify free radicals. It boosts our natural antioxidant defense, which can get depressed by all the things just mentioned that challenge our NAD function, in addition to aging.
What happens to NAD function and metabolism as we age?
Aging is harder to study in the lab than metabolic stress, but NAD in certain tissues has been shown to decline as we age, as does metabolism, our resiliency against cellular damage, and our ability to repair that damage. In other words, we aren’t able to function as efficiently—it’s harder to stay up late, to hop on a redeye and go to a meeting the next morning, or bounce back from the flu or a night of drinking. We think that challenges to the NAD metabolome are a key part of this decline.
“I don’t want to go back to being twenty—aging well and aging better is the goal, really.”
Can supplementing for NAD help to fill that gap?
NR is the most powerful NAD-boosting compound. It’s the largest molecule that can go into cells and regenerate NAD. It’s available to boost NAD in the most cells and tissues because NR genes are essentially turned “on” throughout the body.
Important note: NR is sold over-the-counter (as TRU NIAGEN), so it’s not intended to treat any disease or condition. It’s meant to help maintain NAD stores, help deal with metabolic stress, and support healthy cellular metabolism.
Are there any other lifestyle changes that can make a difference when it comes to NAD and aging?
There are some animal experiments that suggest that exercise and calorie restriction may help maintain NAD levels and circadian functions that fall off as we age but it’s not entirely clear how this would work in humans. I don’t advocate for calorie restriction (or really any extreme dietary practices) and it’s not something that most people would be able to do sustainably.
“Being socially connected and having relationships with people of different ages might be better than a twice-a-year detox.”
In terms of diet, we know that a diet high in process carbs is not good for us and that eating a balanced diet with a lot of whole foods is. I think a healthy diet rather than dieting, social engagement, trying new things with your brain, and getting physical activity, are the best things you can do to stay healthy overall. Being socially connected and having relationships with people of different ages might be better than a twice-a-year detox.
The goal of boosting NAD with NR supplementation is to help your body be more resilient and more resistant to metabolic stresses. Because, frankly, we enjoy all of those things that are metabolic stressors. Who doesn’t enjoy hopping on a plane to go someplace? Having a big dinner and a couple glasses of wine? Hanging out in the sun? That’s why I call these the inevitable stresses of life. We actually want to age, and we want to age gracefully and have the wisdom that comes with it, and to be able to provide for our families in our maturity. I don’t want to go back to being twenty—aging well and aging better is the goal, really. We think supplementing with NR can support that.
Charles Brenner, Ph.D. is the Roy J. Carver Chair and Head of Biochemistry at the University of Iowa, as well as a founding co-director of the University of Iowa Obesity Initiative. In 2004, while a faculty member at Dartmouth College, Brenner discovered nicotinamide riboside (NR) to be a vital precursor of nicotinamide adenine dinucleotide (NAD). A world expert in NAD metabolism, Brenner is also the Chief Scientific Advisor of ChromaDex, Inc. He received his B.A. in biology from Wesleyan University and his Ph.D. from Stanford University in cancer biology before doing his postdoctoral fellowship in chemistry and biochemistry at Brandeis University.
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