The Third Way to Boost NAD+

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How can we conserve NAD+ by preventing overactivation of the enzymes PARP-1 and CD38, which guzzle NAD+?

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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

There are three NAD-boosting strategies. Increasing the supply of NAD+ precursors is just one way. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, by, for example, conserving it by using less. Besides sirtuins, the major consumers of NAD+ are PARP-1 and CD38. PARP-1 is an enzyme that uses NAD+ to repair DNA. The more oxidative DNA damage, the more single- and double-stranded DNA breaks, the more enzymes like PARP-1 need to be activated to come to the rescue. This uses up a lot of NAD. As DNA damage accumulates with age, the rising need for repair enzymes like PARP-1 causes a major drain on NAD+ levels.

Exposing cells in vitro to DNA-damaging agents, such as gamma radiation or genotoxic chemicals, can cause an 80 to 90 percent drop in NAD+ levels within a matter of minutes. This has led to the search for PARP-1 blockers to preserve NAD+ levels. But rather than blocking DNA repair, why not work to prevent so much damage in the first place? For example, the severe oxidative stress of a high-fat diet can lead to PARP-1 activation and NAD+ depletion in mice, but NAD+ levels can be “dramatically restored” by feeding them “purple sweet potato color,” the natural anthocyanin pigments found in purple sweet potatoes. Or, of course, you can just not feed them a high-fat diet.

DNA repair is a good thing. PARP-1 may be one of the reasons NAD+ boosting interventions can improve healthspans and lifespans in laboratory animals. Greater PARP activity strongly correlates with longer lifespan across about a dozen mammalian species, and the PARP activity of human centenarians averages 60 percent higher than younger controls. However, persistent activation can lead to NAD+ depletion, and overactivation can even lead to cell death. So, we should try to keep oxidative stress to a minimum.

CD38 is another major guzzler of NAD+. It’s an enzyme that uses NAD+ found concentrated on the surfaces of immune cells, and is robustly induced in the context of inflammation. The rise of CD38 activity with age has been blamed on persistent “inflammaging” activation––the rise in systemic low-grade inflammation in our bodies when we get older, which may be a major culprit for falling NAD+ levels. For example, blocking CD38 has been found to raise NAD+ levels in old mice comparable to that of younger mice.

So, oxidation and inflammation can lead to a drop in NAD+ levels due to the excess activation of the NAD+ consuming enzymes. This may explain why protective sirtuin activity is reduced in obesity, a condition characterized by oxidative stress and inflammation. A study of identical twin pairs in which one, on average, was obese and the other not, found significantly less sirtuin expression in the obese twin, despite having the same genetics. And, randomize people to a six-month trial of 25 percent caloric restriction, and you can show a boost in sirtuin expression along with a decrease in DNA damage. Protein restriction may have a similar effect, since men and women with higher protein intake tend to have lower levels of NAD+ in their blood, thought to be due to the oxidative stress induced by protein breakdown byproducts.

If oxidation and inflammation are responsible for a drop in NAD+ levels, then what about the antioxidant and anti-inflammatory phytonutrients in healthy plant foods? After screening more than 14,000 compounds, almost all flavonoids were found to be effective in a test for CD38 inhibition. The two most effective were cyanidin, found in red cabbage and blackberries, and quercetagetin, found in marigold flower tea. Another study found the three most potent compounds were luteolin, kuromanin, and luteolinidin. Luteolin is found concentrated in oregano, radicchio, and chrysanthemum tea. Kuromanin is found in black berries, purple corn, and hibiscus tea. Corn tortillas are surprisingly easy to make; so, why not choose blue or purple masa to make them even healthier? Luteolinidin, found to increase NAD+ in the hearts of rats, can be found in red sorghum, one of the components of my prebiotic BROL mix, when I can find it.

The flavonoid apigenin is a well-established CD38 inhibitor. When given to mice, apigenin boosts NAD+ levels by about 50 percent, which is what people would get taking the maximum tolerable daily dose of NR. The best sources are parsley and chamomile tea. A wide range of flavonoids found in green tea, turmeric, and fruits and vegetables have also been found to prevent NAD+ depletion in human cells in vitro at levels found in the blood after consumption. How much do you have to eat, though?

Proanthocyanidins have been found to lower PARP-1 and CD38 expression in rats. NAD+ and sirtuin activity was significantly boosted at the human equivalent dose of about 280 mg a day. How much is that? That’s the amount of proanthocyanidins found in a single apple. You could also reach that dose eating two plums, a half cup (75 g) of wild blueberries, a little over a teaspoon of cinnamon, or a little over a tablespoon, like four teaspoons, of cocoa powder.

Quercetin is another suppressor of PARP-1 and CD38 shown to increase sirtuin activity in mice. The concentration necessary to lower PARP-1 in vitro can be achieved by taking a quercetin supplement, but typical supplement manufacturers’ recommended doses are up to 100 times the average daily dietary intake. Thankfully, food works, too. Researchers fried up one and a half yellow onions and raised quercetin blood levels to about 75 percent there. And so, two onions might do it. There are no long-term safety data on high-dose flavonoid supplementation; so, public health researchers suggest “caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet.”

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

There are three NAD-boosting strategies. Increasing the supply of NAD+ precursors is just one way. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, by, for example, conserving it by using less. Besides sirtuins, the major consumers of NAD+ are PARP-1 and CD38. PARP-1 is an enzyme that uses NAD+ to repair DNA. The more oxidative DNA damage, the more single- and double-stranded DNA breaks, the more enzymes like PARP-1 need to be activated to come to the rescue. This uses up a lot of NAD. As DNA damage accumulates with age, the rising need for repair enzymes like PARP-1 causes a major drain on NAD+ levels.

Exposing cells in vitro to DNA-damaging agents, such as gamma radiation or genotoxic chemicals, can cause an 80 to 90 percent drop in NAD+ levels within a matter of minutes. This has led to the search for PARP-1 blockers to preserve NAD+ levels. But rather than blocking DNA repair, why not work to prevent so much damage in the first place? For example, the severe oxidative stress of a high-fat diet can lead to PARP-1 activation and NAD+ depletion in mice, but NAD+ levels can be “dramatically restored” by feeding them “purple sweet potato color,” the natural anthocyanin pigments found in purple sweet potatoes. Or, of course, you can just not feed them a high-fat diet.

DNA repair is a good thing. PARP-1 may be one of the reasons NAD+ boosting interventions can improve healthspans and lifespans in laboratory animals. Greater PARP activity strongly correlates with longer lifespan across about a dozen mammalian species, and the PARP activity of human centenarians averages 60 percent higher than younger controls. However, persistent activation can lead to NAD+ depletion, and overactivation can even lead to cell death. So, we should try to keep oxidative stress to a minimum.

CD38 is another major guzzler of NAD+. It’s an enzyme that uses NAD+ found concentrated on the surfaces of immune cells, and is robustly induced in the context of inflammation. The rise of CD38 activity with age has been blamed on persistent “inflammaging” activation––the rise in systemic low-grade inflammation in our bodies when we get older, which may be a major culprit for falling NAD+ levels. For example, blocking CD38 has been found to raise NAD+ levels in old mice comparable to that of younger mice.

So, oxidation and inflammation can lead to a drop in NAD+ levels due to the excess activation of the NAD+ consuming enzymes. This may explain why protective sirtuin activity is reduced in obesity, a condition characterized by oxidative stress and inflammation. A study of identical twin pairs in which one, on average, was obese and the other not, found significantly less sirtuin expression in the obese twin, despite having the same genetics. And, randomize people to a six-month trial of 25 percent caloric restriction, and you can show a boost in sirtuin expression along with a decrease in DNA damage. Protein restriction may have a similar effect, since men and women with higher protein intake tend to have lower levels of NAD+ in their blood, thought to be due to the oxidative stress induced by protein breakdown byproducts.

If oxidation and inflammation are responsible for a drop in NAD+ levels, then what about the antioxidant and anti-inflammatory phytonutrients in healthy plant foods? After screening more than 14,000 compounds, almost all flavonoids were found to be effective in a test for CD38 inhibition. The two most effective were cyanidin, found in red cabbage and blackberries, and quercetagetin, found in marigold flower tea. Another study found the three most potent compounds were luteolin, kuromanin, and luteolinidin. Luteolin is found concentrated in oregano, radicchio, and chrysanthemum tea. Kuromanin is found in black berries, purple corn, and hibiscus tea. Corn tortillas are surprisingly easy to make; so, why not choose blue or purple masa to make them even healthier? Luteolinidin, found to increase NAD+ in the hearts of rats, can be found in red sorghum, one of the components of my prebiotic BROL mix, when I can find it.

The flavonoid apigenin is a well-established CD38 inhibitor. When given to mice, apigenin boosts NAD+ levels by about 50 percent, which is what people would get taking the maximum tolerable daily dose of NR. The best sources are parsley and chamomile tea. A wide range of flavonoids found in green tea, turmeric, and fruits and vegetables have also been found to prevent NAD+ depletion in human cells in vitro at levels found in the blood after consumption. How much do you have to eat, though?

Proanthocyanidins have been found to lower PARP-1 and CD38 expression in rats. NAD+ and sirtuin activity was significantly boosted at the human equivalent dose of about 280 mg a day. How much is that? That’s the amount of proanthocyanidins found in a single apple. You could also reach that dose eating two plums, a half cup (75 g) of wild blueberries, a little over a teaspoon of cinnamon, or a little over a tablespoon, like four teaspoons, of cocoa powder.

Quercetin is another suppressor of PARP-1 and CD38 shown to increase sirtuin activity in mice. The concentration necessary to lower PARP-1 in vitro can be achieved by taking a quercetin supplement, but typical supplement manufacturers’ recommended doses are up to 100 times the average daily dietary intake. Thankfully, food works, too. Researchers fried up one and a half yellow onions and raised quercetin blood levels to about 75 percent there. And so, two onions might do it. There are no long-term safety data on high-dose flavonoid supplementation; so, public health researchers suggest “caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet.”

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Doctor's Note

​​This is the final video in my NAD+ series. If you missed any of the previous ones, check out:

For more on aging, go to your local public library and check out my longevity book, How Not to Age, available in print, e-book, and audio. (All proceeds I receive from the book are donated directly to charity.)

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