More on NAD+ Boosting Supplements

Today, we wrap up our series on the important enzyme NAD+. And, we start with a cautionary tale about NAD+ boosting supplements.

Most of the reported side effects for NAD+ precursors, like NAM, NR, and NMN, are relatively rare and minor––for example, diarrhea, nausea, rashes, hot flashes, and leg cramps. Both NR and NMN raise NAM levels, so may share in the same concerns regarding sirtuin inhibition, methyl depletion, and potential adverse effects of NAM breakdown products.

Another theoretical concern of NAD+ boosting is the exacerbation of infections by a group of bacteria called Haemophilus (from the Greek meaning “blood-loving,” though they can also cause infections of the lungs, brain, throat, flesh, and joints). Haemophilus bacteria lack the ability to make NAD+, so rely on host levels, raising the possibility that higher blood levels might worsen the disease course of infected individuals. Ironically, elevated NAD+ levels may also fuel immune system overreaction in cases of auto-immune and inflammatory disease.

When fully activated, the immune system is voracious. The immune reaction to a blood infection or extensive burns can burn 4,000 calories a day, approximating military training in the Arctic. Since NAD+ is used by cells to produce energy, it’s no surprise that we find the primary NAD+ synthesizing enzyme strongly upregulated in tissues that are actively inflamed. For example, the enzyme NAMPT is elevated in colonoscopy biopsies taken from inflamed areas in patients with inflammatory bowel disease, and higher levels are correlated with greater disease severity. So, for those suffering from chronic autoimmune diseases, such as rheumatoid arthritis, NAD+ boosting could potentially have a “profound negative impact.” This explains why tamping down NAD+ with NAMPT inhibitors has been shown to ameliorate colitis and arthritis in mice. But this has yet to be tested in people. Such NAD+ depleting drugs have, however, been used in cancer patients.

Malignancy is another heavily energy-consuming process. NAD+ may, therefore, have a tumor-promoting effect by promoting cancer cell growth and spread. For example, NAMPT, the NAD+-forming enzyme, is highly expressed in cancerous brain tumors, and correlates with decreased patient survival. This has led to attempts to use NAD+depleting therapies to try to starve cancer progression. But this approach is confounded by rapid onset injury to another energy-intensive tissue, the retina, risking blindness.

Giving NMN to mice with pancreatic cancer accelerates the progression of the cancer, thought due to the aggravation of inflammation. The researchers conclude that consumers of NAD+ supplements must “balance the advantageous anti-ageing effects with the potential detrimental pro-tumorigenic side effects.” Perhaps this explains why the best NAD+ boosters have ever been able to do is increase mice lifespan by five percent.

On the other hand, as you’ll remember, NAM successfully prevented human skin cancers and has been found to reduce the incidence of a variety of carcinogen-induced tumors in rodents. The disparate results may in part be due to the disparate impact sirtuin activation may have on different cancers. Sirtuin activity can be overexpressed in some cancers (like thyroid carcinomas and lung metastasis) but reduced in others (like brain, bladder, prostate, and ovarian tumors).

The bottom line is that particular caution should be used for NAD+ boosting supplements by those with cancer, or a personal or strong family history of cancer, and perhaps also by those with inflammatory disorders and certain active infections.

In our next story, we look at how to naturally get your body to make more NAD+ by boosting the NAD+ synthesizing enzyme NAMPT.

So, which NAD+ boosting supplement is best? There’s no clear standout, as hardly any of the preclinical effects found in the lab have translated into evidence of human clinical benefit. Perhaps this failure is to be expected, given the complexity of NAD+ physiology with its juggling of multiple precursors, production pathways, and recycling routes. The bottom line is that it’s just too early to say if NAD+ booster supplementation will ever live up to even a fraction of the hype. Many more, larger, and longer-term studies are necessary to establish safety and efficacy.

The problem is that because NA, NAM, NR, and NMN are all natural products, they can’t be patented; so, the money for well-designed clinical trials is not as available. The reason there have been comparatively more trials done on NR than NMN is that patents were originally issued for NR before being invalidated as unpatentable.

Perhaps blindly overloading the system with NAD+ precursors is not the best way to go about NAD+ restoration. The body seems too smart to allow such blunt incursion to affect tissue levels. Maybe these supplements are just profit-making distractions from more natural approaches.

Broadly, there are three main ways to increase NAD+ levels. Increasing the supply of NAD+ precursors is just the first. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, via an inhibition of excess NAD+ degradation. The primary determinant of NAD+ synthesis is the enzyme NAMPT. An abundance of NAMPT tends to decrease with age in human muscle, dropping steadily by about 40 percent between the ages of 20 and 80. In our liver, it drops by half. However, age-related diseases, such as atherosclerosis, cancer, diabetes, and rheumatoid arthritis, have been found to exacerbate NAMPT decline, raising a chicken-or-the-egg question. There’s where interventional trials come in.

Similar NAMPT declines have been noted in aging rats and mice. Does boosting NAMPT help? Increasing NAMPT or its species equivalent increases the lifespans of yeast, fruit flies, and rodents. An NAMPT boost also increases aerobic capacity and exercise endurance in mice, in addition to helping them live longer.

Enhanced expression of NAMPT increases the NAD+ levels in the muscles in mice comparable to feeding them dietary NAD+ precursors. But if you remember, NAD+ precursors don’t seem to able to affect NAD+ muscle levels in most people. In fact, such supplements can actually suppress NAMPT, while boosting that methylating enzyme to rid the body of the excess. In addition to methyl depletion, chronic administration of these supplements could potentially then leave people worse off should they ever stop them.

There is, however, a way to naturally boost NAMPT and NAD+ levels in humans without any supplements: exercise. Athletes have about twice the NAMPT expression in their musculature compared to sedentary individuals. To prove cause and effect, sedentary men and women started a stationary bike exercise protocol, and within three weeks, NAMPT levels increased by 127 percent. Resistance training can also increase NAMPT, and this can also translate into a 127 percent increase in muscle NAD+ levels and a rise in sirtuin activity. In other words, exercise can do what NAD+ boosting supplements can’t.

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

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 calorie 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.