Key Learning Objectives
- Discover why slowing CD38 is an indirect way to support better NAD+ levels.
- Find out what happens to CD38 as we get older and how this affects NAD+.
- Learn why slowing CD38 can help other NAD+ supportive strategies work better.
- Discover which nutrients support healthier CD38 function.
Why NAD+ Benefits from Slowing CD38
In our three-part series on How to Make NAD+ (see De Novo Synthesis, Preiss-Handler Pathway, and Salvage Pathway articles), we described direct ways to increase NAD+. These direct approaches had to do with (1) giving substrates (i.e., niacin equivalent precursors such as L-tryptophan, niacin, and niacinamide), and (2) improving the performance of NAD+ synthesizing pathways. Nutritional support of these direct approaches allows cells to make more NAD+.
In this article, we’re going to introduce an indirect way of supporting NAD+. Rather than making more, this article will be teaching you about using less. Using less requires downregulating a protein called cluster of differentiation 38 (CD38 for short). When CD38 is not as active, less NAD+ is used by it. The result is higher NAD+ levels and greater NAD+ availability for important healthy aging uses.
At the end of our introductory article to NAD+ consumption (see NAD+ Consumption Uses: An Overview), we wrote, “Less NAD+ is made during aging. And what we do make gets consumed differently. The goal is to address both … make more NAD+ and use it better.” You’ll find out in this article that CD38 is one of the ways NAD+ is used differently as we age. It’s also part of the reason NAD+ levels decrease as we get older.
A combination of making more and using less NAD+ is a more powerful NAD+ strategy than either on its own.
What is NAD+ Consumption and Why is it Important?
NAD+ is literally consumed (i.e., broken apart) for certain cellular signaling reactions. There are three main NAD+-consuming uses. One involves sirtuins. These are genes that turn on and off many other genes involved in healthspan and lifespan. Another is a group of enzymes called PARPs involved with cellular DNA repair. The third is CD38, a cellular second messenger used in calcium signaling. The key thing to remember is that there’s a finite pool of NAD+: if one consumption use is too active, it can, in a sense, starve the others.
NAD+ levels decline with aging. By the time we reach middle age, levels of NAD+ can be about half of youthful levels.[1] They can fall even further in older age.[2] Why do NAD+ levels fall as we get older? While there are several reasons, one major culprit is CD38.[3]
As you’ll discover in this article, expression and activity of CD38 gradually increases over the aging process—by older age it can be several fold higher in some tissues and cells. Since the three NAD+-consuming pathways—sirtuins, PARPs, and CD38—compete for the same finite pool of NAD+, when CD38 consumes too much, less is available for sirtuins and PARPs. The result is that the important jobs they do suffer. The way to reverse this is to slow CD38, which indirectly boosts NAD+ and leaves more of it available to be used by sirtuins and PARPs.
As we get older CD38 consumes more than its fair share of the NAD+ in our cells.
What is CD38 and What Does It Do?
Note: This section will be focused on some biochemistry of CD38. Feel free to skip past it understanding this isn’t important to you.
CD38 (cluster of differentiation 38) is encoded by the CD38 gene. It acts as an enzyme in several cellular reactions involved in calcium (Ca2+) mobilization and signaling. As part of the reactions NAD(P)+ is degraded (i.e., broken down). It can deplete NAD+ and/or NADP levels depending upon the tissue and the degree of enzyme activity. Because of the use of NAD(P) as part of the enzyme activity, CD38 plays a significant role in modulating NAD(P) homeostasis.
One of the CD38 reactions mainly generates ADPR and nicotinamide (NAM) when it consumes NAD+ (see below), but also produces cyclic ADPR (cADPR), a cellular second messenger involved in calcium (Ca2+) signaling.[4–10]
NAD+ + H2O (i.e., water) ⇌ ADP-ribose (ADPR) + nicotinamide (NAM)
Another CD38 reaction catalyzes the synthesis of nicotinic acid adenine dinucleotide phosphate (NaADP) from NADP and nicotinic acid (i.e., niacin).[11] NaADP is a second messenger and potent trigger for Ca2+ mobilization.[12,13] In this reaction NADP gets consumed, and so can become depleted if the enzyme activity is overactive.
CD38 is a type II transmembrane glycoprotein. This means it is permanently attached to and spans the entire width of cell membranes. CD38 is found on the surface of cells in tissues throughout the body (e.g., red and white blood cells, adipose tissue, heart, liver). The majority of its activity occurs outside cells in the surrounding medium; however, CD38 has been detected in intracellular organelles including the nuclei and the mitochondria.[14–16]
Because the majority of activity is extracellular, CD38 is believed to be a significant regulator of extracellular NAD+ pools, with increasing activity of CD38 depleting NAD+ and repression of CD38 increasing NAD+.[17]
In addition to its role in Ca2+ signaling and extracellular NAD+ homeostasis, CD38 is involved in immune and inflammatory responses, endothelial function, and cellular responses to low oxygen conditions.[18]
The key biochemistry point to remember is that CD38 is used in two enzyme reactions. If these enzymes are too active, NAD+ and NADP molecules get depleted.
What is the Role of CD38 in Aging and Poor Health?
Expression and activity of CD38 gradually increase with aging. As an example, in mice CD38 increased several fold with older age in all tissues tested including liver, kidney, fat tissue, and skeletal muscle. This is accompanied by both decreased NAD+ and activity of other NAD+ consumption uses (e.g., PARP1, SIRT1). In humans, a similar age-related increase has been reported in fat tissue, with expression of CD38 increased up to two and a half times in tissue obtained from older compared to younger persons.[3]
One of the nine hallmarks of aging is called cellular senescence.[19] Senescent cells are sometimes referred to as “zombie” cells, because they (1) aren’t fully functional (they can’t divide) but haven’t been killed off, and, (2) can turn nearby cells senescent because of molecules they secrete. While senescent cells do not have high expression of CD38, the senescent associated secretory phenotype (SASP) factors they secrete induce CD38 mRNA and protein expression and increase NAD+ consumption in non-senescent cells.[20] Another way of putting this is that senescent cells causes other cells to be bigger users of NAD+.
During aging NAD+ declines because it is, at least in part, being consumed by CD38 more rapidly than it can be produced.
Overexpression of CD38 has been linked to a variety of age-related functional and metabolic issues. In general, many of what would be considered the most common diseases of aging are characterized by excessive CD38 expression/activity.[21] Obesity is an example. CD38 is highly expressed in fat tissue of people with obesity.[22,23] In animals, CD38 activity appears to be required to create diet-induced obesity, while low expression of CD38 protects against obesity when fed high-fat diets.[24,25]
Sirtuins are a conserved longevity pathway, which means it has been passed on as organisms have evolved. Sirtuins are responsible for some of the health and longevity benefits that occur with calorie restriction. CD38 activity is involved with the regulation of sirtuins since both enzyme systems compete for NAD+ as a substrate.
Sirtuins use and degrade NAD+ as part of their enzymatic reaction, which makes NAD+ availability a limiting factor for sirtuin activity. When CD38 is less active, it leaves more NAD+ available for other purposes, including activating sirtuins, such as SIRT1 and SIRT3. This has been observed in mice bred to have low CD38 levels. These mice have higher NAD+ levels and increased SIRT1 activity compared with wild-type mice.[25] The inverse relationship between CD38 and SIRT1 has also been seen when CD38 inhibitor molecules are administered to animals.[3,16]
CD38 plays an important role in immune responses, causing migration of white blood cells toward sites of inflammation. In the process, CD38 consumes large amounts of NAD+.[5,6,22,26] Because of how CD38 is used in immune responses, the so called “inflammaging” that typically accompanies aging would be expected to stress NAD+ supplies substantially.
Why Does Slowing CD38 Boost NAD?
CD38 is a significant regulator of extracellular NAD+ pools, with a variety of different experiments showing profound effects on NAD+ levels depending on CD38 expression and activity.
The general rule of thumb is that as CD38 goes up, NAD+ goes down.[3,16] In mice, as an example, higher activity of CD38 is required for both (1) age-related NAD+ decline, and (2) mitochondrial dysfunction.[3]
The converse has also been true: When CD38 can be downregulated, NAD+ goes up. As mice age, similar to what occurs in humans, NAD+ levels decline in tissues.[27] If CD38 activity can be sufficiently lowered, mice are protected from the age-related NAD+ decline.[3]
In experiments where mice have been genetically engineered so their DNA does not express CD38 proteins, NAD+ levels are elevated in multiple tissues.[8,16,28] In other experiments, cells and tissues that repress CD38 increase NAD+.[17]
In preclinical experiments, slowing CD38 has produced large changes in NAD+ levels. As an example, in one study, adding a compound to the diet of obese mice that could inhibit CD38 boosted NAD > 5-fold in liver and >1.2-fold in muscle.[29]
Treatment of old mice with a CD38 inhibitor increased NAD+ in tissues where it was low, acting to prevent age-related NAD+ decline. It also led to improvement in physiological and metabolic parameters, including glucose tolerance, muscle function, exercise capacity, and cardiac function. And it activated pro-longevity and healthspan-related factors (e.g., sirtuins, AMPK), attenuated telomere-associated DNA damage, and reduced activity of several pathways that negatively affect health span (e.g., mTOR, ERK).[30]
Nutritional support with niacin equivalents allows cells to make more NAD+.[31] But these approaches might not work as well if CD38 is ignored. In addition to its effects on NAD+ levels, in an animal experiment, CD38 activity influenced the metabolic response to several NAD+ precursors (e.g., nicotinamide mononucleotide [NMN], nicotinamide riboside [NR]). NMN and NR were cleared more rapidly from the blood in normal mice, but stayed at higher levels longer in mice genetically designed to be deficient in CD38. NR also had a more pronounced effect on glucose tolerance in mice deficient in CD38.[3] This suggests that strategies aimed at boosting NAD+ by supplying niacin equivalents might produce better metabolic responses if CD38 activity is also lessened.
Supplementing niacin equivalents is a popular strategy to support better NAD+ levels. Evidence suggests we’ll get more out of these approaches if we also slow CD38.
How to Improve CD38 Function
Several ingredients support healthy CD38 activity. Apigenin modulates CD38. Treatment of cells with apigenin inhibits CD38 and promotes an increase in intracellular NAD+ levels. In mice fed a high-fat diet, treatment with apigenin decreased CD38 activity in the liver and increased intracellular NAD+ levels.[32]
Resveratrol is a part of a CD38 stack, because it is an apigenin bioenhancer. Co-administration of apigenin and resveratrol allows more apigenin to survive liver metabolism, resulting an a greater than doubling of plasma apigenin levels (compared to administration of apigenin alone).[33] Since CD38 is widely expressed in the liver but also throughout the body (including in blood and fat cells) getting more apigenin into circulation is an important part of getting the most CD38 support.
Proanthocyanidins (found for example in Grape Extract) downregulate CD38 and upregulate SIRT1, resulting in higher NAD+.[34]
Several other flavonoid molecules have effects on CD38 in cell cultures. These include Kuromanin (cyanidin 3-O-β-glucopyranoside)[36,37] (one of the main polyphenols in Strawberry Seed Extract), Luteolin (found in Rosemary Extract),[36] and Quercetin[32,38] (found in small amounts in Cocoa Extract and the Apple Peel component of ElevATP®)
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Edward OBrien