The last months have seen a couple publications highlighting a link between the expression and activity of the NADase CD38 and the declining levels of NAD+ as we age. This protein CD38 is multi-functional and serves not only as an antigen but also as an enzyme for various processes. NAD+ is basically found in every cell in the body and is essential to life. NAD+ enables the transfer of energy from the foods we eat to vital cell functions. It is also required to “turn off” genes that accelerate degenerative aging processes by supporting the activity of Sirtuins amongs others.
For some time it is known that in the case of NAD consumption, enzymes such as poly (ADP-ribose) polymerases (PARPs), NAD-dependent deacetylases (Sirtuins), and NADases such as CD38 degrade this molecule during their catalytic processes. The enzyme CD38 is known as one of the main NAD-degrading enzymes in mammalian tissues. CD38 was originally identified as a cell-surface enzyme that plays a key role in several physiological processes such as immune response, inflammation, cancer, and metabolic disease. Treatment of obese mice in the past with CD38 inhibitors increased intracellular NAD levels and improved several aspects of glucose and lipid homeostasis.
What is new is that in this study the researchers showed that expression and activity of the NADase CD38 increases strongly with age. Its rise correlates strikingly with the age-related NAD decline and mitochondrial dysfunction, possibly via a pathway mediated at least in part by regulation of SIRT3 activity. They also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN), indicating further that CD38 has a key role in age related and metabolic changes and diseases. The study did not reveal why CD38 rises exponentially. However CD38 has been linked to inflammatory processes which are known to increase as we age. The exponential rise suggests that CD38 may deplete NAD+ needed for other processes. That makes the containment of CD38 activity and the underlying causes an area of investigation.
This also puts new perspective on a study carried out in the end of 2013 showing that both quercetin and the flavonoid apigenin increase NAD+ levels via inhibition of CD38. Flavanoids are known to posses anti-inflammatory and anti-inflamatory properties.
The researchers noted that in small scale studies CD38 knockout mice (mice that that cannot produce CD38) have increased average and maximum life span compared with wild-type mice when they are fed a high-fat diet. However, in the PARP1 knockout mice, which also have increased cellular NAD+ levels, the outcome was opposite this, with the PARP1 knockout mice having a decreased life span compared with the wild-type mice. This difference in survival could be explained by the fact that PARP1 is involved in genomic stability and DNA repair both in the nucleus and in mitochondria and suggests that the CD38 is somewhat less critical.
In the study it was demonstrated that apigenin and quercetin promote an increase in NAD+ levels through inhibition of CD38, resulting in changes in protein acetylation, most likely through stimulation of SIRT1. They noted as well that, interestingly, CD38 is also present and active in the mitochondria, where it may regulate mitochondrial NAD+ levels and mitochondrial sirtuin activity. Other important findings were that pharmacological inhibition of CD38 can contribute to a strategy to treat obesity and obesity-related diseases.
Overall the results demonstrated that combating the rise of CD38 is a promising approach to protect NAD+ levels and hence promote sirtuin actions and treat metabolic diseases. It also adds to growing evidence that supplementation with quercetin provides health benefits. Unfortunately the mice where injected with quercetin so no further guidance on oral dosing can be derived from the study.