Research & Education

Inflammation Reduces NAD+ Status

Chronic, low-grade inflammation can have a significant impact on many body processes. Studies have found a link between chronic inflammation and the development of common chronic diseases, including cardiovascular disease, cancer, diabetes, non-alcoholic fatty liver disease, metabolic syndrome, autoimmune disorders, and neurodegenerative disorders, such as Alzheimer’s disease. It has also been shown to play a role in aging and age-related dysfunction and disease.

Many contributing factors activate the inflammatory response and affect its impact on function, one of which may be that inflammation reduces nicotinamide adenine dinucleotide (NAD+) levels. NAD+ is an important molecule located in every cell of the body and is involved in many key functions, including cellular metabolism, energy creation, DNA repair, and gene expression. Studies have found that NAD+ levels decrease in aging and potentially play a role in age-related disorders.

A possible link between increased inflammation and decreased NAD+ levels is the activation of CD38. This enzyme, found in immune cells, forms cyclic adenosine diphosphate (ADP)-ribose (cADPR), ADP-ribose (ADPR), and nicotinamide (NAM). The cADPR and ADPR mediate intracellular calcium signaling, and NAM is a byproduct that enters the salvage pathway to be synthesized back into NAD+. CD38 plays a role in mitochondrial dysfunction, inflammation, immune response, metabolic disease, diet-induced obesity, cancer, oxytocin release, and social skills.

It may just be one of several NAD-consuming enzymes that are part of the more than 500 enzymatic reactions in which NAD+ plays a role, but CD38 is a major consumer of NAD+, as 100 molecules of NAD+ are necessary to generate just one molecule of cADPR. CD38-deficient mice have been found to have 10 to 20 times the NAD+ levels as their wild-type counterparts. During inflammatory conditions, the expression of CD38 increases, which likewise increases the amount of NAD+ required, lowering the overall NAD+ levels in the body. A recent study elucidated some of the mechanisms behind this activity.

In a human cell and mouse study, researchers found increased expression of CD38 in white adipose tissue and the liver in aging. Investigators observed pro-inflammatory M1 macrophages and found an increased expression of CD38, NAD+-glycohydrolase (NADase), and the NAD+/CD38 activity byproducts NAM and ADPR. The CD38 levels were higher in the older mice compared with the younger ones, as well as the mice who were in a pro-inflammatory state due to treatment with lipopolysaccharides. During both acute and low-grade chronic inflammation, there was an increase in CD38 activation. The researchers determined that the change in NAD+ levels were solely due to this increase in CD38; this could be one reason for reduced NAD+ levels in older age.

The researchers also concluded that senescent cells drove this increased activity in the liver and white adipose tissue. Senescent cells stop dividing when there is DNA damage and excrete pro-inflammatory proteins. Senescent cells have been shown to increase progressively in both adipose tissue and the liver as one ages, demonstrating a potential causal link between this increase of senescent cells and NAD decline in aging due to the activation of CD38.

This study, as well as others, begins to uncover some potential mechanisms behind aging and many age-related conditions. More research is necessary to discover more of the mechanisms behind the link between chronic inflammation, NAD+ levels, and chronic disease. Supplemental substrates of NAD+, such as nicotinamide mononucleotide (NMN), may support normal NAD+ levels and healthy aging.

By Kendra Whitmore, MS, CNS