The Link Between Senescent Cells and NAD+ Levels
We know that the CD38 molecule plays a role in the decrease of NAD+ in human tissue. A 2019 study, from the journal Biochemical and Biophysical Research Communications, helps explains exactly how.
CD38 is a molecule important for many different cellular processes, including calcium signalling, which regulates basic cell functions. However, too much CD38 is a sign of inflammation. Research has linked overexpression of CD38 to obesity, cancer, and infectious diseases, like HIV. Scientists also know that the presence of CD38 levels increase with age, and that CD38 is involved in decreasing levels of NAD+, an important molecule for all living tissues. CD38 is an NADase, or NAD+-consuming enzyme, meaning it needs NAD+ to function (much like sirtuins).
Supplementing with NAD+ does not necessarily increase CD38 activity. Rather, it increases the pool of available NAD+ for other vital functions.
Understanding the minutiae of how we age is crucial to understanding what can be done to slow or even reverse it. Both the decline in NAD+ and the presence of senescent cells (cells that no longer divide and resist death) are hallmarks of aging. But until recently, it was unclear exactly how rising CD38, declining NAD+, and the presence of senescent cells were all related.
Enter the latest study on CD38: “The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD decline.” For this study, published by scientists at the Kogod Aging Center at the Mayo Clinic College of Medicine, the researchers hypothesized that because senescent cells are known to secrete inflammatory chemicals (known as senescence-associated secretory phenotype, or “SASP” factors), perhaps it’s this phenotype that regulates CD38 expression and in turn, its breakdown of the all-important NAD+.
What They Studied:
Lead author Claudia Chini and her colleagues were interested in CD38 because prior research had established CD38’s key role in age-related NAD+ decline. And yet: “To date several aspects of the biology of this enzyme remain to be elucidated,” the authors write. “Surprisingly, the possible link between CD38 expression and the cellular senescence phenotype has not been explored.”
To study that link, the scientists collected samples of two types of human cells — endothelial cells from human umbilical cords and fat cells collected from two consenting female patients — as well as bone marrow cells from mice. These cell types were chosen for this in vitro (latin for “in the glass”) study because they have been shown previously to most closely mimic how cells behave in vivo (meaning “in life”).
The human cell samples were then irradiated to induce senescence (cellular senescence is caused not only by aging, but also by environmental factors like radiation, which causes DNA damage). And then the senescent cells were mixed with the healthy, non-senescent mouse bone marrow cells to mimic a cellular environment, where senescent cells and healthy cells live alongside one another.
Finally, using those combined samples, the scientists ran a series of tests to measure the presence of CD38 in the samples. They also measured different signaling molecules that could trigger a pro-inflammatory response as well as the signs of CD38 breaking down NAD+.
What They Discovered:
What the scientists found was two-fold: First, they observed that inducing senescence did not lead the senescent cells themselves to produce more CD38. But, the senescent cells did, as expected, begin secreting a cascade of inflammatory chemicals (SASP) that in turn, up-regulated CD38 in surrounding non-senescent cells. Interestingly, they found that different SASP factors did not individually evoke CD38, but when combined led to a strong increase in CD38 activity. In the end, the scientists observed this affect in all the types of cells tested.
What to Know Now:
In short, Chini and her colleagues demonstrated that CD38 expression in cells can be induced by factors associated with cellular senescence, which gives us a possible link between cellular senescence and the decline of NAD+. This adds on to the team’s growing body of research, which earlier definitively revealed that NAD+ declines largely due to CD38’s ability to catalyze it.
All of this matters because aging researchers consider cellular senescence and NAD+ decline as crucial to understanding the aging process. For example, this research may help inform the development of what’s known as senolytics, compounds that help clear out senescent cells and have shown great promise in lab studies. Or it may help scientists develop drugs that blunt or block the production of CD38.
Aging doesn’t have a single cause, so understanding how NAD+ is linked to other hallmarks of aging, like senescence, is what will help usher in the next generation of therapies that will help people stay healthier, longer.