Researchers show that an enzyme called p38gamma that prevents toxicity associated with memory loss. CD38 on immune cells exhausts levels of an essential molecule for life called NAD+ and its precursor NMN during aging.
The vital compound nicotinamide adenine dinucleotide (NAD+) binds to enzymes in cells involved in reactions that generate energy for the body and enzymes called PARPs and sirtuins to maintain the health of cells. Levels of NAD+ decline with age, which contributes to the dysfunction of life-sustaining chemical reactions (metabolism) and reduced overall physical fitness, but how this happens isn’t clear. Scientists have proposed multiple mechanisms for how the levels of NAD+ in cells decline during aging: a reduction in levels of an enzyme in cells involved in the synthesis of NAD+ called NAMPT, an increase in consumption of NAD+ by a DNA repair enzyme PARP1, and an increase in the levels of an enzyme called CD38 that consumes NAD+. The inhibition of CD38 preserves NAD+ tissue levels during chronological aging, yet several aspects of CD38’s role in consuming NAD+ have remained unclear in the aging research field, such as which cells possess CD38 during aging, what drives increased levels of CD38, and what role does CD38 play in regulating levels of NAD+ and its precursor molecules.
Chini and colleagues from the Mayo Clinic in Rochester, Minnesota, published a study in Nature Metabolism indicating that the presentation of CD38 on the exterior of immune cells increases with age due to inflammation resulting from aging processes and that the accumulation of CD38 leads to decreased levels of NAD+ and its precursor molecule, nicotinamide mononucleotide (NMN).
Evidence indicating CD38 enzymes from immune cell surfaces reduce NAD+ levels came from experiments where the scientists transferred bone marrow between mice. Genetically altered mice without CD38 enzymes received bone marrow from normal mice because the marrow from normal mice contained stem cells that can restore the presence of cells with CD38 enzymes. In tissues that typically contain high levels of immune cells like the intestine and spleen, NAD+ levels decreased as CD38 activity increased in the mice without CD38 that had CD38 activity restored with bone marrow transplantation, suggesting that CD38 diminishes NAD+ levels.
The results of the study also suggested that inflammation induced the accumulation of immune cells with CD38, leading to decreased NAD+ and NMN levels. Treatment of fat tissue called white adipose tissue (WAT) with an inflammation-inducing molecule called lipopolysaccharide led to reductions in NAD+ and NMN levels. An experiment where the scientists again transferred bone marrow from normal mice to mice without CD38 showed that inflammation from lipopolysaccharide administration exacerbated the effects of CD38 in reducing NAD+ and NMN levels. This shows that inflammation can increase CD38’s consumption of NAD+ and NMN.