NAD+ (nicotinamide adenine dinucleotide), an integral metabolite central to an efficient and healthy metabolism, also declines with age. This previously unexplained phenomena is associated with numerous age-related ailments and has spawned the development of many nutritional supplements aimed at restoring NAD+ into more youthful levels. Publishing in Nature Metabolism, researchers at the Buck Institute have identified chronic inflammation as a catalyst of NAD+ decline. They show an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD through the activation of CD38 (cyclic ADP ribose hydrolase) a protein that is found on the cell membranes both inside and on the surface of many immune cells.
“We are very excited to link two phenomena which have been separately associated with aging and age-related disease,” said Eric Verdin, MD, Buck Institute President and CEO and senior author of the paper. “The fact that NAD+ decline and chronic inflammation are intertwined provides a more holistic, systemic approach to aging and the discovery of CD38 macrophages as the mediator of the link between the two gives us a new target for therapeutic interventions.”
The faucet or even the sink? Or both?
Scientists have been aware that NAD+ levels decrease with age. Verdin says what has not been clear is whether the decline stems from decreased production of NAD+, a issue with this “faucet,” or out of its degradation, an issue like a “leaky sink”. “Our data suggests that, at least in some cases, the issue stems from the leaky sink,” he said, “Ultimately I think supplementation will be part of the equation, but filling the sink without dealing with the leak will be insufficient to address the problem.” Verdin says preliminary data suggests that blocking CD38 activity in older animals restores NAD+ levels in specific tissues.
Unique Buck collaboration drives the study
The research, led by Anthony J. Covarrubias, PhD, a postdoctoral fellow at the Verdin lab, also included Buck professor Judith Campisi and her lab, which is famous internationally for pioneering work in the field of cellular senescence. Tests were performed in mice and entailed metabolic tissue from visceral white fat and the liver which were analyzed during aging and severe responses . The job was confirmed in primary human macrophages. “Our initial hypothesis was that CD38 activation would be driven by inflammation,” Covarrubias said, “But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise.”
Inflammaging: Cellular senescence and the SASP
A large number of pro-inflammatory proteins, called the senescence-associated secretory phenotype or SASP. Evolution selected cellular senescence as a protective measure against cancer; but as senescent cells accumulate in tissues over the span of a lifetime, the SASP compels low grade chronic inflammation that is associated with celiac disease, including late life cancer. “These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38 and degrade NAD+. It’s a maladaptive process,” said Covarrubias, “But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+.”
NAD: Essential for lifestyle
NAD+ is located in each cell; it boosts cellular energy generation and supports mobile metabolism. NAD is also crucial for the action of sirtuins which have international anti-aging properties. Assessing our cellular metabolism into a cash economy, Verdin explains NAD+ as the Armored trucks which move money between institutions. “Money is the fuel. If you can’t transport the money, then the whole economy comes to a halt. It all comes crashing down. That’s how important NAD+ is to our cellular health and we look forward to applying this discovery to our efforts to stem the ravages of age-related disease.”
Related Journal Article: https://www.nature.com/articles/s42255-020-00305-3