Over the years, the molecule nicotinamide adenine dinucleotide (NAD+) has gone from being a player in some biochemical pathways to a crucial substrate required by proteins that help control longevity and metabolism. NAD+ became the focus of research that found that levels of the molecule decline as people age, and it's related to neurodegeneration, cancer, diabetes, and other diseases that are associated with aging.
New work reported in Nature Metabolism has shown that chronic inflammation can reduce NAD+ levels. Senescent cells are cells that have ceased to divide and have been connected to aging. As the number of senescent cells increases, a molecule called CD38 (cyclic ADP ribose hydrolase) is activated, triggering the degradation of NAD. CD38 can be found on many immune cells' surfaces.
"We are very excited to link two phenomena which have been separately associated with aging and age-related disease," said senior study author Eric Verdin, M.D., Buck Institute President and CEO. "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."
While NAD+ levels are known to go down as age advances, Verdin noted that it was not known whether that decline was because NAD+ production was going down or if the molecule was degrading; in other words, if the problem was with the supply from the faucet, or 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 added that preliminary data indicates that NAD+ levels in some tissues can be restored by blocking CD38 activity in older animals.
Senescent cells, which cease to divide because they have accumulated damage in their DNA, can release proteins that promote inflammation, which is known as the senescence-associated secretory phenotype (SASP). Though senescence will protect the body from cancer at first, because DNA-damaged cells cannot divide, as these senescent cells accumulate, it seems that diseases including cancer start to become more likely.
"These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38, and degrade NAD+. It's a maladaptive process, but drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+," suggested study author Anthony J. Covarrubias, Ph.D., a postdoctoral fellow in the Verdin lab.
Sources: AAAS/Eurekalert! via Buck Institute for Research on Aging, Nature Metabolism
