Senescent Cells Contribute to Lowered NAD+ Levels in Aging

Mitochondria are the power plants of the cell, packaging the chemical energy store molecule adenosine triphosphate that is used to power cellular processes. NAD+ is important to mitochondrial function, but levels fall with age for reasons that have yet to be fully explored. The outcome is less efficient mitochondria, a decline that is implicated in the onset and progression of numerous age-related diseases. Reduced mitochondrial function means less functional cells, tissues, and organs, and particularly so in energy-hungry parts of the body such as the brain and muscles.

The research and development community has become increasingly interested in ways to boost NAD+ levels in order produce benefits to metabolism and tissue function in older individuals. So far, supplements based on vitamin B3 derivatives are the most studied approach, with results in old people that appear to be in the same ballpark as those produced by structured exercise programs. Combining those two approaches might be better still, but there is no evidence as yet as to whether or not that is the case, and these are still not radical reversals of the impact of aging. We all understand the bounds of the possible when it comes to what exercise can do for an older individual. It might be technically rejuvenation, in some ways, but only mildly so.

Can the medical community do better by identifying and targeting the deeper causes of NAD+ decline? In today's research materials, scientists demonstrate that at least some of this decline is due to the chronic inflammation that is characteristic of aging. They specifically call out the inflammatory signaling generated by senescent cells as a contributing cause, and reinforce the known link between CD38 expression and loss of NAD+. This is great work, and exactly the sort of thing we'd like to see more of in the future, strengthening the connections between known deeper causes of aging and known manifestations of aging, and thus bolstering the case for targeting those deeper causes in order to effectively treat aging.

Chronic inflammation causes a reduction in NAD+

NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism, declines with age. This previously unexplained phenomena is associated with numerous age-related diseases and has spawned the development of many nutritional supplements aimed at restoring NAD+ to more youthful levels. Researchers have now identified chronic inflammation as a driver of NAD+ decline. They show that an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD via 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.

Experiments were done in mice and involved metabolic tissue from visceral white fat and the liver which were examined during aging and acute responses to inflammation. The work was validated in primary human macrophages. "Our initial hypothesis was that CD38 activation would be driven by inflammation. But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise."

Senescent cells, which stop dividing in response to DNA damage, spew a multitude 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 course of a lifetime, the SASP drives low grade chronic inflammation which is associated with age-related 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. But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+."

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels.

We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence, and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Comments

So basically a senolytic not only clear senescent cells but also boost NAD+ . NAD+ supplements might be useless after all.

Posted by: Jonathan Weaver at November 18th, 2020 4:23 PM

In my mid-sixties, I do resistance exercise 5 days a week and I also practice fasting, both are known to raise NAD+ levels. For six months I have taken an NAD+ booster that claims a 60% increase in NAD+, the following 6 months a different one that claims a 260% increase.

In both cases, I haven't noticed any difference. What happens at the cellular level I can't tell.

Posted by: Stephan at November 18th, 2020 9:40 PM

"So basically a senolytic not only clear senescent cells but also boost NAD+ . NAD+ supplements might be useless after all." - a hasty conclusion not supported by the data.

Posted by: Steve Hill at November 19th, 2020 6:54 AM

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