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NAD boosting to reverse senescence and inflammaging

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Senescent cells promote NAD tissue decline during aging through CD38 enzymes which can now become a novel therapeutic target.

Nicotinamide adenine dinucleotide (NAD) is a crucial metabolic coenzyme and reducing cofactor for oxidising enzymes such as poly-ADP-ribose polymerases (PARPs). Low levels of NAD have been linked to aging diseases and more recently it has been established that natural NAD levels decrease with age – yet the mechanisms behind the pathogenic effects of decreasing NAD remain elusive.

Longevity.Technology: NAD can be made in the body in two ways: through the de novo pathway from tryptophan or the salvage pathway from precursor vitamins nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). The levels of NAD are therefore dependent on synthesis, metabolic consumption, as well as NAD hydrolase enzymes such as CD38 and CD157.

A study by Camacho-Periera et al. found that CD38 specifically dictates age-related NAD decline and mitochondrial dysfunction, one hallmark of aging [1]. Yet, specifically what cells and mechanisms are behind rogue CD38 expression during aging were not explored.

Dr Yie Liu’s team has experimented on mouse fibroblast cells and established that natural NAD decline was correlated with telomere dysfunction, a key marker in aging. In fact, they found that NAD supplementation ameliorated telomere dysfunction by restoring NAD levels.

CD38 is expressed in immune cells and increases with inflammatory conditions; aging is accompanied by a low chronic inflammation known as inflammaging.

The authors of a novel study published in Nature Metabolism focus on CD38, NAD levels and Longevity. They note that “sustained activation of the immune system is energetically costly” – they set out to find potential links between age-associated NAD decrease and inflammation, with a focus on two major metabolic tissues: visceral white adipose tissue and liver cells [2].

 


 

“We found adipose tissue from old animals to be significantly more inflamed, have increased accumulation of senescent cells and macrophages, a noticeable shift in macrophage activation to a pro-inflammatory M1 state characterised by increased CD38 expression.”

 


 

To begin with, a type of immune cell called macrophages in the adipose tissue were studied. M1 macrophage activation was found to increase CD38 and CD157 expression and thus enhance NAD degradation. Furthermore, the de novo pathway was not found to significantly contribute to NAD synthesis in aging macrophages – in fact the NAM salvage pathway was established as the primary and main regulator of NAD levels.

These M1 macrophages expressed CD38 almost exclusively as the NAD degrading enzyme. Using knock-out mice it was established that while CD157 may indirectly influence NAD levels in M1 macrophages through NR consumption, the enhanced NADase activity came from CD38.

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Furthermore, mRNA levels in wild-type mice were monitored to probe for a link between age-related NAD decline and inflammation. The authors conclude, “We found adipose tissue from old animals to be significantly more inflamed, have increased accumulation of senescent cells and macrophages, a noticeable shift in macrophage activation to a pro-inflammatory M1 state characterised by increased CD38 expression.”

Senescent cells are known to contribute to inflammaging along with some microbial endotoxins, which were also considered in this study. After myriad experiments and controls, Dr Eric Verdin amassed both in vivo and in vitro data proof that both microbial and senescent cell inflammatory cytokines, known as senescence-associated secretory phenotype, are crucial in NAD levels and CD38 expression in macrophages.

These results were consistent in liver resident macrophages – Kupffer cells. The team also had an unexpected observation that Kupffer cells from aged animals tended to cluster, thus hinting towards NAD levels having an effect on tissue organisation and changing gene expression patterns.

This detailed and extensive research paper gives a promising therapeutic target for senolytic drugs – by inhibiting CD38 NADase activity, NAD homeostasis can be restored thus potentially preventing or treating Longevity diseases.

In the field, it is well established that the selective killing of senescent cells during aging can increase mortality and delay aging, Dr Eric Verdin continues to amass evidence for this.

Despite the senolytic and Longevity field growing exponentially, it is not surprising to Dr Verdin that Big Pharma has been reluctant in dabbling their toes in the Longevity treatments.

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Dr Eric Verdin comments: “Aging interventions are intensely disruptive to Big Pharma’s business model, which is traditionally organised into therapeutic areas … [Aging intervention] doesn’t fit in the traditional field of medicine. One of the biggest challenges is convincing people that we should be studying disease in the Longevity context that is universal across different organs [3].”

[1] https://pubmed.ncbi.nlm.nih.gov/27304511/
[2] https://www.nature.com/articles/s42255-020-00305-3
[3] https://www.lsxleaders.com/longevity-leaders-congress/resources/an-interview-with-eric-verdin-buck-institute-for-research-on-ageing

Eleanor Garth
Deputy Editor Now a science and medicine journalist, Eleanor worked as a consultant for university spin-out companies and provided research support at Imperial College London and various London hospitals in a former life.
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