Boosting Levels of NAD+ May Make Senescent Cells More Aggressively Inflammatory

Enhancing levels of NAD+ in mitochondria via delivery of various precursor compounds as supplements is growing in popularity as an approach to boost faltering mitochondrial function and thus modestly slow the progression of aging. A human trial demonstrated improved vascular function as a result of nicotinamide riboside supplementation, for example. Researchers here show that increased NAD+ will likely make worse the inflammatory signaling of senescent cells, however. Senescent cells accumulate with age, and are an important cause of the chronic inflammation of aging that drives the progression of many age-related diseases.

The results here suggest that efficient senolytic treatments to selectively destroy senescent cells should proceed any of the current approaches to raising levels of NAD+ in older individuals - and it is an open question as to whether any of the existing available options are efficient enough to make NAD+ enhancement safe in the longer term. Those people self-experimenting with NAD+ precursor supplementation should consider keeping a close eye on markers of inflammation.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest.

NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

Link: https://doi.org/10.1038/s41556-019-0287-4

Comments

I am not a NAD advocate, but this seems very hypothetical. Maybe I am missing something

Posted by: JohnD at May 6th, 2019 1:53 PM

Several thoughts:

1) Lots of people are using NAD+ boosters these days. Some use NR; some use NMN; some take the inexpensive old standbys, niacin and nicotinamide. We don't really know, in the long term, whether doing so will be beneficial or not. But there's enough evidence of benefits, it makes sense to many of us to keep taking them.

2) It makes sense also that if we're going to use NAD+ boosters, we should first try to keep our senescent cell populations under control. (Some senescent cells may be beneficial, but most seem problematic. So, best to keep their populations tightly controlled.)

3)Senescent cells are destroyed by prolonged fasting, and also by taking senolytics such as fisetin. When I'm fasting (and taking senolytics), I don't take NAD boosters (though I do take resveratrol and pterostilbene, which help the body use NAD+ more effectively). At the end of a fast, I go back to taking NAD boosters again.

4) It's all a big experiment, of course. But alternating periods of fasting and taking senolytics with periods during which we are taking NAD+ boosters a reasonable way to keep getting the benefits of higher NAD levels while dealing with the senescent cell problem.

Posted by: Nils at May 6th, 2019 4:01 PM

@Nils

I would appreciate if you can provide some detailed information about your fasting regime.

How many days are you fasting? Is it pure water fasting?
What is your dosage of Fisetin and Pterostilbene during your fasting?
How often do you fast?

Thanks in advance.

Posted by: Stephan at May 6th, 2019 5:40 PM

Nils, is there really any solid evidence which indicates that fasting destroys senescent cells and that some senescent cells might be beneficial (outside of wound healing)?

Posted by: Florin at May 6th, 2019 6:00 PM

I think the research by Valter Longo suggests or demonstrates some of the positive effects of fasting. He seems "data driven."

Posted by: John Gibson at May 6th, 2019 7:50 PM

My dog has been on NAD booster for 2 years and a telomere product too. She looks fantastic and have heaps of energy no sign of slowing down. Turns 16 this year and the vet has commented how great she looks, and little grey hair she has for a dog of her age. The NAD gives her energy for sure.

Posted by: katie Larking at May 9th, 2019 7:04 AM

Exercise boosts NAMPT so this makes no sense at all. Charles Brenner also had some fair criticism.

Posted by: Nathan at May 11th, 2019 11:31 AM

Did anyone of FA crowd read the complete article? Since biological pathways are messy, it would not be surprising to find side effects of any supplement. Here it depends, if the study was done in vivo, and what was the exact protocol...

Posted by: Cuberat at May 11th, 2019 12:34 PM

"..Those people self-experimenting with NAD+ precursor supplementation should consider keeping a close eye on markers of inflammation.."
I wonder what you would include as there are quite a few. I keep track in blood of CRP, ferritin, ESR, fibrinogen, IL-6, TNF-alpha, leucocytes.

Posted by: albedo at May 11th, 2019 11:51 PM

katie, I would be interested in knowing what NAD booster you are using with your dog and what dosage you are using. Also, it would be helpful to know the breed and weight of your dog. Thanks.

Posted by: Robert Atwell at May 12th, 2019 12:39 AM

I take 125 mg / day Niagen and also a few senolytics. Since some supplements are expensive and the research is not all that adequate...I hedge my bets by taking a bit of everything...expecting synergistic effects. My BMI is just under obese levels...but the stat I pay attention to is the one saying avg life expectancy is around 85 for anyone over 65 or so....I'm almost 1/2 way there. Will be looking to lose some weight.

I also take several supplements that are supposed to reduce inflammation...such as curcumin...etc.

Of course real life isn't going to pay any attention to the stats...so who knows.

The process of aging is one of trying to avoid aging issues and the downsides...not waking up as a teenybopper one day. Those I know seem to be OK with the traditional processes of aging such as their parents and grandparents went through...and they are experiencing the same...while I'm dragging my feet.

I see the brick wall up ahead and I think I know how old I am...so how much brain do you need to make some connections???

There is a patent for using NAC with dogs to prolong life...my 70 lb dog gets 300 mg / day...plus glucosamine...COQ10...etc. I use Setria and MAP amino acids.

A lot more research coming out now as far as protein levels vs sarcopenia and aging...I'm in the process of upping my protein intake...but trying to avoid CAFO sources. Best bet is 1.5 to 2xs the established recommended levels?

Posted by: roger at May 14th, 2019 8:24 AM

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