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 precede 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.



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


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 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 how much brain do you need to make some connections???

There is a patent for using NAC with dogs to prolong 70 lb dog gets 300 mg / 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

Just a note on inflammation.

I suffer from Crohn's disease in my colon so my inflammation levels (CRP and calprotectin) along with a load of other health measures are constantly monitored.

Since taking NR daily my blood work has been great and my inflammation levels have plummeted. I'm at remission levels now for the first time since diagnosis.

So, at least for me, NR has been nothing other than overwhelmingly positive.

Posted by: Matthew at June 3rd, 2019 3:37 AM

I started taking NMN for general health benefits. I am over 50. I have had back problems for years. The diagnosis is the common degenerative disk disease. The last few years have been particularly bad. My back would go into spasms getting out of a chair. Reaching across my desk my back would go into spasms. The background levels of pain never went below a 3.
After approx. 3 months of 375mg NMN per day, I noticed I could move pain free in ways that I couldn't before. After 6 months I would say I am pain free 90%. It has now been almost a year. For example, today I just spent 2 hours cutting down a tree with a chain saw, cutting it into pieces and bending and lifting the pieces to haul it away. Honestly, the thought of that much bending and lifting would have been horrifying a year ago. I would have viewed it as torture.
The only difference in my diet is 375mg daily of NMN.
I have seen no research on NMN and back problems. I didn't take it for that purpose to begin with. All I know is that I can now be active, and pain free and move in ways that I literally couldn't a year ago.

Posted by: Mark at July 21st, 2019 9:10 PM

I started intravenous NAD at a clinic last December to treat my ugly 11-year benzodiazepine dependency. The effects were phenomenal. After 12 day-long sessions, my use of benzos was cut by 80% and I am in the process of weaning myself off the last small doses (always the hardest step). I used to suffer from panic attacks and sweats upon waking up two or three times a week beforehand, and now they are gone. My generalized anxiety and OCD have also decreased. My mental clarity has improved.

I am 40 years old and injured myself in a gruelling summer job in my early 20s. I have suffered from chronic back and knee pain for 18 years. Inflammation runs in my family. Since beginning the NAD, my joint and muscle pain has dropped drastically, my energy has increased and I have gained about 10 lb. of muscle without lifting weights. My naturopath and I discussed this and theorized that the frequent cortisol spikes I used to get inhibited muscle growth for many years.

I continue to get an intravenous treatment once a month. I only have very good things to say about NAD. I question the findngs on inflammation because I have not experienced any problems of that kind.

Posted by: Kaiser at July 27th, 2019 2:21 AM

This could mean nothing but... wife's hsCRP went up after a 30-day of NR. Comments or your experiences appreciated.

Wife: 68 yo, female, T1 Diabetic (since her 20's.) Started a 30-day trial Elysium (dose is 2 capsules = 250 mg NR, 100 mg pterostilbene)
Blood test taken the day after the last dose showed high hsCRP (High Sensitivity C Reactive Protein) out of line with previous blood tests. Recent test was 5.461 mg/L
Normal range of values:
Low 3.0 mg/L
3.452 6/5/2017
2.181 8/10/2018
3.743 4/30/2019
5.461 9/6/2019 (current)

Posted by: Allen at September 10th, 2019 10:09 AM

Correction (due to the 'less than' and 'greater than' character, some of my last post got left out:
Should have read:

Normal range of values:)
Low 'less than' 1.0 mg/L
Average 1.0-3.0 mg/L
High 'greater than' 3.0 mg/L

Posted by: Allen at September 10th, 2019 10:14 AM

Thank you for the article. I am male, 62, good health, eat a regular low carbs diet, 175 lbs, take PQQ, Pterosilbene, CoQ10 (the typical mitochondria stack), lecithin, D3, K2, sometimes a good multivitamin (methyl formulated), Vita-E. I have done NMN for @ two years, for the last four months a rotate NADH with NMN (experiment). Since March I eat almost no vegetables (don't need any oxalates, lectins, phytates) with exception of olives and avocado for the oil. I daily take 2-3 Tbsp of coconut oil in my coffee (catechins; coffee, cocoa, cinnamon, green tea) throughout the day, sometimes with a tsp of butter. Most all meat is grass fed bovine, rotate with cuy (guinea pig), goat, sheep, turkey, and chicken, organs and fish weekly. I make my own butter from good cows (not always grass fed, darn). I try to get Brazil nuts. I fast. Sometimes two days, or three days, twice a year longer fasts. Since March I do not feel hungry much, I eat twice a day, once in a while once a day. If I eat three times a day, social occasions, I feel under-par the following day, but I will not eat vegetables.

So, what gives? I started on the NAD boosters about the same time I started to get inflammation of my tendons, 2016. First the neck-right shoulder area, then the left heel, then the left wrist, each one eventually going away just as they came on. When this all started I was up in the high Andean's for a few months, very cold nights (I live in Peru since years before). I thought the original pain was from the terrible bed and cold. Now (2019) I have bad shoulder tendon-ligament pain in my left and right arms; mostly right. If I sleep wrong I wake up unable to lift the arm of which side I was sleeping and it is very painful. If I move my arm wrong the pain is incredible. Weird is I lift light weights and exercise with nearly no problem at all.

I appreciate this article because the thought occurred to me to stop the NAD boosters. I have always wondered...What is going to happen to me when I can not purchase NAD boosters? Maybe learn to ferment my own bacteria? So I have been looking at the research and this is the first time I found something besides someone mentioning they suffered from joint pain in the Longecity forum not long ago, when they were taking NR(?), I think it was. So now I stopped all NAD boosters this week, life five days ago, to experiment if the inflammation/tendon-ligament pain reduces or goes away.

Plant based diet induces inflammation because the sugar is there (carbohydrate). I never experienced any problem, although I have never experimented with being a vegetarian. I have always gone for the articles and jazz of antioxidants, green leafy veggies, fruit, plant based diet stuff...because it is so prevalent in the news and Internet. Fake news I guess. Like religiously I used to drink the three P's every morning; Pineapple, Papaya, Platano (banana) and eat liver and fish, each once a week minimum along with lots of veggies, so as to get the Omega 3 and B-12. I did not feel any better, just felt mentally at peace, thinking that I was doing the right thing for my body. But then again I would get constipated, thinking it was part of the plan, although not liking that at all.

I have follow Dr. Sinclair and Dr. Bredesen since 2013; I don't care for dementia nor diabetes. Now I have included Dr. Jason Fung, Dr. Benjamin Bikman and some others. I feel good, I look good, I just need to find out what is happening with the shoulder pains. I call it inflammation because I don't know what else to call it. In the back of my mind I am hoping that it is not the NAD boosters either. So if this experiment is successful and the pain goes away, I will concentrate on a diet based NAD boost and see what happens then.

Anyone else with any NAD booster associated negative manifestations, please comment. Please. Thank you.

Posted by: Fat Slim at December 20th, 2019 2:34 PM

QUOTE: "Plant based diet induces inflammation because the sugar is there.."

Huh? You are confusing complex carbs with refined carbs. Where do you get your information? From an old Atkins pamphlet? Not every yahoo on Youtube knows what they are talking about.

And the reference to "fake news" is just bizarre: Most people have the basic knowledge to distinguish drinking fruit juices (not really healthy, lots of sugar) from eating whole fruits and vegetables (healthy).

Just one example:

Posted by: Bob at January 11th, 2020 9:01 PM

Is it possible that increasing SASP could be beneficial? If NAD+ actually increased SASP then wouldn't this send a stronger signal to the immune system to get rid of the senescent cell?

Posted by: Brian Dravis at January 19th, 2020 3:19 PM

quote " 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"

Which products did you give your dog?

Posted by: Frank Sabia at February 10th, 2020 8:08 PM

I would also be interested to know what NAD+ product Katie is giving to her dog, or if there is any research on that. Would love to give my 9 year old 75 lb. mix something if it would be beneficial. He is very healthy except for some arthritis so I wouldnt want to do something that would increase inflammation.

Posted by: dave hall at March 28th, 2020 1:24 AM

I have been taking NAD for 3 weeks. I`m 50 years old and has an active lifestyle. Running and gym almost every day but I always had joints pain around level 2 or 3 with some inflammation. Amazing result after the second week. Every movement was easier, my inflammation level went down, energy level up, but I had some weird pain in the back of my head and neck some kind of stiffness after 30 min I take the NAD supplement. the stiffness disappeared after an hour or two. I went down to 1 pill (300mg) every 2 days and it seams the stiffness is not there anymore but energy level is still up and no inflammation.
Anybody had experienced the stiffness in the back of the neck, head area?

Posted by: Beatrix Balog at November 5th, 2020 11:24 AM

"The results here suggest that efficient senolytic treatments to selectively destroy senescent cells should proceed any of the current approaches"

Precede. Document correction. I'm not into correction often, but the current word 'Proceed" is very different from the word precede.

Posted by: MIC at February 4th, 2022 1:40 PM

@MIC: Corrected, thanks.

Posted by: Reason at February 4th, 2022 1:58 PM

@Beatrix Balog
I was taking Niacin, doing some fisetin. I witness much larger effects even from a couple of days of fasting.
YMMV, though.

Posted by: Cuberat at February 4th, 2022 5:03 PM

Yes, I also get the stiffness in the back of the head when taking 300mg of NMN powder.

Posted by: Francis at October 24th, 2022 6:20 AM

I have been taking NMN supplement for over 2 weeks, 250 mg per day. Amazingly, it stopped my chronic backache which lasted for 5 years. However, I have developed very big pain in my lower left leg instead, and I think it is NMN related. I don't want to stop taking NMN , it has so many benefits... What should I do?

Posted by: Kate at November 15th, 2022 4:43 AM

I just started taking nmn. I developed sore hands wrists, feet and ankles. I stopped and read started… sure enough the soreness went and returned, coinciding with nmn. I feel awful and don't know why. Any insights?


Posted by: Sophie at February 15th, 2023 7:05 PM

I started to notice stiffness in the back of the neck, at about the same time I started taking 500mg of NMN on a daily basis. Not sure that is the cause, could be a coincidence.

Posted by: Valério Marques at July 5th, 2023 11:31 AM
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