Nicotinamide Supplementation Looks Little Better than Resveratrol in Mice

Hopefully the Fight Aging! audience recalls the years-long hype over resveratrol, driven by the self-serving processes that enabled investors in Sitris Pharmaceuticals to make a sizable profit at the expense of GSK, and supplement sellers to open up a new market for the credulous. The only meaningful results from all of that turned out to be an increased knowledge of the biochemistry of sirtuins, one very thin slice of the broad metabolic response to calorie restriction. Resveratrol and its ilk are not meaningful calorie restriction mimetics, and you are far better off cutting a few hundred calories from your daily intake or exercising a little more.

In light of this history I think it is entirely appropriate to be skeptical of the current hype surrounding the role of NAD+ in metabolism, and the various precursor molecules that can increase levels of NAD+ when taken as dietary supplements. When compared with sirtuins and resveratrol, the publicity here involves many of the same people, similar for-profit companies engineering the news cycle, and the same area of cellular biochemistry, which is to say aspects of calorie restriction closely related to sirtuins. My expectation is that, at the end of the day, this will result in nothing more than another increase in the knowledge of this portion of cellular biochemistry, while all the other claims regarding longevity and health are largely smoke and mirrors. Some people will make a lot of money, supplement sellers will prosper, and nothing will meaningfully change in human health as a result of all of this.

The first study in mice noted below is very similar in outcome to past studies of resveratrol, which is to say little in the way of gains in healthy mice, and some compensation for the detrimental effects of being overweight or obese. It is important to remember that mouse longevity is far more plastic than that of humans in response to calorie restriction and interventions that affect the same portions of cellular biochemistry as are involved in the calorie restriction response. Mice live 40% longer when calorie restricted; in humans the gain is unlikely to be larger than a few years, even though the observed health benefits are sizable. So an alleged calorie restriction mimetic that produces no gain in mouse longevity, or only helps to make overweight mice less metabolically abnormal, is not all that interesting. You might compare this with the second paper, which is a commentary from the usual suspects on how great the prospects are for supplementation related to NAD+ levels.

Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice

The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+, is elusive. In the present study, we aimed to characterize the effects of chronic NAM supplementation on the longevity and healthspan characteristics of male C57BL/6J mice fed a synthetic low-fat diet (SD) and the corresponding high-fat diet (HFD). Because of the liver's importance in maintaining metabolic homeostasis, we carried out histological, biochemical, and untargeted metabolomics surveys to provide an unbiased view of the metabolic impact exerted by 62-week NAM supplementation on liver from SD- and HFD-fed mice.

Protein target validation combined with metabolic flux analysis enabled the identification of the underlying mechanisms of enhanced glucose disposal and reduced oxidative stress in response to NAM supplementation. Surprisingly, our data showed that NAM depresses NAD salvage and has complex effects on sirtuin expression and activity. NAM appears to have greater beneficial effects in mice subjected to HFD than SD, which might provide important clues about its therapeutic potential in the fight against obesity and associated comorbidities.

We report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Analysis revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Nicotinamide adenine dinucleotide (NAD) is one of the most important and interesting molecules in the body. It is required for over 500 enzymatic reactions and plays key roles in the regulation of almost all major biological processes. Above all, it may allow us to lead healthier and longer lives. Much of the renewed interest in NAD over the last decade can be attributed to the sirtuins, a family of NAD+-dependent protein deacetylases (SIRT1-7). Sirtuins have been shown to play a major regulatory role in almost all cellular functions. At the physiological level, sirtuins impact inflammation, cell growth, circadian rhythm, energy metabolism, neuronal function, and stress resistance.

By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

Comments

"I think it is entirely appropriate to be skeptical of the current hype surrounding the role of NAD+ in metabolism, and the various precursor molecules that can increase levels of NAD+ when taken as dietary supplements"

Skeptical of supplements yes but not of the role of NAD+ in aging and metabolism which is supported by credible research and numerous studies. The fact that NR is poor at converting into NAD+ due to the steps it requires and the loss in that process, is still not indicative that NMN which is directly in the scavenging cycle or other more robust and direct approaches will not yield useful effects. NAD+ is central to cellular metabolic processes and signalling. The trick here is how efficiently you increase NAD+ and the increase of that, I remain skeptical of NR and so on but there are far better solutions in development.

Posted by: Steve Hill at March 19th, 2018 3:41 PM

And by far better I am not talking about NMN either but relating to some of the unpublished data at Undoing Aging and non-drug molecule approaches.

Posted by: Steve Hill at March 19th, 2018 3:43 PM

Steve, you were just at Undoing Aging and have your ear pretty close to the ground... how much work is going on that we don't know about? As in unpublished data etc. No breaking non-disclosures etc, but it seems to me that behind closed doors a lot more is going on than we know.

NAD+, telomere work, AGEX and ITR, and the various science that George Church is up too. Last year at the Master Investor show, Lindsay Wu was talking about a compound that extended life in mice by 80% and had the bonus of being a treatment for obesity and diabetes. If so.. this is big news, but they are keeping it quiet at this stage except to private investors.

Souce: Skip ahead to the 9:20 mark.
https://www.youtube.com/watch?v=Gh8q3Iq5Tog

Posted by: Mark Borbely at March 19th, 2018 4:38 PM

@Steve - isn't this still just "messing with metabolism"? What makes you think this will be any more successful than resverstol? That had good data in mice I think? Is there any human or monkey data?

Posted by: Jim at March 20th, 2018 2:12 AM

@jim it's a central regulator of metabolism and cell functions and signalling and it directly addresses the hallmark deregulated nutrient sensing. "messing with metabolism" is a meaningless phrase because literally everything is "messing with metabolism" :)

Let's just wait for the data to come in for NMN and the other more robust approaches before we write this off. I have to say that healthspan increase is the most likely outcome here but still, that isn't worthless.

Posted by: Steve Hill at March 20th, 2018 3:39 AM

Also, resveratrol is useful for various things including antimicrobial activity and potentially anti-cancer applications. However, the problem with it is the poor bioavailability, this is where the chemically similar Pterostilbene is superior. However, it is doubtful it is useful for life extension in humans based on the data.

Posted by: Steve Hill at March 20th, 2018 3:42 AM

Mark Borbely "Lindsay Wu was talking about a compound that extended life in mice by 80%". Herein are novel compositions and methods for the treatment of age-related diseases, mitochondrial diseases, the improvement of stress resistance, the improvement of resistance to hypoxia and the extension of life span, see: "NAD biosynthesis and precursors for the treatment and prevention of cancer and proliferation." https://patents.google.com/patent/US9877981B2/en

Posted by: Dmitry Dzhagarov at March 20th, 2018 4:10 AM

What about, for now at least, using Apigenin to inhibit NAD+ consumers like CD38 instead? Also, btw, Apigenin bioavailability is about as poor as resveratrol's, however, when taken together with resv the enzymes that metabolize these are both competitively inhibited, and thus bioavailability is improved on at least apigenin and only hypothetically, resveratrol. Also the half life on apigenin is pretty long.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663613/
https://www.sciencedirect.com/science/article/pii/S1021949816300965

Posted by: Nathan at March 20th, 2018 8:10 AM

@Dmitry

Thank you for that! interesting IP!

Posted by: Mark Borbely at March 20th, 2018 9:55 AM

@Steve Hill, let me explain you what is 'messing with metabolism'. This is the therapy which try to change metabolic proceses directly to compensate their poor regulation instead of adressing their primary cause -- accumulation of the damage. For example, instead of clearing glucosepane crosslinks which cause hypertension present medicine use a buch of medications posessing many side effects to lower arterial pressure. Likewise, artificially rise NAD+ level will not solve the problem. Because NAD+ level is lowering for a reson, I am not an expert -- hovewer, maybe because of misregulation of OxPhos in mitochondria, maybe because of accumulation of [epi]mutations . So to have actual answers we need to progress in MitoSENS programme.

Posted by: Ariel at March 20th, 2018 6:05 PM

Ariel, with respect you don't need to explain biology to me I understand it well enough. Also, it depends on what model of aging you consider accurate as to if you think NAD+ biology is important. I believe it is and the data supports that deregulated nutrient sensing is a reason we age. But anyway I agree that MitoSENS needs to progress and we are broadly on the same side here so let us not argue about such matters.

Posted by: Steve Hill at March 21st, 2018 6:08 AM

First, pterostilbene is not superior to resveratrol. Pterostilbene (methylated resveratrol) averts being metabolized in the liver (attached to glucuronate, sulfate which are detox molecules) and therefore more free unbound resveratrol is available. But resveratrol has a short half life (~14 minutes) whereas resveratrol/sulfate and resveratrol/glucuronate have a half life of ~9 hours. The liver metabolites of resveratrol are equally or superiorly active when compared to free unbound resveratrol. Furthermore, resveratrol/glucuronate is converted to free resveratrol at sites of inflammation by glucuronidase. And finally, much of the heralded effects of resveratrol are achieved directly in the gut by its action as a prebiotic. Modern medicine uses the myth of poor bioavailability to justify research for analogs that often lose their molecular tail as they are metabolized and revert to being plain resveratrol.

Second, to criticize NMN and NR is to take a swipe at the idea of using NAD to boost cellular metabolism. At the very least boosting NAD will aid cellular health and should increase health span, especially when compared against individuals that don't consume or metabolize niacin very well. But does that equate with longevity? Does it double lifespan as observed in calorie restricted life forms?

I attempted to compare niacin amide against resveratrol. Resveratrol is superior to niacinamide in some measures.
http://www.resveratrolnews.com/question-i-heard-that-niacinamide-might-do-the-same-thing-as-resveratrol-any-truth-to-this/160/

I wrote a history of nicotinamide and its anti-aging effects.
http://www.resveratrolnews.com/history-of-nicotinamide-and-aging/868/

In one measure, resveratrol with a matrix of other molecules is superior to nicotinamide
http://www.resveratrolnews.com/longevinex-promises-reverse-aging-more-powerful-mechanism-than-niacin-like-drugs/882/

Weindruch and Arolla at Univ. Wisconsin have done good work to document CR effects in mice and primates. Life-long CR significantly differentiates 831 genes in mice. Short-term CR activates 198 genes. Short-term resveratrol 225 genes. Short-term resveratrol matrix (with other molecules) 1711 genes (82% of those 831 genes that CR differentiates). So the closest thing to a CR-mimic is a combination of other polyphenols and metal chelators (quercetin + IP6 rice bran).

Posted by: Bill Sardi at March 25th, 2018 7:31 AM

I am not commenting on the above but I would like to present anecdotal evidence cr on resveratrol. In 2006. I started to take a Chinese extract of the root of Japanese knotweed. I Expedia fed. 14 lb weight loss in two weeks and some very moderate hair regrowth on my male pattern bald head. Years later I added piperin within a month I had substantial hair regrowth. I have found that when I do not take it I feel a bit less vigorous. You can look up how piperin increases serum levels 2x and extends the duration from 30 minutes to 3.5 hours. I would like to suggest that the hair regrowth qnd the initial weight loss indicates activity. Also the hair came in dark rather than graying Just google. Resveratrol/piperin. So I disagree with the idea that resveratrol is without much merit. As for life extension I. People I do not know Thanks oh yeah I o tend to start taking nmn. And seeing how that goes. I am wondering if the piperin will e have the adsorption of that substance. I also engage in a fasting mimicking diet I hate doing it but the effects seem very positive. My cholesterol with statins was 204. It went down to 137. Something is going on.

Posted by: Alex Mark at March 25th, 2018 9:27 AM

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