Among the few interventions that demonstrably extend lifespans across multiple species besides calorie restriction are 1. inhibition of the mTOR pathway, 2. the activation of sirtuins such as via calorie restriction or substances such as resveratrol, and 3. Inhibition of the expression of a cell nuclear factor, NF-kappaB. For a long time these pathways were thought to be independent. However, recent research reviewed here shows that these aging and longevity-related pathways are very closely related.
The ability to extend lives of organisms from yeast cells to mammals via inhibition of the mTOR (mammalian target of rapamycin) pathway is discussed in my previous blog entries Longevity genes, mTOR and lifespan, Viva mTOR! Caveat mTOR!, and More mTOR links to aging theories. In my treatise I discuss Aberrant mTOR as one of the Additional Candidate Theories of Aging. Among other actions, Rapamycin fed late in life extends lifespan in mice(ref).
The mammalian sirtuin SIRT1 activates the same pathway that conveys longevity via calorie restriction, and SIRT1 in turn can be activated by resveratrol and other substances being developed by Sirtris Pharmaceuticals. I have a long post on this subject in the works based on a recent visit to the Glenn Laboratory for the Science of Aging at MIT and its key leader Leonard Guarante. A current review of research on the sirtuins over the last 10 years can be found here and discussions of calorie restriction can be found in my December 2009 blog entries Calorie restriction research roundup – Part I and Calorie restriction research roundup – Part II.
Both laboratory and small-animal studies strongly implicate expression of NF-kappaB in aging and suggest anti-aging interventions based on the inhibition of NF-kappaB. In my Anti-Aging Firewalls treatise the role of NF-kappaB in aging is discussed under the Programmed epigenomic changes theory of aging. Also, see the blog posts Updates on NF-kappaB and A further update on NF-kappaB.
The links between SIRT1 activation, mTOR signaling suppression, and inhibition of NF-kappaB
A 2007 publication linked the two pathways in the yeast Saccharomyces cerevisiae: MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae. “Here we show that TOR inhibition extends lifespan by the same mechanism as CR: by increasing Sir2p activity and stabilizing the rDNA locus. Further, we show that rDNA stabilization and lifespan extension by both CR and TOR signaling is due to the relocalization of the transcription factors Msn2p and Msn4p from the cytoplasm to the nucleus, where they increase expression of the nicotinamidase gene PNC1. These findings suggest that TOR and sirtuins may be part of the same longevity pathway in higher organisms, and that they may promote genomic stability during aging.” It was already believed that SIRT1 activation extends lifespan by the same mechanism as CR(see the video). But, it was yet to be established that a clear link exists in mammals between SIRT1 and mTOR signaling.
A 2007 doctoral thesis revealed more about the link: Regulation Of Translation And Transcription By Sirt1: Potential Novel Mechanisms For Regulating Stress Response And Aging. “Both SIRT1 and the target of rapamycin (TOR) are involved in age related diseases and lifespan. We demonstrate for the first time that these two pathways are interconnected. We show that SIRT1 null mouse embryonic fibroblasts (MEFs) have larger cell morphology and upregulated mTOR signaling. Furthermore, SIRT1 activator reduces, whereas SIRT1 inhibitor nicotinamide activates the mTOR pathway. Rapamycin is effective in inhibiting mTOR activity in both SIRT1 positive and deficient cells. Finally, we show that SIRT1 physically associates with TSC2 in HeLa cells. These observations demonstrate that SIRT1 negatively regulates mTOR pathway upstream of mTOR complex-1 (TORC1), potentially, by regulating the TSC1/2 complex.”
The same dissertation relates the expression of SIR1 to the suppression of gene activation by NF-kappaB. “TLE1 is co-repressor for several transcriptional factors including NF-ÎºB. We demonstrate that SIRT1 and TLE1 repress NF-ÎºB activity and that the catalytic activity of SIRT1 may not be critical for this. Using knock-out cell lines, we further demonstrate that both SIRT1 and TLE1 are required for the down-regulation of NF-ÎºB activity. Our results suggest that the interaction between SIRT1 and TLE1 is important for mediating repression of NF-ÎºB activity, potentially through a deacetyalse independent mechanism.” In the blog post A further update on NF-kappaB, I mention the role of histone deacetylation in preventing the expression of NF-kappaB. “it involves coiling up the DNA in the neighborhood of genes so that those genes are not accessible for activation by the NF-kappaB. This appears to be the main mechanism used by curcumin, resveratrol and other dietary polyphenols for inhibition of gene activation by NF-kappaB(ref).” Not surprisingly, SIRT1 is a powerful deacetylase and is activated by resveratrol.
The 2010 publication SIRT1 Negatively Regulates the Mammalian Target of Rapamycin is co-authored by Hiyaa Singhee Ghosh, the author of the aforementioned dissertation, and rounds out our understanding of the linkages even more completely. “We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.” This publication is rich in detail and I suggest it as a good read for those of you interested in digging further. Among the observations in this publication are:
· “Resveratrol suppressed mTOR signaling regardless of stress or growth conditions, suggesting that inducing the catalytic activity of SIRT1 negatively regulates mTOR signaling,”
· “Both SIRT1 and mTOR have been linked to age-associated diseases with SIRT1 activation having a protective effect, whereas inhibition of mTOR conferring a beneficial effect. For example, SIRT1 activation confers a therapeutic effect in type 2 diabetes, obesity and neurodegenerative diseases such as Alzheimer’s and amyotrophic lateral sclerosis, whereas inhibition of mTOR is protective against cardiovascular and neurological diseases, diet-induced obesity and cancer , , , , , , , . Autophagy, a mechanism important in regulating stress response and aging is negatively regulated by mTOR , , whereas SIRT1 has been reported to activate autophagy by deacetylating several essential components of the autophagy machinery , ”
· “The inverse relationship between the roles of SIRT1 and mTOR in aging-associated diseases and lifespan extension suggests a functional interrelationship between these two proteins. Our results demonstrate that SIRT1 and mTOR signaling pathways are indeed interconnected in a way that promotes stress sensing pro-survival signals, where the regulation of mTOR is mediated potentially through an interaction of SIRT1 with the TSC1-TSC2 complex,” and
· “Resveratrol has been reported to affect insulin signaling through SIRT1 independent pathways. Consistent with these reports, our data demonstrated that at lower doses, resvetratrol regulated the mTOR pathway in a SIRT1 dependent manner. However, at higher doses, reveratrol likely activated SIRT1 independent pathways in parallel, to inhibit mTOR activity.”
So, three different theories of longevity seem to be collapsing into one: suppression of mTOR signaling, activation of SIRT1, and inhibition of expression of NF-kappaB. Activating SIRT1 does all of these things, and this seems to be accomplishable to some extent by taking resveratrol supplements. As time goes on, even more powerful activators of SIRT1 are likely to become available.
Why not nicotinamide?
As a side to this discussion, I have often been asked why I do not include nicotinamide, one of the two principal forms of the B-complex vitamin niacin, in my anti-aging supplement regimen. In fact, nicotinamide was recommended by my physician for control of cholesterol levels but I don’t take it and effectively control my cholesterol in other ways. The answer is simple: nicotinamide is a powerful inhibitor of SIRT1 and its anti-aging activities, not only capable of negating any benefits from taking resveratrol but also stopping natural expression of SIRT1 in the body. As stated above “The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner(ref).” That is, nicotinamide is a pro-aging substance so I avoid it.
oh.. so bad..
I am taking 750mg of Niaspan a day to improve my HDL. It is in 35 range. I need to push that to 40+
Also taking crestor 5mg per day to keep my ldl under control.
Is there some other way to improve my HDL.. (I do exercise..but it seems it has no effect on my HDL) Something genetic i guess.
Your reaction is similar to mine when I found out about niacinamide and SIRT1 a couple of years ago. I still have the half-bottle from when I stopped taking it. My HDL is up and LDL down but I am not sure exactly what is doing that. I am not on any statins either. Could be the blueberries and walnuts for breakfast help. I exercise 45 minutes every day. I think my supplements, my diet and my exercise and largely stress-free but active lifestyle are complementary. A very wise longevity researcher commented to me a few days ago that getting any part of the body really healthy tends to make the other parts healthier.
There is interesting research relating niacinamide to telomerase extression and replicative life spans. I may look more thoroughly at the niacinamide literature and do a blog post just on it.
The clinical anti-aging effects of topical kinetin and niacinamide in Asians: a randomized, double-blind, placebo-controlled, split-face comparative trial.
one more link
Nicotinamide extends replicative lifespan of human cells
Thanks for the citations. The second one had already come to my attention yesterday. It seemks like nicotinamide (niacinamide) has both good stuff (longer telomeres) and bad stuff (inhibits SIRT1) going for it from an anti-aging viewpoint. I don’t have a feeling now as to how it all nets out but I am very curious about that. I am also unsure of the actions of nicotinamide vs plain niacin. As I promised, I will dig arounod further, read the full texts of these papers if I can get to them, and do a blog entry on nicotinamide/niacin. Four decades ago I was heavily on the stuff and had my kids on it too. Then we found out that the doctor who was treating us all for hypoglycemia was a fake.
I found your Anti-aging firewalls site and this Blog a few weeks ago so I am new to the site. I find the research you are doing on anti-aging discoveries/theories fascinating and extremely useful.
I have been taking supplements for over eight years now (most of them are in your regiment suggested in the anti-aging firewalls). I have had extreme difficulty in keeping my hdl numbers up around 40 (the bare minimum). A doctor had me on niaspan for a while, which seemed to help (35 went up to 40). I have since switched to straight niacin (nicotinic acid) and I am taking 500 mg/day, which seems to work just as well as niaspan.
I was disturbed to find out that nicotinamide is a powerful inhibitor of SIRT1, since I am also taking resveratrol for its obvious benefits. I did some digging around on the net and found a lot of conflicting data and opinions regarding this subject. It does seem as if nicotinic acid displays almost negligible binding to and inhibition of sirtuins (http://molpharm.wisc.edu/Faculty/fac_pages/denu/Pub16039130.pdf). Also I found an interesting, detailed blog entry at the imminst.org site on the subject of “Resveratrol and Nampt- What is Reseratrol’s true target” (http://www.imminst.org/forum/index.php?showtopic=27350&hl=nampt) which seems to indicate taking niacin several hours after resveratrol might actually be beneficial. (I don’t know the credentials of the blogger, but would be interested in your opinion).
I am a retired physicist and have had virtually zero training in molecular biology. I am currently trying to teach myself enough in the field to be able to at least intelligently interpret new, emerging research. I am nowhere near that stage yet. I am looking forward to your further analysis of the nicotinamide/niacin/SIRT1 inhibition problem. I hope the two references I included help some.
Thanks for your effort in enlightening those of us who are interested in anti-aging. Your efforts are greatly appreciated.
p.s. I read an old blog of yours where you stated you do not take Deprenyl but could not come up with the reason why at the time and said you would post it in a later blog. I haven’t been able to find that answer. I was wondering if you could possibly let me know. (I don’t take it, but was considering it). Thanks again.
First of all thanks for your comments. Knowing that there are people out there who read my stuff and care is very important for motivating me to keep on going. As I mentioned in comments elsewhere I am researching nicotinic acid and niacinamide with respect to SIRT1, telomeres, effect of resveratrol, longevity, etc. and expect to get a blog entry out on these subjects this weekend. My first impression is the same as yours – seemingly conflicting data. I will include your references among those I look at.
One of my doctoral areas of concentration centuries ago at Harvard was quantum physics and I still have an amateur love for it. Good luck in getting up to speed on learning the rudiments of molecular biology. There are free online courses available from MIT, by the way, and I have found them helpful. I am learning a tremendous amount but, as a famous physicist almost-said “I sometimes feel like a small yiping dog following a large truck.”
And yes, I have not delivered in my promise to look further into Deprenyl and have that in the to-do stack too. The real reason why I did not start taking Deprenyl back 5 years ago was that I was already taking two nootropics, piracetam and centrophenoxine and at the time thought Deprenyl would be redundant. Not necessarily a good reason.
Hi Vince, Any luck on hte resaerch on nicotinic acid being a sirt1 inhibitor? my resaerch so far says its not.
Just trying to decide if i should go back on 500mg as it did wonders for my lipid profile along with 5mg rosuvastin. But i dont want it to cancel out my resveratrol. Nicotinamide inhibits sirt1 does inhibit sirt1, even sinclair’s group has shown this. But that doesnt bother me as it does nothing for my lipid profile anyway.
But what about nicotinic acid? whats your research say?
I did have an amazing profile whilst on it. LDL was lower than HDL.
I have reviewed the the ionteresting citations you provide and agree that, based on what I have seen
1. nicotinamide inhibits SIR1 and SIR2 in lower organisms and limits their lifespans and, inhibits SIRT in humans.
2. nicotinic acid does none of the above.
3. However, niacin (nicotinic acid) is converted into nicotinamide in-vivo after ingestion. See http://en.wikipedia.org/wiki/Niacin and http://lib.bioinfo.pl/blid:2072
Therefore, I am personally leary of taking either nicotinic acid or nicotinamide on a regular basis.
Thanks Vince. Your right in-vivo after ingestion it does convert. Even thouh there’s one study that says it doesnt have the same inhibiting effects, there just isn’t enough research done on it. I have a doctor friend who posted me another study confirming it to be safe, cant find it right now.
Your lucky, with my family history and lipid profile, i have no choice but to be on Niacin, even if its just 400mg -500mg daily. its seems safer than 5mg Crestor statin.
Thanks for your comment and I fully understand your decision.
As to resveratrol and NF-kappaB, please comment on this article:
Interesting publication, again illustrating the unexpected and contrarian nature of some research results. It is interesting that the cancer-promoting properties of resveratrol on the MDA-MB-435s cancer cell line appear to exist at low but not higher doses. It would be interesting to learn if a similar effect exists with other cancer cell lines and, if so, with which. In rfetrospective, perhaps the result is not too surprising since different cancers operate through multiple pathways and resveratrol activates/inhibits multiple pathways.
With regard to the particular research cited, the citation points out that inhibiting activation of NF-kappaB negates the cancer-inducing effect of resveratrol. In my anti-aging firewalls supplement regimen, there are 39 substances that inhibit activation of NF-kappaB (including resveratrol itself under usual circumstances). I strongly suspect that a supplement regimen that combines resveratrol with a number of powerful NF-kappaB inhibitors like curcumin would inhibit any pro-cancer effect – though of course I don’t know this as a fact.
are nicotinamide and niacinamide the same thing?
please tell me the dose of nicotinamide for rat to inhibit sirtuins
Very good article and support you continue to write, continue to pay attention !
How much resveratrol do i take each day, i have a bottle of 200 mg pills.
I cannot make individual recommendations in this blog for several reasons, including that I do not know your circumstances of age, health, body condition etc.
I can share with you that as a healthy male turning 81 tomorrow, I personaly am taking two 250mg caps of micronized trans-resveratrol per day
Thanks. I have every intention of keeping it up.
I cannot seem to find a multivitamin that does not contain some amount of niacinamide. Is 9mg of niacinamide enough to inhibit sirt1?
I do not know the answer to your question and am not sure if it has ever been studied. My guess is that the answer is probably no, at lease that is what I have been assuming since I too take about the same amount of niacinamide in a B-complex tablet. I am not sure, however.
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