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.