SIRT6 Overexpression Extends Life in Mice

There was a great deal of interest in sirtuin 1 in relation to aging and life span some years ago, very much overhyped as it turned out. Nothing of any practical use emerged from that research. Sirtuin 6 has a more robust effect on mouse life span, perhaps via improvement of mitochondrial function. Like all such exercises in metabolic manipulation that attempt to slow the progression of aging, targeting processes known to be involved in cellular responses to stress, it is likely that the beneficial effects diminish as species life span increases. A sirtuin with better results in mice remains unlikely to move the needle all that much on human life span.

Of the seven mammalian sirtuins, SIRT1-7, SIRT1, and SIRT6 protein levels increase upon dietary restriction and fasting in various mouse tissues and human cell lines. Interestingly, whole-body SIRT1 overexpression in mice leads to improvement in parameters reflecting healthspan, but not lifespan. Whereas whole-brain-specific SIRT1 overexpression did not affect lifespan and brain plasticity, hypothalamic SIRT1 overexpression delays aging. However, whole-body SIRT6 overexpression in mice background leads to a significant extension of male lifespan and healthspan, associated with inhibition of IGF-1 signaling.

Here, we show that overexpression of SIRT6, but not SIRT1, extends lifespan in C57BL/6JOlaHsd mice in both sexes. SIRT1 does not synergize with SIRT6 to further increase median or maximal survival. Overexpression of SIRT6 reduced the age-related metabolic decline in energy metabolism pathways and inhibited frailty by preserving hepatic NAD+ levels, gluconeogenesis capacity, and maintenance of normoglycemia, key markers of healthy aging. These results emphasize the potential of targeting SIRT6 for maintaining energy metabolism and reducing age-related frailty.

Link: https://doi.org/10.1038/s41467-021-23545-7

Comments

https://forbetterscience.com/2021/06/04/schneider-shorts-4-06-2021/

We remain on this most important topic of anti-aging and life extension. Informed readers will now say, well that's all very nice with Ayurveda and TCM, but science, embodied by Harvard professor and businessman David Sinclair, has spoken already: it's the sirtuins which are the target, and resveratrol or NAD+supplements are the secret to immortality.

And this is where Israeli Scientists, male of course, step in. Meet the academic offspring of Sinclair's own loins, his former postdoc Haim Cohen, now professor for life extension at Bar-Ilan University, Israel. Jerusalem Post informs:

"Researchers from Bar-Ilan University were able to increase the life expectancy of mice by an average of 30%, as detailed in a press release from the university on Monday. […]

"This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging," says Prof. Cohen, of Bar-Ilan University's Mina and Everard Goodman Faculty of Life Sciences. "If we can determine how to activate it in humans, we will be able to prolong life, and this could have enormous health and economic implications," he concluded. "

It was published in a Nature-themed journal, Nature Communications (where you pay €4,530 to publish your stuff).

A. Roichman, S. Elhanati , M. A. Aon , I. Abramovich , A. Di Francesco , Y. Shahar , M. Y. Avivi , M. Shurgi , A. Rubinstein , Y. Wiesner , A. Shuchami , Z. Petrover , I. Lebenthal-Loinger , O. Yaron , A. Lyashkov , C. Ubaida-Mohien , Y. Kanfi , B. Lerrer , P. J. Fernández-Marcos , M. Serrano , E. Gottlieb, R. De Cabo, H. Y. Cohen Restoration of energy homeostasis by SIRT6 extends healthy lifespan Nature Communications (2021) doi: 10.1038/s41467-021-23545-7

Conflicts of interest declared:

"The authors declare the following competing interests: H.Y.C. advises SirTLab Ltd. The remaining authors declare no competing interests".

Cohen is not just advising, here is their scientific director. SirTLab declared on Facebook in 2018: "SirTLab's research team is led by Prof. Haim Cohen, a worldwide leading scientist in the field of aging research and SIRT6 biology." Cohen also holds with SirTLab a joint patent on compounds which they think modulate SIRT6, which suggests he is actually one of the founders of this business.

SirTLab's self-declared business model is to bamboozle a pharma giant to buy it for huge money, then to disband and bury it after incurring yet another huge loss trying to develop drugs which prove useless garbage, while the former owners become multimillionaires many times over. As it happened with Sinclair's own company SIRTIS, sold to GlaxoSmithKline for $740 million, whcih they cite as their role model.

Boosting levels of the NAD-sensitive enzyme SIRT6 extends the lifespan of mice by a whopping 30%!! From the lab of Haim Cohen @BarIlanU, who, in 1999, bravely joined me at Harvard to tackle aging, before my lab had even been built! #fitness https://t.co/yhfogkdZ2u

- David Sinclair, PhD (@davidasinclair) May 31, 2021

Posted by: Jones at June 4th, 2021 9:55 AM

"A sirtuin with better results in mice remains unlikely to move the needle all that much on human life span." - do you have any scientific proof of your claim? like, real science, not your blog posts

Posted by: t at June 4th, 2021 11:07 AM

Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins

https://pubmed.ncbi.nlm.nih.gov/24052263/

'Given that SIRT6 is a poor deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1.'

Posted by: Jones at June 4th, 2021 11:41 AM

@Jones

We won't achieve indefinite lifespan with these supplements. Sinclair just trying to sell his useless book and his marvelous NAD boosters to earn more money as usual ...

Posted by: alberto marcelo at June 4th, 2021 4:07 PM

@t
I'm not Reason but fwiw:
DNA doublestrand break repair and/or genomic maintenance mediated by sirtuins is considered to be weak in short lived species. Long lived species have evolved 'better' working sirtuins.
Hence short lived species have more to gain by sirtuin manipulation than long lived species which already have 'strong' sirtuin function.

With reagard to SIRT6 this sheds some light on the matter:

SIRT6 is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499390/

'DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.'

Posted by: Jones at June 6th, 2021 5:19 AM

@alberto marcelo
Sinclair doesn't sell any supplements or "NAD boosters". Any companies claiming to be endorsed by him are lying.

Posted by: J C at June 6th, 2021 5:58 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.