Molecular Medicine Israel

Israeli Study – The sirtuin SIRT6 regulates lifespan in male mice

Nature  (2012) doi:10.1038/nature10950  Yariv Kanfi, Shoshana Naiman, Gail Amir, Victoria Peshti, Guy Zinman, Liat Nahum, Ziv Bar-Joseph & Haim Y.Cohen
A member of the celebrated sirtuin family of proteins has been shown to extend lifespan in mammals — although it’s not the one that has received the most attention and financial investment.  Sirtuin genes and the proteins they encode have intrigued many researchers who study ageing ever since they were first linked to longevity in yeast. Results published today in Nature suggest that the overexpression of one gene, called sirtuin 6 (SIRT6), can lengthen lifespan in male mice by as much as 15.8%.For years, another member of the family, SIRT1, has hogged much of the spotlight because it is the mammalian member of the sirtuin clan most closely related to the longevity-linked yeast gene. Some researchers speculated that SIRT1 may also boost lifespan in mammals, and that it was the target of resveratrol, a compound found in red wine that had been linked to a variety of health benefits.&nbsp.

Amid the excitement about SIRT1, it was in part the relative obscurity of SIRT6 that drew molecular biologist Haim Cohen of Bar-Ilan University in Ramat-Gan, Israel, to study the gene.

In 2006, researchers had reported that mice lacking SIRT6 seemed to age more quickly2. The mice were small and sickly, had a reduced capacity to repair damaged DNA, and died a month after birth.

Cohen and his colleagues decided to find out what would happen if mice expressed higher levels of the SIRT6 protein than normal. They found that longevity in female mice was unaffected by the excess protein, but that the median lifespan of male mice rose by 14.5% in one line of their transgenic mice and 9.9% in another1.

Another measure of longevity, maximum lifespan (generally more valued by researchers into ageing because it is less likely to be affected by other factors such as changes in infant mortality), rose by 15.8% in the first line of mice, and 13.1% in the second, although the latter increase was not statistically significant.

Furthermore, in the transgenic mice, levels of proteins involved in the ‘insulin-like growth factor 1’ pathway, which has been previously linked to longevity, were also affected by SIRT6 expression.

The strain of mice used in the study is particularly prone to tumours, especially in males, says Miller. It’s possible, then, that the longer lifespans could be the result of an anti-cancer effect of SIRT6 rather than a direct effect on ageing.

Cohen acknowledges that this is a possibility, but notes that statistical analyses found no evidence that differences in tumour rates were contributing to the longevity effects of SIRT6.


And why does SIRT6 affect males and females differently? Cohen’s lab is trying to piece that together, but for now he can only offer speculation. He notes that in the strain of mice his team used, females live about 15% longer than males and that over expression of SIRT6 simply allowed the males to catch up to the females. Perhaps, then, SIRT6 is mimicking effects already seen in the females of this strain of mice. In this context, Rafael de Cabo, who studies ageing at the National Institute on Ageing in Baltimore, Maryland, notes that the expression of some proteins in the transgenic mice producing excess SIRT6 matched the expression of those proteins in normal, control female mice.

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