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Sirtuin proteins

Sirtuin proteins

What's a sirtuin protein? Perhaps this will jog your memory. Not quite two months ago I wrote about resveratrol – the trace ingredient in red wine that may (or may not) have longevity-extending effects. See the article for plenty of details, but there are a few summary points to repeat here.

First, resveratrol may not occur in sufficiently high concentrations in red wine to offer practical health benefits to humans. Second, there are other compounds in red wine (and red or purple grape skins) which may play a larger role than resveratrol in the reported health benefits of red wine. Third, it is suspected that some of the health benefits observed in experiments with mice fed diets having high concentrations of resveratrol may be a result of its activation of a gene that produces the enzyme called SIRT1, which is a "sirtuin" protein. But, fourth, the observed health benefits of resveratrol may also be due to other effects. In summary, that situation with red wine and resveratrol is still not very clear.

However, it's specifically the sirtuin protein SIRT1 (and some closely related variants) we're interested in here, for reasons we'll get to in a moment. But to set the stage a little further, SIRT1 itself (and related proteins) has been of interest to biologists for over ten years because SIRT1 and its relatives appear to affect the longevity (usually in a positive way) of individuals belonging to several diverse eukaryotic species, ranging from yeast and nematodes to mammals. And this effect seems to be closely related to the observed beneficial effects on longevity of calorie restriction – effects that have been observed for many decades.

There's a little history behind the name of the protein SIRT1. It begins with certain proteins, which were observed in yeast, and which seemed to have something to do with the longevity of yeast cells. There were several of these proteins, which were called Silent Information Regulators. Three of them, in particular, known as SIR2, SIR3, and SIR4, seemed to be implicated in the longevity effect, although they are not structurally similar. Ultimately SIR2 proved to be the most important, and remarkably, a gene in the nematode Caenorhabditis elegans turned out not only to be a close analogue of SIR2 but also to have similar longevity-enhancing effects.

Because of their interesting effects, such proteins became known as "sirtuins" (get it?). It turns out that there are at least seven similar human proteins, named SIRT1 through SIRT7. Of these, it is SIRT1 that has (for good reason) attracted the most attention. It is an enzyme, in particular a histone deacetylase enzyme. Such enzymes are able to efficiently silence the expression of a variety of genes, so they are involved in a wide diversity of biological processes, as I've written about before. (And as I hope to write much more about.)

There are all sorts of interesting things to note about the human sirtuins, but the most notable recent finding, which is very relevant to calorie restriction and was announced at almost the same time as my resveratrol post, is this:

Eat Less To Live Longer: Calorie Restriction Linked To Long Healthy Lives (9/26/07)

Now, reporting in the September 21 issue of the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.

"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.

The new genes that Sinclair's group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)

David Sinclair, of course, has been heavily involved in research on SIRT1 and resveratrol, as discussed here. He is also co-founder of Sirtris Pharmaceuticals, which is investigating drugs that target sirtuins. Sinclair is a former student of Leonard Guarente, who is also very prominent in sirtuin research, and who had a great deal to do with investigation of the analogous proteins in yeast and nematodes.

One of the most interesting things about the longevity-enhancing effects of sirtuin proteins in yeast and nematodes is that they seem to achieve their effects by rather different means. In yeast, one cause of aging is the formation of "ribosomal DNA circles", and SIR2 (under appropriate conditions) can inhibit this. In C. elegans, on the other hand, the biological effect that retards aging is the inhibition of "insulin signaling". So what is it that SIRT3 and SIRT4 do in the cells of humans (and other mammals)?

In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.

Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell's battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.

When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly.

Other news stories on this research:

Researchers Pinpoint Link Between Caloric Restriction and Longevity

When under stress, two genes within mitochondria guard against cell death

By Jeffrey Perkel

Posted 9/20/07

THURSDAY, Sept. 20 (HealthDay News) -- Harvard researchers report they have uncovered a molecular clue that seems to explain why cutting calories might lengthen your life.

It turns out that mitochondria guard against cell death, and two specific genes within the mitochondria actually carry out that task, the scientists say. Mitochondria are compartments within a cell that are dedicated to energy production, and their loss is thought to be a major cause of aging.

The research also identifies two potential drug targets that could be exploited to slow down the aging process, said lead researcher David Sinclair, director of the Paul F. Glenn Laboratories for Aging Research at Harvard Medical School.

Sinclair and his colleagues found that, when either rat or human cells were deprived of nutrients (as in a caloric-restriction diet), the overall cellular concentration of a compound known as NAD dropped precipitously -- but not within mitochondria. Indeed, following any kind of cellular stress, mitochondrial NAD concentration actually increased.

Sinclair's team found that mitochondria can synthesize their own NAD to withstand stress, thereby helping the cells stay alive long enough to repair themselves.

Two members of a family of genes called sirtuins were required for this effect to occur, the authors found. Those proteins, SIRT3 and SIRT4, both reside within the mitochondria, and they need NAD to do their jobs.

"We were able to mimic calorie restriction in a dish," said Sinclair, "and that's important, because for decades, people knew calorie restriction made the cells less prone to death, but not how it worked, and we tracked it down to the mitochondria and to SIRT3 and SIRT4."

The findings were published in the Sept. 21 issue of Cell.

"This is really a great paper, and it basically provides very new knowledge about how NAD biosynthesis is regulated in our cells," said Dr. Shin-ichiro Imai, an assistant professor of molecular biology and pharmacology at the Washington University School of Medicine, in St. Louis.

The mammalian sirtuin family contains seven members, one of which, SIRT1, had previously been implicated in mammalian aging. "What we publish now is there are two more [sirtuins] that could lead to important drugs," Sinclair said.

"What's exciting is these genes make proteins that reside in mitochondria, and we discovered that if those genes keep mitochondria active, that's the gatekeeper of cell health," he added. "The cell can be essentially dead, but if the mitochondria and the sirtuins are active, the cells will live."

This suggests that if SIRT3 and SIRT4 could be chemically activated, it might be possible to achieve the benefits of caloric restriction without the diet. That could slow the progress of diseases based on cell death, such as Alzheimer's, cancer and diabetes, he said, and possibly extend life span as a result.

Sinclair said he is now looking for compounds that could activate SIRT3, and, as co-founder of Sirtris Pharmaceuticals, a drug development company that focuses on sirtuins, he is in a position to do so.

Imai was guarded on the question of whether pharmacologic activation of sirtuins is necessarily a good idea -- cell death is nature's way of eliminating severely damaged, and potentially cancerous, cells, after all.

"In general, there are benefits to increasing cell survival, but still we don't know precise details to this decision-making process," he explained. "So, I am very cautious about this. However, scientifically, I think this discovery is great, because it gives hope to us to develop a drug via the sirtuins."

Sirtris already has one sirtuin-activating compound in clinical trials. The company recently announced it was initiating early clinical trials of SRT501, a SIRT1 activator based on resveratrol, a compound found in red wine.

"This paper indicates that several other sirtuins, SIRT3 and SIRT4, also play an important role in sensing the energy environment and linking calorie restriction to beneficial effects on health," said Sirtris Chief Executive Officer Christoph Westphal.

"We have continued to develop new drugs to target SIRT1, but we also think SIRT3 and SIRT4 are going to be very promising drug targets," he added.

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