Monday, January 21, 2008

Sirtuin news

Back in November we had a series of posts about sirtuin proteins. This included an overview, with a particular focus on the relevance to calorie restriction and longevity, especially in light of recent research announcements at the time. This was followed by a couple of posts (here, here) on background history.

Now is a good time to return to that thread and continue the discussion of sirtuins, because of additional related research announcements, including especially this:

Sirtris Announces Positive Results with Proprietary Version of Resveratrol, SRT501, in a Phase 1b Type 2 Diabetes Clinical Study (1/7/08)
Sirtris Pharmaceuticals, Inc. ... announced today that the Company's first product to enter the clinic, SRT501, was found to be safe and well-tolerated, and was found to significantly lower glucose in an oral glucose tolerance test conducted as part of a 28 day Phase 1b clinical study in patients with Type 2 Diabetes.

This 28-day Phase 1b study was designed to assess the safety, tolerability and pharmacokinetics of once-daily, orally administered doses of either 2.5 g or 5 g of SRT501 in patients with Type 2 Diabetes who were naive to other diabetes drug treatments. Both doses of SRT501 were found to be safe and well-tolerated, and pharmacokinetics, a measure of drug levels in the blood, were identical at days one and 28, suggesting no drug accumulation. There were no serious adverse events and no dose-related adverse events. Importantly, SRT501 showed a statistically significant improvement in an oral glucose tolerance test on day 28 at two hours and a trend towards lower fasting plasma glucose levels.

SRT501 is also being tested in patients with Type 2 Diabetes in a Phase 1b BID (twice daily administration) study and in a Phase 2a study in combination with metformin, the current first-line therapy for Type 2 Diabetes. SIRT1 is the founding member of the human sirtuin family of enzymes which control the aging process. Specifically, SRT501 acts by increasing mitochondrial activity and therefore is targeted to address metabolic diseases, such as Type 2 Diabetes.

"This is the first time that a small molecule targeting sirtuins, the genes which control the aging process, has shown efficacy in a disease of aging," said Peter Elliott, Ph.D., Senior Vice President of Development at Sirtris.

OK, this is obviously a self-promotional PR piece from the drug developer. In particular, sirtuins aren't "the genes which control the aging process", merely some of them. However, if the claims hold up under further testing, especially the one stated in the last paragraph, this is an important validation of much prior research into the effect of sirtuins on longevity as a result of action in various cellular pathways. Our previous discussions reviewed some of this research conducted on model organisms like yeast and the nematode C. elegans.

More information: Resveratrol-like drug works in humans-Sirtris (1/7/08), Sirtris Anti-Aging Drug Generates Buzz, But May Already Be Old News (1/8/08)

This drug, SRT501, has been in human clinical trials for about a year and a half already. The initial trial (called "Phase 1") involved 85 healthy volunteers and began in June 2006 (see here). Results from that trial were reported in October 2006 (see here) and demonstrated that the drug was reasonably safe and well-tolerated.

SRT501 is a small molecule drug that achieves its effects by activating the mammalian SIRT1 NAD-dependent deacetylase enzyme, which has been investigated extensively for a decade (as discussed here). The drug is essentially just a proprietary formulation of resveratrol, the well-known component of red wine that has been shown to have lifespan-extending and anti-diabetes properties in several model organisms. (See here for an extended discussion, including reports of important research announced in late 2006.) SRT501, however, is a much more practical way to take advantage of resveratrol, compared to consumption of red wine, where hundreds or thousands of bottles of wine would be needed to achieve the same effect.

Perhaps the most important result shown by this newly reported result is that SRT501 actually seems to provide measurable beneficial effects of improved glucose tolerance and reduced blood glucose levels for humans with diabetes.

SIRT1 activators which are apparently much more powerful than SRT501 are under active investigation at Sirtris and in the laboratory of Sirtris co-founder David Sinclair. This has been documented in research that was published last November:

Sirtris unveils promising, novel SIRT1 activators for treating diseases of aging (11/28/07)
In November 2006, Sirtris scientists and Sirtris co-founder, Prof. David Sinclair from Harvard Medical School, published consecutive papers in the journals Cell and Nature showing that resveratrol, a SIRT1 activator found in red wine, could reduce the impact of a high fat diet, increase stamina two fold and significantly extend lifespan of mice. Unfortunately, it was estimated that a person would need to drink 1000 bottles of red wine to obtain an equivalent dose of resveratrol. Now, scientists at Sirtris have developed SIRT1 activating molecules that are chemically distinct from resveratrol and are 1000 times more potent.

"The new drug candidates represent a significant milestone because they are the first molecules that have been designed to act on genes that control the aging process. For this reason, we feel they have considerable potential to treat diseases of aging such as Type 2 Diabetes," said Christoph Westphal, M.D., Ph.D., Chief Executive Officer and Vice Chair of Sirtris Pharmaceuticals. "The breakthrough in potency we have achieved with the novel chemical entities (NCEs) means that we can obtain the health benefits of resveratrol with a considerably lower dose."

Here's a useful professional assessment of these results: Sirtuin activators as anti-diabetes drugs, and beyond (11/29/07) More: Sirtris Drug May Slow Aging, Create 'Armstrong' Cells (11/28/07)

Additional information:

Gene Believed To Promote Long Life Linked To Cholesterol Flushing (10/12/07)
Research conducted in part by sirtuin-research pioneer Leonard Guarente has established one mechanism through which SIRT1 provides health and longevity benefits. The mechanism promotes flushing harmful buildups of cholesterol in macrophage cells of the immune systems of mice. This mechanism could explain part of the health benefits of SIRT1-activators such as resveratrol and calorie restriction.

Red Wine Ingredient -- Resveratrol -- Fights Diabetes In Mice (10/4/07)
Chinese researchers have reported that relatively low doses of resveratrol can improve insulin sensitivity in mouse cells, and they believe this effect is due to SIRT1 activation by resveratrol. Additionally, the researchers found that SIRT1 levels are reduced in insulin-resistant cells, and that increased SIRT1 activity improved insulin sensitivity

Sirtris Pharmaceuticals – Treating Disease by Modulating Sirtuins
This is a brief overview of Sirtris Pharmaceuticals drug development focus.

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