A new study confirms that the human sirtuin protein known as SIRT1, which has been shown to combat age-related diseases in many animals, can be directly activated by resveratrol—a natural compound found in the skin of grapes used to make red wine. Resveratrol is one of many so-called sirtuin-activating compounds, or STACs.

The discovery helps to settle a long-standing debate regarding whether resveratrol and other STACs influence the activity of sirtuin proteins themselves or if they rely on other molecules to produce an indirect effect. Years of conflicting results in various laboratories had cast doubt upon a landmark study that, in 2003, first suggested such direct effects of STACs upon SIRT1.

Basil Hubbard from Harvard Medical School in Boston, Massachusetts, along with corporate and academic colleagues from around the world, now show that SIRT1 can indeed be activated by resveratrol and other STACs in the laboratory—but only under certain conditions.

Their study appears in the 8 March issue of the journal Science.

“We show that there is a critical amino acid in SIRT1 that mediates activation of the protein with small molecules both in the laboratory and in living organisms,” said David Sinclair from Harvard Medical School, a co-author of the Science report. “This amino acid is required for all the STACs that we tested—118 in all—including resveratrol, to activate SIRT1.”

Sinclair is also a co-founder of Sirtris, a GlaxoSmithKline company with a number of sirtuin-activating compounds currently in clinical trials.

Sirtuins are a specific class of genes that encode enzymes controlling a wide range of cellular processes, such as inflammation and DNA repair. They were first discovered in baker’s yeast cells, where they appeared to amplify the health benefits of calorie-restrictive diets. But, follow-up studies used various synthetic fluorescent molecules to gauge the effects of STACs on SIRT1, and labs around the world produced conflicting results.

“Such fluorescent molecules do not exist in nature,” Sinclair explained. When the molecules were removed or substituted with others, he said, “the activation of SIRT1 was not seen and this was interpreted as proof that the activation was artificial.”

So, Sinclair and Hubbard teamed up with researchers in the public and private sectors to figure out why their particular fluorescent chemical was required for resveratrol’s activation of SIRT1. They discovered that it had been mimicking the actions of molecules—a particular group of amino acids, including tryptophan—that are found naturally in cells.

Once the researchers replaced their fluorescent molecules in the test tube with a tryptophan residue, resveratrol and other STACs were able to activate SIRT1 in the lab again. Hubbard and his team also identified a particular mutation in an amino acid that blocks the activation of SIRT1 by all known STACs.

In light of their findings, the researchers suggest that specific small molecules must bind to STACs before the STACs can bind to SIRT1 and increase its activity. This activation of SIRT1 by STACs remains a viable strategy for addressing many diseases associated with aging, such as cancer, Alzheimer’s disease and type 2 diabetes, they say.

But, don’t go upping your red wine intake. Hubbard and the other researchers say more potent STACs are needed to eventually treat age-related diseases.

“Red wine only has a few milligrams of resveratrol, well below the levels we fed mice in the pre-clinical studies,” Sinclair said. “At least 100 glasses would be needed each day to get the levels shown to improve health in mice, which is a major reason why we and others are pursuing more potent, synthetic STACs.”

Links

Read the abstract, “Red Wine, Toast of the Town (Again),” by Hua Yuan and Ronen Marmorstein.

Read the abstract, “Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators,” by Basil Hubbard et al.