The article is entitled Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators, and reveals how interaction with a single amino acid in the SIRT1 enzyme is crucial for the ability of drugs that can activate the enzyme.
SIRT1 is an enzyme in the class of molecules called Sirtuins. Significant research shows that activation of sirtuins reduces cellular aging through its interaction with other cellular master switches such as FOXO3a and PGC-1a
“At the cellular level,” explain the authors. “SIRT1 controls DNA repair and apoptosis, circadian clocks, inflammatory pathways, insulin secretion, and mitochondrial biogenesis”
Resveratrol a polyphenol found in red wine and grapes may be a weak natural activator of sirutin and has been linked in some studies with the extension of animal lifespan. Data on these sitruin activators or STACs is inconsistent. “The legitimacy of STACs as direct SIRT1 activators has been widely debated,” write the authors.
In the present study, the researchers developed a sirtuin activation assay. They tested 117 experimental STACs and were able to prove that the enzyme could be directly activated and uncovered the exact molecular mechanism by which this occurred.
The authors conclude:
The data presented here favor a mechanism of direct “assisted allosteric activation” mediated by an N-terminal activation domain in SIRT1 that is responsible for at least some of the physiological effects of STACs. Thus, allosteric activation of SIRT1 by STACs remains a viable therapeutic intervention strategy for many diseases associated with aging.
“Ultimately, these drugs would treat one disease, but unlike drugs of today, they would prevent 20 others,” says Sinclair, from Harvard University. “In effect, they would slow ageing.” He points out this research shows something never previously described ”In the history of pharmaceuticals, there has never been a drug that tweaks an enzyme to make it run faster,” he said.
From this work, Sinclair believes safe new drugs of this class could be available in as little as five years. There will still be the need to prove their effectiveness.
“Now we are looking at whether there are benefits for those who are already healthy. Things there are also looking promising,” he says. ”We’re finding that ageing isn’t the irreversible affliction that we thought it was,”
“Some of us could live to 150, but we won’t get there without more research,” he adds.