But while numerous studies, from Sinclair's lab and elsewhere, underscored a direct causal link between resveratrol and SIRT1, some scientists claimed the studies were flawed.
The contention lay in the way SIRT1 was studied in vitro, using a specific chemical group attached to the targets of SIRT1 that fluoresces more brightly as SIRT1 activity increases. This chemical group, however, is synthetic and does not exist in cells or in nature, and without it the experiments did not work. As a response to this, a paper published in 2010 surmised that resveratrol's activation of SIRT1 was an experimental artifact, one that existed in the lab, but not in an actual animal. SIRT1 activity in mice was, the paper claimed, at best an indirect result of resveratrol, and perhaps even a sheer coincidence.
As a result, a debate erupted over the particular pathway that resveratrol and similar compounds affected. Does resveratrol directly activate SIRT1 or is the effect indirect? "We had six years of work telling us that this was most definitely not an artifact," said Sinclair. "Still, we needed to figure out precisely how resveratrol works. The answer was extremely elegant."
Sinclair and Basil Hubbard, then a doctoral student in the lab, teamed up with a group of researchers from both the National Institutes of Health and Sirtris Pharmaceuticals to address this question.
First, the team addressed the problem of the fluorescent chemical group. Why was it required for resveratrol to rev up SIRT1 in the test tube? Instead of dismissing the result as an artifact, the researchers surmised that the chemical might be mimicking molecules found naturally in the cell. These turned out to be a specific class of amino acid, the building blocks of proteins. In nature, there are three amino acids that resemble the fluorescent c
|Contact: David Cameron|
Harvard Medical School