Web address:
http://www.sciencedaily.com/releases/2013/03/
130307145259.htm
New Study Validates Longevity Pathway: Findings Identify Universal Mechanism
for Activating Anti-Aging Pathway
enlarge
Resveratrol-like compound binds to sirtuin protein. (Credit: Image courtesy of
Sinclair lab)
Mar. 7, 2013 A new study demonstrates what researchers consider conclusive
evidence that the red wine compound resveratrol directly activates a protein
that promotes health and longevity in animal models. What's more, the
researchers have uncovered the molecular mechanism for this interaction, and
show that a class of more potent drugs currently in clinical trials act in a
similar fashion. Pharmaceutical compounds similar to resveratrol may
potentially treat and prevent diseases related to aging in people, the authors
contend.
These findings are published in the March 8 issue of Science.
For the last decade, the science of aging has increasingly focused on sirtuins,
a group of genes that are believed to protect many organisms, including
mammals, against diseases of aging. Mounting evidence has demonstrated that
resveratrol, a compound found in the skin of grapes as well as in peanuts and
berries, increases the activity of a specific sirtuin,SIRT1, that protects the
body from diseases by revving up the mitochondria, a kind of cellular battery
that slowly runs down as we age. By recharging the batteries, SIRT1 can have
profound effects on health.
Mice on resveratrol have twice the endurance and are relatively immune from
effects of obesity and aging. In experiments with yeast, nematodes, bees, flies
and mice, lifespan has been extended.
"In the history of pharmaceuticals, there has never been a drug that binds to a
protein to make it run faster in the way that resveratrol activates SIRT1,"
said David Sinclair, Harvard Medical School professor of genetics and senior
author on the paper. "Almost all drugs either slow or block them."
In 2006, Sinclair's group published a study showing that resveratrol could
extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was
started by HMS researchers, was founded to make drugs more potent than
resveratrol. (Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company,
and remains a scientific advisor. Sirtris currently has a number of
sirtuin-activating compounds in clinical trials.)
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 chemical
group, one of which is tryptophan, a molecule abundant in turkey and notable
for inducing drowsiness. When researchers repeated the experiment, swapping the
fluorescing chemical group on the substrate with a tryptophan residue,
resveratrol and similar molecules were once again able to activate SIRT1.
"We discovered a signature for activation that is in fact found in the cell and
doesn't require these other synthetic groups," said Hubbard, first author of
the study. "This was a critical result, which allowed us to bridge the gap
between our biochemical and physiological findings.
"Next, we needed to identify precisely how resveratrol presses on SIRT1's
accelerator," said Sinclair. The team tested approximately 2,000 mutants of the
SIRT1 gene, eventually identifying one mutant that completely blocked
resveratrol's effect. The particular mutation resulted in the substitution of a
single amino acid residue, out of the 747 that make up SIRT1. The researchers
also tested hundreds of other molecules from the Sirtris library, many of which
are far more powerful than resveratrol, against this mutant SIRT1. All failed
to activate it.
The authors propose a model for how resveratrol works: When the molecule binds,
a hinge flips, and SIRT1 becomes hyperactive.
Although these experiments occurred in a test tube, once the researchers
identified the precise location of the accelerator pedal on SIRT1 -- and how to
break it -- they could test their ideas in a cell. They replaced the normal
SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they
could test precisely whether resveratrol and the drugs in development work by
tweaking SIRT1 (in which case they would not work) or one of the thousands of
other proteins in a cell (in which they would work). While resveratrol and the
drugs tested revved up mitochondria in normal cells (an effect caused
activating by SIRT1), the mutant cells were completely immune.
"This was the killer experiment," said Sinclair. "There is no rational
alternative explanation other than resveratrol directly activates SIRT1 in
cells. Now that we know the exact location on SIRT1 where and how resveratrol
works, we can engineer even better molecules that more precisely and
effectively trigger the effects of resveratrol."
The researchers plan on continuing academic-industry collaborations with the
goal of bringing to fruition drugs that treat diseases associated with aging.
This research was funded by the Glenn Foundation for Medical Research, the
Ellison Medical Foundation, the Juvenile Diabetes Research Foundation, the
United Mitochondrial Disease Foundation, NIH and NIAID grants (RO1AG028730,
PO1AG027211; RO1 AG019719), an NSERC fellowship, the Portuguese Science and
Technology Foundation, the Intramural Research Program, and NIH/NHLBI.
Sinclair is a consultant and inventor on patents licensed to Sirtris, a GSK
company.
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Story Source:
The above story is reprinted from materials provided by Harvard Medical
School. The original article was written by David Cameron.
Note: Materials may be edited for content and length. For further
information, please contact the source cited above.
Journal Reference:
B. P. Hubbard, A. P. Gomes, H. Dai, J. Li, A. W. Case, T. Considine, T. V.
Riera, J. E. Lee, S. Y. E, D. W. Lamming, B. L. Pentelute, E. R. Schuman, L. A.
Stevens, A. J. Y. Ling, S. M. Armour, S. Michan, H. Zhao, Y. Jiang, S. M.
Sweitzer, C. A. Blum, J. S. Disch, P. Y. Ng, K. T. Howitz, A. P. Rolo, Y.
Hamuro, J. Moss, R. B. Perni, J. L. Ellis, G. P. Vlasuk, D. A. Sinclair.
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators.
Science, 2013; 339 (6124): 1216 DOI: 10.1126/science.1231097
Need to cite this story in your essay, paper, or report? Use one of the
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Harvard Medical School (2013, March 7). New study validates longevity pathway:
Findings identify universal mechanism for activating anti-aging pathway.
ScienceDaily. Retrieved March 9, 2013, from http://www.sciencedaily.com
/releases/2013/03/130307145259.htm
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis
or treatment. Views expressed here do not necessarily reflect those of
ScienceDaily or its staff.
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