New research reinforces the claim that
resveratrol—a compound found in plants and food groups, notably red
wine—prolongs lifespan and health-span by boosting the activity of
mitochondria, the cell's energy supplier.
"The
results were surprisingly clear," said David Sinclair, a professor of
genetics at Harvard Medical School and the study's senior author. "Without
the mitochondria-boosting gene SIRT1, resveratrol does not work."
The
findings are to be published May 1 in the journal Cell Metabolism.
Over
the last decade, Sinclair and colleagues including Leonard Guarente at
Massachusetts Institute of Technology have published a body of research
describing how resveratrol improves energy production and overall health in
cells by activating a class of genes called sirtuins that are integral to
mitochondrial function.
The
cell's power supplier, mitochondria are essential not just for longevity but for
overall health.
Sinclair
and colleagues had studied sirtuins in a variety of model organisms: yeast,
worms, flies and mice. For the first three organisms they were able to
thoroughly knock out SIRT1 and show that cells lacking the gene don't respond
to resveratrol. But no one had been able to demonstrate the effect in mice,
which die at birth without the SIRT1 gene.
In
order to solve this obstacle, Nathan Price and Ana Gomes, graduate students in
the Sinclair lab, spent three years engineering a new mouse model. These mice,
seemingly normal in every way, were designed so that SIRT1 would systemically
switch off when the mice were given the drug Tamoxifen.
"This
is a drug inducible, whole body deletion of a gene," said Sinclair.
"This is something that's rarely been done so efficiently. Moving forward,
this mouse model will be valuable to many different labs for other areas of
research."
The
results were plain: when mice were given low doses of resveratrol after SIRT1
was disabled, the researchers found no discernable improvement in mitochondrial
function. In contrast, the mice with normal SIRT1 function given resveratrol
showed dramatic increases in energy.
While
the tantalizing prospect of increasing healthy lifespan has made resveratrol
the subject of intense scientific interest, some researchers have questioned
the link to SIRT1. A competing theory holds that resveratrol may work by
activating a separate energy pathway called AMPK, which, while also related to
mitochondria, does not involve sirtuin genes.
In
their new paper, Sinclair and colleagues report that when mice lacking SIRT1
were given low doses of resveratrol, AMPK was unaffected. When doses were
significantly increased in these mice, AMPK was activated, but still no benefit
to mitochondrial function resulted.
"Resveratrol
is a dirty molecule, so when you give very, very high doses, many things could
be happening," said Sinclair. "It's standard when you study molecules
that you use the lowest dose that gives you an effect because of the risk of
hitting other things if you use too much. But for the downstream benefits on
energy, you still need SIRT1. Our paper shows that SIRT1 is front and center
for any dose of resveratrol."
More
information: Cell
Metabolism, May, 2012, Vol 15, No 5
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