LA JOLLA, Calif. and
JUPITER, Fla., Dec. 22, 2014 /PRNewswire-USNewswire/ --
Scientists at The Scripps Research
Institute (TSRI) have found that resveratrol, the red-wine
ingredient once touted as an elixir of youth, powerfully activates
an evolutionarily ancient stress response in human cells. The
finding should dispel much of the mystery and controversy about how
resveratrol really works.
"This stress response represents a layer of biology that has
been largely overlooked, and resveratrol turns out to activate it
at much lower concentrations than those used in prior studies,"
said senior investigator Paul
Schimmel, professor and member of the Skaggs Institute for
Chemical Biology at TSRI.
"With these findings we have a new, fundamental mechanism for
the known beneficial effects of resveratrol," said lead author
Mathew Sajish, a senior research associate in the Schimmel
laboratory.
The discovery is reported in the advance online edition of
Nature on December 22.
Resveratrol is a compound produced in grapes, cacao beans,
Japanese knotweed and some other plants in response to stresses
including infection, drought and ultraviolet radiation. It has
attracted widespread scientific and popular interest over the past
decade, as researchers have reported that it extended lifespan and
prevented diabetes in obese mice and vastly increased the stamina
of ordinary mice running on wheels.
More recently, though, scientists in this field have disagreed
about the signaling pathways resveratrol activates to promote
health, calling into question some of resveratrol's supposed health
benefits—particularly given the unrealistically high doses used in
some experiments.
Outsiders to the Controversy
Schimmel and Sajish came to this controversy as outsiders.
Schimmel's laboratory is known for its work not on resveratrol but
on an ancient family of enzymes, the tRNA synthetases. The primary
and essential function of these enzymes is to help translate
genetic material into the amino-acid building blocks that make
proteins. But as Schimmel and others have shown since the late
1990s, tRNA synthetases have acquired an extensive set of added
functions in mammals.
Earlier Xiang-Lei Yang, a TSRI
professor in the Departments of Chemical Physiology and Cell and
Molecular Biology and former member of Schimmel's laboratory, began
to find hints that a tRNA synthetase called TyrRS, which links the
amino acid tyrosine to the genetic material that codes for it, can
move to the cell nucleus under stressful conditions—apparently
taking on a protective, stress-response role. Sajish noted that
resveratrol appeared to have broadly similar stress-response
properties and also resembled TyrRS's normal binding partner
tyrosine. "I began to see TyrRS as a potential target of
resveratrol," he said.
For the new study, Sajish and Schimmel put TyrRS and resveratrol
together and showed with tests including X-ray crystallography that
resveratrol does indeed mimic tyrosine, well enough to fit tightly
into TyrRS's tyrosine binding pocket. That binding to resveratrol,
the team found, takes TyrRS away from its protein translation role
and steers it to a function in the cell nucleus.
Tracking the resveratrol-bound TyrRS in the nucleus, the
researchers determined that it grabs and activates the protein,
PARP-1, a major stress response and DNA-repair factor thought to
have a significance influence on lifespan. The scientists confirmed
the interaction in mice injected with resveratrol. TyrRS's
activation of PARP-1 led, in turn, to the activation of a host of
protective genes including the tumor-suppressor gene p53 and
the longevity genes FOXO3A and SIRT6.
Compatible with Red
Wine
The first studies of resveratrol in the early 2000s had
suggested that it exerts some of its positive effects on health by
activating SIRT1, also thought to be a longevity gene. But
SIRT1's role in mediating resveratrol's reported
health-boosting effects has been questioned lately in terms of its
particular role.
The team's experiments showed, however, that the TyrRS-PARP-1
pathway can be measurably activated by much lower doses of
resveratrol—as much as 1,000 times lower—than were used in some of
the more celebrated prior studies, including those focused on
SIRT1. "Based on these results, it is conceivable that
moderate consumption of a couple glasses of red wine (rich in
resveratrol) would give a person enough resveratrol to evoke a
protective effect via this pathway," Sajish said. He also suspects
that effects of resveratrol that only appear at unrealistically
high doses may have confounded some prior findings.
Why would resveratrol, a protein produced in plants, be so
potent and specific in activating a major stress response pathway
in human cells? Probably because it does much the same in plant
cells, and probably again via TyrRS—a protein so fundamental to
life, due to its linkage to an amino acid, that it hasn't changed
much in the hundreds of millions of years since plants and animals
went their separate evolutionary ways. "We believe that TyrRS has
evolved to act as a top-level switch or activator of a fundamental
cell-protecting mechanism that works in virtually all forms of
life," said Sajish.
Whatever activity resveratrol naturally has in mammals may be an
example of hormesis: the mild, health-promoting activation
of a natural stress response. "If resveratrol brought significant
benefits to mammals, they might have evolved a symbiotic
relationship with resveratrol-producing plants," Sajish said.
"We think this is just the tip of the iceberg," said Schimmel.
"We think there are a lot more amino-acid mimics out there that can
have beneficial effects like this in people. And we're working on
that now."
Schimmel and his laboratory also are searching for molecules
that can activate the TyrRS stress response pathway even more
potently than resveratrol does.
The National Cancer Institute (CA92577), the National Foundation
for Cancer Research and aTyr Pharma, Inc. provided funding for the
study, "A human tRNA synthetase is a potent PARP1-activating
effector target for resveratrol." For more information, see
http://www.nature.com
About The Scripps Research
Institute
The Scripps Research Institute
(TSRI) is one of the world's largest independent, not-for-profit
organizations focusing on research in the biomedical sciences. TSRI
is internationally recognized for its contributions to science and
health, including its role in laying the foundation for new
treatments for cancer, rheumatoid arthritis, hemophilia, and other
diseases. An institution that evolved from the Scripps Metabolic
Clinic founded by philanthropist Ellen
Browning Scripps in 1924, the institute now employs about
3,000 people on its campuses in La Jolla,
CA, and Jupiter, FL, where
its renowned scientists—including two Nobel laureates—work toward
their next discoveries. The institute's graduate program, which
awards PhD degrees in biology and chemistry, ranks among the top
ten of its kind in the nation. For more information, see
www.scripps.edu.
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