Harvard Medical School Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity.
The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal.
"Mice are much closer evolutionarily to humans than any previous model organism treated by this molecule, which offers hope that similar impacts might be seen in humans without negative side-effects," says co-senior author David Sinclair, HMS associate professor of pathology, and co-director of the Paul F. Glenn Labs for the Biological Mechanisms of Aging.
"After six months, resveratrol essentially prevented most of the
negative effects of the high calorie diet in mice," said Rafael de
Cabo, Ph.D., the study's other co-senior investigator from the National
Institute on Aging's Laboratory of Experimental Gerontology, Aging,
Metabolism, and Nutrition Unit. "There is a lot of work ahead that will
help us better understand resveratrol's roles and the best applications
for it."
Resveratrol is found in red wines and produced by a variety of plants
when put under stress. It was first discovered to have an anti-aging
properties by Sinclair, other HMS researchers, and their colleagues in
2003 and reported in Nature. The 2003 study showed that yeast treated
with resveratrol lived 60 percent longer. Since 2003, resveratrol has
been shown to extend the lifespan of worms and flies by nearly 30
percent, and fish by almost 60 percent. It has also been shown to
protect against Huntington's disease in two different animal models
(worms and mice).
"The "healthspan" benefits we saw in the obese mice treated with
resveratrol, such as increased insulin sensitivity, decreased glucose
levels, healthier heart and liver tissues, are positive clinical
indicators and may mean we can stave off in humans age-related diseases
such as type 2 diabetes, heart disease, and cancer, but only time and
more research will tell," says Sinclair, who is also a co-founder of
Sirtris, a company with an author on this paper and which is currently
in a phase 1b trial in humans with diabetes using an enhanced,
proprietary formulation of resveratrol. [Harvard has license and equity
interests with Sirtris, which is not a public company.]
Investigators identified resveratrol while looking for compounds that
activate Sir2, an enzyme linked to lifespan extension in yeast and
other lower organisms. For the last 70 years, scientists have been able
to increase the lifespan of a variety of species by reducing their
normal food consumption by 30 to 40 percent - a diet known as calorie
restriction. Through this research, scientists identified Sir2 as a key
contributor to life extension. Without Sir2, for example, fruit flies
see none of the benefits from either calorie restriction or treatment
by resveratrol. The mammalian version of the Sir2 gene is SIRT1, which
has the same enzymatic activity as Sir2, but modifies a wider variety
of molecules throughout cells. Indicators in this study show that
resveratrol might also be activating SIRT1 in mice, as well as other
known longevity pathways.
The study examined three groups of mice, one on a standard diet (SD),
another on a high calorie diet (HC) with 60 percent of calories coming
from fat, and a third group of mice on the same high calorie diet but
also treated with resveratrol (HCR). At middle age, or roughly 52 weeks
of life, the researchers put the mice on the different diets.
At 60 weeks of age, the survival rates of HC and HCR fed mice groups
began to diverge and remained separated by a three to four month span.
At 114 weeks of age, 58 percent of the HC fed mice had died, compared
to 42 percent of the HCR and SD groups. Presently, the team has found
resveratrol to reduce the risk of death from the HC diet by 31 percent,
to a point where it is not significantly increased over the SD
group.(Note: Given that mice are still living, final calculations can't
be made.)
"The median lifespan increase we are seeing is about 15
percent at this point," says Sinclair. "We won't have final lifespan
numbers until all of the mice pass away, and this particular strain of
mouse generally lives for two-and-a-half-years. So we are around five
months from having final numbers, but there is no question that we are
seeing increased longevity.
The team also found that the HCR fed mice had a much higher quality of
life, outperforming the HC fed mice on motor skill tests. "The mice on
resveratrol have not been just living longer," says Sinclair. "They are
also living more active, better lives. Their motor skills actually show
improvement as they grow older."
Mice on rotarodThe resveratrol fed mice also showed improved motor
function with age over its HC fed counterparts. Researchers watched how
well the mice did walking on a rotarod, similar to walking on a log in
the water, a common measure of balance and motor coordination. At 24
months of age, the HC fed group would fall off the rotarod after 60
seconds, while the HCR group would stay on for nearly 120 seconds. The
HCR group steadily improved their motor skills as they aged to the
point where they were indistinguishable from the SD fed group.
The research team also wanted to see if resveratrol could reverse the
changes in gene expression patterns triggered by high calorie diets.
Using liver tissue of five mice at 18 months of age from each group,
the team performed a whole-genome microarray and identified which genes
were turned on or off. The researchers then used a database generated
by the Broad Institute that groups individual genes into common
functional pathways to see where there were major differences.
"We made a striking observation," says Sinclair. "Resveratrol opposed
the effects of high caloric intake in 144 out of 153 significantly
altered pathways. In terms of gene expression and pathway comparison,
the resveratrol fed group was more similar to the standard diet fed
group than the high calorie group."
In humans, high calorie diets can increase glucose and insulin levels
leading to diabetes, cardiovascular disease, and non-alcoholic fatty
liver disease. In the HC fed mice, researchers found biomarkers that
might predict diabetes, including increased levels of insulin, glucose
and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group
had significantly lower levels of these markers, paralleling the SD
group. For example, a standard diabetes glucose test on the HCR fed
group found considerably higher insulin sensitivity, meaning the HCR
group had a lower disposition toward diabetes than the HC fed group.
Lower insulin levels also predict increased lifespan in mice.
The researchers also found that the livers of mice at 18 months of age
on the HC diet were greatly increased in size and weight. Liver tissue
studies of these mice showed a loss of cellular integrity, and a
build-up of lipids, which is common to high fat diets. In contrast, the
HCR group had normal, healthy livers.
The researchers also looked for metabolic ties to resveratrol's impact:
pathway changes that mimicked those caused by calorie restriction. They
examined AMP-activated kinase (AMPK), a metabolic regulator that
promotes insulin sensitivity and fatty acid oxidation. It's been shown
in previous work that the lifespan of worms has been extended by the
addition of copies the AMPK gene, and chronic activation of AMPK is
seen on calorie-restricted diets. The researchers examined the livers
of the HCR fed group and found a strong tendency for AMPK activation,
as well as two downstream indicators of its activity.
Calorie restriction and exercise have also been previously shown to
increase the number of mitochondria in the liver. Mitochondria generate
energy in cells. Through electron microscopy, investigators showed that
the livers of the HCR fed mice had considerably more mitochondria than
the HC group, and were not significantly different from those of the SD
group.
The team also asked if SIRT1 was activated by resveratrol in mice, as
Sir2 is in lower organisms. To determine this, they looked at the
amount of a specific chemical modification (acetylation) on the
molecule PGC-1alpha. Removal of the "acetyl" chemical groups on
PGC-1alpha activates this protein so that it can turn on certain genes
that generate mitochondria and turn muscle into the type suited for
endurance. The only enzyme known to remove the acetyl chemical groups
on PGC-1alpha is SIRT1, and therefore the activity of PGC-1alpha is one
of the most reliable and specific markers of SIRT1 activity in mammals.
The research team found that levels of PGC-1alpha were three-fold lower
in the HCR fed mice than in the HC mice, consistent with what would be
expected when SIRT1 was being activated by resveratrol.
"This work demonstrates that there may be tremendous medical benefits
to unlocking the secrets behind the genes that control our longevity,"
says Sinclair, "No doubt many more remain to be discovered in coming
years."
Posted by Casey Kazan from materials provided by Harvard Medical School.
http://web.med.harvard.edu/sites/RELEASES/html/11_1Sinclair.html
While some have been scanning our nearest neighbors for signs of life, excited by the existence of ice and methane plumes on Mars, others have been looking farther afield. Much farther afield. Twenty-five thousand light years afield, in fact, which is a bit more afield than the human brain can actually picture without popping, and in the far flung locale of HMC G31.41+0.31 one of the basic components of life has been found.
