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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

FFA60961-1AD1-4CEF-808D-ED81E98A212E.jpgThe New York Times, by Nicholas Wade — A new insight into the reason for aging has been gained by scientists trying to understand how resveratrol, a minor ingredient of red wine, improves the health and lifespan of laboratory mice. They believe that the integrity of chromosomes is compromised as people age, and that resveratrol works by activating a protein known as sirtuin that restores the chromosomes to health.

The finding, published online Wednesday in the journal Cell, is from a group led by David Sinclair of the Harvard Medical School. It is part of a growing effort by biologists to understand the sirtuins and other powerful agents that control the settings on the living cell’s metabolism, like its handling of fats and response to insulin.

Researchers are just beginning to figure out how these agents work and how to manipulate them, hoping that they can develop drugs to enhance resistance to disease and to retard aging.

Sirtris, a company Dr. Sinclair helped found, has developed a number of chemicals that mimic resveratrol and are potentially more suitable as drugs since they activate sirtuin at much lower doses than resveratrol. This month, one of these chemicals was reported in the journal Cell Metabolism to protect mice on fatty diets from getting obese and to enhance their endurance in treadmills, just as resveratrol does.

Though the sirtuin field holds considerable promise, the dust has far from settled. Resveratrol is a powerful agent with many different effects, only some of which are exerted through sirtuin. So drugs that activate sirtuin may not be as splendid a tonic for people as resveratrol certainly seems to be for mice.

The new finding concerns maintenance of the chromosomes, the giant molecules of DNA that make up the genome.

Each cell has six feet of DNA packed into its nucleus, carrying the 20,000 or so genetic instructions needed to operate the human body. Each cell must provide instant access to the handful of these genes needed by its cell type, but also keep the rest firmly switched off to avoid chaos.

Sirtuin’s normal role is to help gag all the genes that a cell needs to keep suppressed. It does so by keeping the chromatin, the stuff that wraps around the DNA, packed so tightly that the cell cannot get access to the underlying genes.

But sirtuin has another critical role, one that is triggered by emergencies like a break in both DNA strands of a chromosome. After a double strand break, sirtuin rushes to the site to help knit the two parts of the chromosome back together. But in this salvage operation, it leaves its post, and the genes it was repressing are liable to come back into action, causing mayhem.

This, Dr. Sinclair and his colleagues suggest, may be a fundamental cause of aging in mice and probably people, too.

The gene-gagging role of sirtuin was discovered in the 1980s by biologists studying yeast, a standard laboratory organism. Dr. Sinclair and Leonard Guarente of the Massachusetts Institute of Technology found in 1997 that sirtuin could also repair a certain kind of genomic damage in yeast, and in doing so extended the yeast cell’s lifespan. But this particular kind of damage does not occur in mammalian cells, raising the puzzle of why extra sirtuin should be good for them.

Dr. Sinclair’s new report, if verified, resolves this problem by showing that sirtuin has retained its genomic repair role in higher organisms but that the repair is focused on a different kind of genomic damage — that of breaks in a chromosome.

These experiments “elegantly demonstrate” that sirtuin works in much the same way in mammals as in yeast, Dr. Jan Vijg of the Albert Einstein College of Medicine wrote in a commentary in Cell. The question now is whether sirtuin is a pro-longevity factor in mammals, he said in an e-mail message.

Ronald Evans, a biologist at the Salk Institute, said the new report was provocative but did not prove the case that the relocation of sirtuin was a cause of aging. Tests with mice genetically engineered to lack the sirtuin gene could show if the mice suffered from premature aging, as Dr. Sinclair’s idea would predict.

Dr. Sinclair said he agreed that the case for sirtuin’s role in aging had not been proved. “We are careful not to say this is the cause of aging, but based on everything we know it’s not a bad hypothesis,” he said.

It would be nice to test aging in mice that lack the sirtuin gene, as Dr. Evans proposed, but they die too young, Dr. Sinclair said.

Dr. Sinclair has been taking large daily doses of resveratrol since he and others discovered five years ago that it activated sirtuin. “I’m still taking it, and I feel great,” he said, “but it’s too early to say if I’m young for my age.”

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NEW – Researchers from the University of Kentucky annouced that grape seed extract induced leukemia cells to kill themselves. According to the study, within 24 hours of grape seed extract exposure, 76 percent of leukemia cells had died. (Grape seed extract contains Resveratrol). According to the study’s lead author, Professor Shi, “These results could have implications for the incorporation of agents such as grape seed extract into prevention or treatment of hematological malignancies and possibly other cancers”. Further according to Shi, “What everyone seeks is an agent that has an effect on cancer cells but leaves normal cells alone, and this shows that grape seed extract fits into this category”.

Note: These grape seed extract results are not suprising considering Resveratrol has been proven to induce cancer cells to kill themselves; Furthermore, Resveratrol induces cancer cells to kill themselves in a preferable (i.e. normal) manner (like healthy cells die in their natural life cycle). This is opposed to radiation and chemotherapy treatment which cause cancer cells to break open and release their contents into the body, creating inflammation in neighboring cells.

NEW!! Researchers at Harvard Medical School believe they have discovered the universal cause of aging in all animals. As animals age (including humans) their cell’s DNA becomes damaged. This damage decreases their cell’s ability to regulate which genes are turned on and off. If the wrong genes are switched on, this can harm the cell. Helping to solve this problem, sirtuins help ensure that the the incorrect genes remain switched off. Sirtuins also repair the damaged DNA. Resveratrol is a proven activator of sirtuins in animals and humans.

Resveratrol – The Basics

Resveratrol is a powerful antioxidant that is produced by
some plants to protect against environmental stresses.
Perhaps the most notable producer of resveratrol is the
grapevine, which produces large amounts of resveratrol in
the skins of grapes to protect against fungal diseases and
sun damage. It is therefore no suprise that wine (in
particular red wine – which is fermented with grape
skins) has some of the highest levels of resveratrol out of
any natural food.

While it has been know for thousands of years that wine is
a healthful drink (thus the old Roman saying ‘In Vino
Sanitas’- In wine there is health), the scientific community
started taking wine’s health benefits seriously after 60
Minutes reported the famous ‘French Parodox’ study in
which people in France were less likely to die of heart
attacks than Americans despite similar high fat diets. The
study concluded that the relatively large amounts of red
wine consumed by the French protected their hearts.

From the French Paradox study numerous other studies
were launched to attempt to identify compounds responsible
for red wine’s apparent health benefits. From these studies
the compound that gained by far the largest amount of
interest was Resveratrol – AND RIGHTLY SO! Recent
studies have concluded that:

· Adding resveratrol to the diet of yeast, fruit flies, worms, and a species of fish increased their life spans up to 70%, 29%, 24%, & 50% respectively.

· Resveratrol made fat related deaths drop 31% in obese mice. The resveratrol fed obese mice also performed much better in movement and agility tests than obese mice not fed resveratrol.

· Mice fed resveratrol had 100% more endurance than mice not fed resveratrol (i.e. they were able to run twice as far on a treadmill).

· Resveratrol inhibits blood platelet aggregation that can lead to dangerous clots that can cause heart attacks and strokes.

· Resveratrol is a powerful antioxidant that can help prevent cell damage caused by free radicals (free radicals are unstable atoms caused in part by pollution, sunlight, and our bodies natural burning of fat that can lead to cancer, aging, and brain degeneration)

· Resveratrol has been proven to fight cancer in vitro at all three stages; (1) initiation, (2) promotion, (&) progression.

Sources of Resveratrol

Resveratrol is found naturally in:
red wine, grapes, blueberries, peanuts, and various other plants.

It is also found in dietary supplements including:
red wine extracts, grape seed pills and extracts, & polygonum cuspidatum extracts among others.

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Availability of rat stem cells may help link genes to human disorders

FORBES.com, (HealthDay News) — The first embryonic stem (ES) cells from rats have been derived by University of Southern California researchers, who said their success will enable the creation of far more effective animal models to study a wide range of human diseases.

“This is a major development in stem cell research because we know that rats are much more closely related to humans than mice in many aspects of biology,” principal investigator Qi-Long Ying, an assistant professor of cell and neurobiology at the Keck School of Medicine, said in a university news release. “The research direction of many labs around the world will change because of the availability of rat ES cells.”

The ability to derive rat ES cells advances efforts to create rats for use in biomedical research that are genetically modified to lack one or more genes. The ability to observe what happens to an animal when specific genes are removed helps scientists pinpoint the function of genes and whether they’re associated with specific diseases.

“The availability of rat ES cells will greatly facilitate the creation of rat models for the study of different human diseases, such as cancer, diabetes, high blood pressure, addiction and autoimmune diseases,” said Ying, who is also a researcher at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the university.

The first ES cell lines from mice were created in 1981, and researchers have long been trying to establish rat ES cells. But conventional methods developed for deriving mouse ES cells didn’t work in rats. The research team finally found a laboratory-based way to grow rat stem cells indefinitely in the primitive embryonic state.

The research appears in the Dec. 26, 2008 issue of Cell.

In another study published in the same issue of the journal, a team led by researchers at the University of Cambridge in England report similar findings. This provides independent verification that authentic ES cells can be established from rats.

More information

The U.S. National Institutes of Health has more about stem cells.

FORBES.COM, HealthDay News — A key compound in red wine known as resveratrol appears to protect against many of the health ravages associated with growing old, new animal research reveals.

“It’s very hard to extrapolate from this finding to comment on the benefits of red wine directly, because red wine has many other compounds besides resveratrol, including ethanol, which have very active biological effects,” noted study author Rafael de Cabo, unit chief of the laboratory of experimental gerontology at the National Institute on Aging in Baltimore.

“But red wine is a good source of resveratrol,” he added. “And, in this mouse study, we have shown that this particular compound has very strong positive effects on preventing cardiovascular disease, reducing heart inflammation, keeping bone health in terms of structure and function, and maintaining loco-motor and balance activity. So, if these effects translate into humans, it will have a very good impact on the standard of human health.”

De Cabo conducted the research with David A. Sinclair, of Harvard Medical School. Their team published its findings in the July 3 online issue of Cell Metabolism.

Although daily consumption of the compound — also found in the skin of grapes and the crust of peanuts and walnuts — broadly improved the long-term quality of life of middle-aged mice, although most mice did not end up living longer.

Nevertheless, the age-defying health benefits of resveratrol closely mimicked those previously associated with rigorous calorie-restricted diets — raising hopes for simpler and easier means by which to help fight off age-related decline.

The authors noted that prior research has touted the healthy benefits associated with daily caloric restriction of between 30 percent and 50 percent below average, as well as with fasting every other day. Such diets have been linked to a reduction in the risk for age-associated disease and stress, alongside a slowing of age-related functional decline.

“But we can’t have half of America going permanently on a diet,” said de Cabo. “We just can’t do it. It’s not practical, and it’s not going to happen.”

Alternatively, he and his colleagues began to explore the potential of resveratrol — a compound that has already been shown to extend the lives of yeast, worms, flies and fish.

In initial studies, the team found that consuming the compound did improve the health and survival of obese mice — despite consuming a high-calorie diet.

To follow up, the researchers now compared the health and life spans of middle-age mice given either a standard diet or a calorie-restricted diet, with or without high or low daily dosages of resveratrol.

De Cabo and his colleagues found that resveratrol had the same positive impact on mouse livers, muscles, hearts and bones as calorie restriction alone.

Regardless of dietary protocol, the general health and vigor of mice on a long-term regimen (approximately one year) of resveratrol improved overall, without apparent side effects. However, only mice consuming resveratrol alongside a high-calorie diet were found to actually live longer.

“This certainly is consistent with previous studies,” noted Dr. Edward A. Fisher, a professor of cardiovascular medicine and cell biology at the New York University School of Medicine in New York City. “So, I’m not surprised by the finding.”

“But by looking at specific outcomes in specific tissues, this work is certainly more detailed and rigorous,” he added. “And it further supports the hypothesis that this compound staves off the effects of aging.”

On another food front, researchers out of Athens Medical School in Greece have published a new study in the current issue of the European Journal of Cardiovascular Prevention and Rehabilitation suggesting that drinking green tea is good for the heart.

Consuming green tea, the authors noted, appeared to quickly improve the function of cells that line the circulatory system, known as endothelial cells. Because endothelial cell damage is a key contributor to the onset of atherosclerosis, boosting the performance of such cells could help stave off heart disease.

More information

For additional information on health benefits associated with red wine and resveratrol, visit the Mayo Clinic.

Red wine and something in red wine called resveratrol might be heart healthy. Learn the facts, and hype, regarding red wine and its impact on your heart.

Mayo Clinic, Red wine has long been touted as heart healthy. Some have suggested that the apparent health benefits of red wine, namely reducing your risk of heart disease, are behind the so-called French paradox. The French are regular drinkers of red wine and have relatively high amounts of saturated fat in their diet. Despite this fat intake, the French have lower rates of heart disease.

While the news about red wine might sound great if you enjoy a glass of red wine with your evening meal, doctors are wary of encouraging anyone to drink alcohol because too much alcohol can have a host of harmful effects on your body.

But despite the caution, doctors do agree that something in red wine appears to help your heart, though it’s unclear just exactly what that “something” is. Recent research has indicated a substance called resveratrol, which is found in the skin and seeds of grapes used to make wine, has promising heart-healthy benefits.

Resveratrol isn’t the only substance in red wine that looks promising. The alcohol in red wine also appears to be heart healthy. Understand what’s known — and not known — about red wine and its possible heart-health benefits.

How does alcohol help the heart?

Various studies have indicated that moderate amounts of all types of alcohol benefit your heart, not just alcohol found in red wine. Some heart-healthy benefits of alcohol include:

§ Raises high-density lipoprotein (HDL) cholesterol, the “good” cholesterol

§ Inhibits the formation of blood clots

§ Helps prevent artery damage caused by high levels of low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol

Is red wine better?

Red wine in particular seems to have even more heart-health benefits than other types of alcohol, according to a large Danish study from 2000. The study, known as the Copenhagen City Heart Study, found that those who drank red wine had about half the risk of dying of heart disease as those who didn’t.

Additional studies have given mixed results — some confirming the Danish finding, others showing red wine isn’t any better than beer, white wine or liquor for heart health. As a result, the American Heart Association says there’s no clear evidence yet that red wine is superior to other forms of alcohol when it comes to possible heart-health benefits.

The pro-red wine studies suggest antioxidants in red wine called polyphenols help protect the lining of blood vessels in your heart. These antioxidants come in two main forms: flavonoids and nonflavonoids.

§ Flavonoids. These antioxidants are found in a variety of foods, including oranges, apples, onions, tea and cocoa. Other types of alcohol, such as white wine and beer, contain small amounts, too, but red wine has higher levels.

§ Nonflavonoids. These antioxidants found in red wine have recently been of particular interest because they appear to help prevent arteries from becoming clogged with fatty blockages. However, these studies mostly involved mice — not humans. Resveratrol is the nonflavonoid that researchers are most interested in.

Resveratrol in red wine

Some researchers believe that resveratrol might be the key ingredient in red wine that helps prevent damage to blood vessels, reduces “bad” cholesterol and prevents blood clots.

Research in mice given resveratrol has indicated that the antioxidant might also help protect them from obesity and diabetes, both of which are strong risk factors for heart disease. However, those findings were reported only in mice, not in people. In addition, to achieve the dose of resveratrol used in the mice studies, a person would have to consume 100 to 1,000 bottles of red wine a day.

Some companies sell supplements containing resveratrol. However, doctors caution that not enough is known about resveratrol’s effects to endorse resveratrol supplements. Research into the potential heart-health benefits of resveratrol is continuing.

Resveratrol in grapes and other foods

The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Some studies have suggested that red and purple grape juices have some of the same heart-healthy benefits of red wine.

Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.

Drink in moderation — or not at all

Red wine’s potential heart-health benefits look promising. Those who drink moderate amounts of alcohol, including red wine, seem to have a lower risk of heart disease. However, more research is needed before we know whether red wine is better for your heart than are other forms of alcohol, such as beer or spirits.

The American Heart Association doesn’t recommend that you start drinking alcohol just to prevent heart disease. Alcohol can be addictive. Too much increases your risk of high blood pressure, high triglycerides, liver damage, obesity, certain types of cancer, accidents and other problems. In addition, even small amounts of alcohol can cause cardiomyopathy — weakened heart muscle — and heart failure in some people. If you have heart failure or a weak heart you should avoid alcohol completely.

If you already drink red wine, do so in moderation. Moderate drinking is defined as an average of two drinks a day for men and one drink a day for women.

§ A drink is defined as 12 ounces (oz.) of beer, 5 oz. of wine or 1.5 oz. of 80-proof distilled spirits.

The limit for men is higher because men generally weigh more and have more of an enzyme that metabolizes alcohol than women do.

Abstract – Nature 444, 337-342

1. Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

2. Laboratory of Experimental Gerontology,

3. Gene Expression and Genomics Unit,

4. Research Resources Branch,

5. Laboratory of Cardiovascular Science, and

6. Laboratory of Clinical Investigation, Research Resources Branch of the Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA

7. Centre for Education and Research on Ageing, and the ANZAC Research Institute University of Sydney, Concord, New South Wales 2139, Australia

8. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

9. Centro Andaluz de Biologia del Desarrollo, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain

10. Sirtris Pharmaceuticals, Inc., 790 Memorial Drive, Cambridge, Massachusetts 02139, USA

11. Molecular and Cell Biology Laboratory, The Salk Institute, 10010 N Torrey Pines Road, La Jolla, California 92037, USA

12. Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA

13. These authors contributed equally to this work.

Abstract

Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Abstract – New York Academy of Sciences

MAURIZIO STEFANI a , M. ANDREA MARKUS a , RUBY C. Y. LIN b , MARK PINESE b , IAN W. DAWES b , AND BRIAN J. MORRIS a

a Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia b Ramaciotti Centre for Gene Function Analysis, University of New South Wales, Sydney, New South Wales, Australia

ABSTRACT

The natural polyphenol resveratrol stimulates sirtuins and extends lifespan. Here resveratrol inhibited expression of replicative senescence marker INK4a in human dermal fibroblasts, and 47 of 19,000 genes from microarray experiments were differentially expressed. These included genes for growth, cell division, cell signaling, apoptosis, and transcription. Genes involved in Ras and ubiquitin pathways, Ras-GRF1, RAC3, and UBE2D3, were downregulated. The changes suggest resveratrol might alter sirtuin-regulated downstream pathways, rather than sirtuin activity. Serum deprivation and high confluency caused nuclear translocation of the SIRT1-regulated transcription factor FOXO3a. Our data indicate resveratrol’s actions might cause FOXO recruitment to the nucleus.

Abstract – Nature 450, 712-716

1. Sirtris Pharmaceuticals Inc., 790 Memorial Drive, Cambridge, Massachusetts 02139, USA

2. Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

3. Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

4. These authors contributed equally to this work.

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes1, 2. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.