Wang works at the ARS Diet, Genomics and Immunology Laboratory, part of the Beltsville (Md.) Human Nutrition Research Center. He published a complementary cell-culture and animal-model study showing that concentrations of resveratrol—a highly bioactive compound found in grapes and other plant foods—actually turned out to be a double-edged sword when it came to mitigating cancer risk.
First, Wang exposed human prostate cancer cells to resveratrol and found that it inhibited the cells' growth. He further tested the cells' gene expression. Then Wang tested the effects of resveratrol on a group of laboratory animals that had sex-hormone-dependent tumor cells.
Half of those animals were fed a daily diet that included 3 to 6 milligrams of purified resveratrol (equal to roughly the amount in five glasses of wine or grape juice). At first, the tumor cells in the resveratrol-fed lab animals grew slower. But as the animals continued to consume resveratrol, there was an increase in blood vessels developing around the tumors of the resveratrol-fed animals, effectively setting up a system of feeding the tumors.
Blood vessel growth (angiogenesis) is key to enabling tumors to grow. In fact, many research labs work on development of anti-angiogenesis compounds to inhibit tumor growth.
Resveratrol still might cut all-cause mortality in humans. But that remains to be proven.
Resveratrol reduces the severity of type II insulin-resistant diabetes. A new study finds that resveratrol works against diabetes by altering brain metabolism.
Chevy Chase, MD—Resveratrol, a molecule found in red grapes, has been shown to improve diabetes when delivered orally to rodents. Until now, however, little has been known about how these beneficial changes are mediated in the body. A new study accepted for publication in Endocrinology, a journal of The Endocrine Society, shows that the brain plays a key role in mediating resveratrol's anti-diabetic actions, potentially paving the way for future orally-delivered diabetes medications that target the brain.
Resveratrol activates sirtuins, a class of proteins that are thought to underlie many of the beneficial effects of calorie restriction. Previous studies in mice have provided compelling evidence that when sirtuins are activated by resveratrol, diabetes is improved. Sirtuin activators are now being tested in humans as anti-diabetic compounds.
I continue to wonder whether I should take resveratrol. Anyone have well-informed views on this question?
Previous studies have shown that intermittent calorie restriction provided greater protection from mammary tumor development than did the same overall degree of restriction, which was implemented in a chronic fashion. The researchers compared changes of a growth factor (IGF-1) in relationship to these two calorie restriction methods — chronic and intermittent — and tumor development beginning in 10-week old female mice at risk to develop mammary tumors. Their hope was to explain why intermittent restriction is more effective.
The overall degree of restriction was 25 percent reduction compared to control mice. Mammary tumor incidence was 71 percent in the control mice who ate the amount of food they wanted, 35 percent among those who were chronically restricted and only nine percent in those who intermittently restricted calories.
If one does not want to do intermittent or constant calorie restriction how best to lower insulin-like growth factor (IGF-1) and insulin in the blood? A lower glycemic index and lower carbo diet probably helps. But I wonder if any reader knows of some good tricks for lower IGF1. Maybe some dietary compound lowers it?
For the guys: It is worth noting that IGF-1 also appears to boost prostate cancer growth. Most of the dietary advice that applies to cutting breast cancer risk also applies to cutting prostate cancer risk. Couples would do well to keep that in mind.
The researchers were surprised intermittent calorie restriction helped since they expected a big IGF1 surge after calorie restriction would cancel out the benefit of brief IGF1 reduction.
The researchers were initially surprised by these findings for several reasons. First, the prevailing wisdom is that the degree of protection from calorie restriction is proportional to the degree of mammary tumor prevention. Second, they originally thought that intermittent calorie restriction might enhance tumor growth due to growth factors being secreted in response to re-feeding, Cleary said.
I did some searching on compounds that'll lower IGF-1. One study reports resveratrol lowering IGF-1 in mice on a high calorie diet. But a paper in Plos One found that while resveratrol delivered many of the benefits of calorie restriction (CR) it didn't lower IGF-1 in mice.
Some of the phenotypes that are observed in animals with altered IGF-1 or insulin signaling are also observed in CR mice, such as reduced levels of IGF-1, insulin and glucose . To investigate if resveratrol inhibits transcriptional profiles of aging and mimics CR through an endocrine mechanism, we measured glucose, T3, insulin, IGF-1 and GH in five month-old control, CR and resveratrol fed mice. Following two months of dietary intervention, we observed reduced IGF-1 levels in CR mice, but not in resveratrol treated mice (Figure 2B). We did not observe significant alterations in any other hormones examined. Surprisingly, because we observed a large overlap of transcriptional shifts induced by resveratrol and CR in all organs examined, our findings also suggest that a large component of the transcriptional program induced by CR may be independent of CR-mediated alterations in plasma IGF-1, or insulin. This conclusion is supported by the finding that dwarfism and CR may impact lifespan through independent mechanisms , and the finding that GH deficiency and CR display minimal overlap at the gene expression level .
Can any flavonoids lower IGF-1?
“Our findings indicate that each tumor cell bears a signature that determines whether or not that cell will be affected by dietary restriction,” says Nada Kalaany, first author of the paper and a postdoctoral researcher in the lab of Whitehead Member David Sabatini. “We think that mutations in the PI3K pathway are a major determinant of the sensitivity of tumors to dietary restriction.”
Do not wait until late in life to clean up your diet. By then the damage has already accumulated.
Chronic inflammation accelerates aging. At least in some species resveratrol extends life. Whether resveratrol will extend life in the average human is still an open question (for which I'd sure like to have an answer). Some researchers in Scotland and Singapore find that resveratrol blocks an inflammation response in mice.
Scientists from Scotland and Singapore have unraveled a mystery that has perplexed scientists since red wine was first discovered to have health benefits: how does resveratrol control inflammation? New research published in the August 2009 print issue of The FASEB Journal (http://www.fasebj.org), not only explains resveratrol's one-two punch on inflammation, but also show how it—or a derivative—can be used to treat potentially deadly inflammatory disease, such as appendicitis, peritonitis, and systemic sepsis.
"Strong acute inflammatory diseases such as sepsis are very difficult to treat and many die every day due to lack of treatment," said Alirio Melendez, senior lecturer on the faculty of medicine at Glasgow Biomedical Research Centre in Scotland and one of the researchers involved in the work. "Moreover, many survivors of sepsis develop a very low quality of life due to the damage that inflammation causes to several internal organs. The ultimate goal of our study was to identify a potential novel therapy to help in the treatment of strong acute inflammatory diseases."
Of course, inflammation response often serves a useful purpose - or else we wouldn't have inflammation response in the first place. So a general suppression of inflammation isn't guaranteed to benefit us.
Sounds like resveratrol down-regulates synthesis of sphingosine kinase and phospholipase D. These are both enzymes involved in inflammation response.
In this study, researchers administered an inflammatory agent to two groups of mice. One group was pretreated with resveratrol and the other group was not. The mice that were not pretreated with resveratrol experienced a strong inflammatory response, simulating disease in humans, while the group pretreated with resveratrol was protected from the inflammation. The scientists then examined the tissues of the mice to determine exactly how resveratrol was able to protect the mice from inflammation. They found that resveratrol used a one-two punch to stop inflammation in the mice by preventing the body from creating two different molecules known to trigger inflammation, sphingosine kinase and phospholipase D. This finding suggests that resveratrol may be harnessable as a treatment for inflammatory diseases and may also lead to entirely new resveratrol-based drugs that are even more effective.
My own suspicion is that resveratrol will extend the lives of some people but have neutral or harmful effects on others. Why? Some people have too much inflammation and others do not. Now, as we age genes for inflammation generally increase in activity. Compounds that reduce inflammation might become more valuable to consume as we get older. So perhaps the odds shift in favor of getting a benefit from resveratrol as we get older. You can also follow the Mediterranean diet to lower inflammation markers.
A recent report found that centrally acting ACE inhibitors (a class blood pressure medications) reduced inflammation in the brain and reduce the incidence of dementia in old folks. Since I do not want to lower my blood pressure I'd like to some other ways to get the same brain aging benefits. Maybe resveratrol is the ticket?
The sirtuin genes activated by resveratrol seem to shift their behavior in stressed mouse cells in ways similar to how they behave in yeast. This provides an important clue about the causes of changes in gene regulation as we age. But is this an argument for taking resveratrol?
One function of the mouse version of Sir2, called SIRT1, is to regulate how genes are expressed in various tissues. Patterns of expression differ among organs--many genes that need to be active in the liver, for instance, must remain silent in the brain. By binding to regulatory regions alongside certain genes, SIRT1 helps dictate those patterns. Because SIRT1 has also been shown to participate in DNA repair, Sinclair and his colleagues wondered whether increasing DNA damage would compromise the protein's normal regulatory role, as is the case with Sir2 in yeast.
Sure enough, when the researchers treated mouse embryonic stem cells with DNA-damaging hydrogen peroxide, SIRT1 migrated away from regulatory regions of the genome and toward the many areas where DNA strands had broken. As a result, genes that were normally shut off suddenly became active. Gene expression patterns, once exquisitely fine-tuned, went haywire.
Lots of patterns of gene expression change as we age. Some of the genes that get turned on might be to try to do repair. Some are involved in inflammatory response. But the turning on of other genes might simply be mistakes that only cause harm.
"This is something that's eerily parallel to what we know in yeast," says Jan Vijg, chair of genetics at Albert Einstein College of Medicine, who was not involved in the study.
Okay, suppose the SirT1 moves to go deal with damaged DNA as we age. Suppose that leaves assorted genes no longer repressed. Then does the use of resveratrol redirect the genes back toward the genes it was originally bound to? If so, does that leave the damaged DNA unrepaired? Or does resveratrol make the SirT1 more active and therefore capable of handling more tasks at once? How can resveratrol allow SirT1 to perform both tasks at once? Anyone have an insight on this?
Connecting the dots, does the unrepression of lots of genes as SirT1 unbinds from them cause obesity?
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.
I am very tempted to start taking resveratrol. Haven't done it yet. I'm reluctant because I keep thinking there's no free lunch. If up-regulation of SirT1 activity will allow us to live longer why was this not selected for already? What is the cost of that higher SirT1 activity? There must be a cost or we'd already have mutations that make SirT1 more vigorous.
The researchers found in studies of mammalian stem cells that the protein SIRT1 controls the packaging of DNA into chromatin, thereby setting the youthful pattern of gene activity by keeping select genes switched off. In response to DNA damage, those SIRT1 proteins leave their posts to go off and assist in the necessary repairs. That change in SIRT1's job description leads to shifts in gene activity that parallel those seen in the aging mouse brain, they show. They suspect similar changes would also be found in other body tissues as well.
Again, do any readers follow the resveratrol research literature closely? What's the trade-off here when using resveratrol?
Resveratrol acts as a sirtuin activator. So does it make SirT1 do more things at once?
Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1.
I'd like to prevent or reverse gene regulation changes associated with aging. But can this be done with a net benefit using a single chemical compound? I'm skeptical but open to evidence.
Update: Giving extra copies of SirT1 to mice which get lymphoma causes them to live longer. But would an extra copy of the SirT1 gene cause standard lab mice to live longer? Would it cause humans to live longer?
The researchers also discovered that lab mice with an excess of SIRT1 showed fewer unwanted changes in gene expression and improved ability to repair DNA. Perhaps this is a way to slow down the aging process; by developing a drug that stimulates SIRT1, said the researchers. There is already evidence that the red wine ingredient resveratrol works via SIRT1, as do several other targeted drugs that are in various stages of development. Following a calorie restricted diet is also thought to slow aging and improve health via SIRT1.
They showed this by using mice genetically altered to model lymphoma. They gave them extra copies of SIRT1, or fed them the SIRT1 activator resveratrol, and found this extended their lifespan by between 24 and 46 per cent.
If youthful patterns of gene expression could be restored would that cause us to live longer? Or are some of the age-related changes in gene expression necessary for adjustment to accumulated damage?
What's not yet clear is how much youthful patterns of gene expression matter. Scientists not involved in the study pointed out that even if that particular aspect of aging is reversible, it is not clear that keeping gene expression young is the key to staying young.
"The paper says you might be able to maintain or go back to a younger gene expression profile, but does that mean you will be younger? You may have passed through that gate already, and you can't go back," said Dr. Stephen Helfand, a professor in the department of molecular biology, cell biology and biochemistry at Brown University.
I am especially interested in sirtuin enhancement drugs for the brain since the brain is going to be the hardest organ to rejuvenate.
Children of people who live to 100 suffer less from heart disease, stroke, and diabetes. So choose your parents wisely.
Boston, Mass. – November 20, 2008 - A recent study appearing in the November issue of Journal of American Geriatrics Society revealed that centenarian offspring (children of parents who lived to be at least 97 years old) retain important cardiovascular advantages from their parents compared to a similarly-aged cohort. The study is the first to assess the health of centenarian offspring over time and could be important for future research, as the subjects may be used as a model of healthy aging.
The findings show that centenarian offspring have a 78 percent lower risk for heart attacks, 83 percent lower likelihood of stroke and an 86 percent lower risk of developing diabetes mellitus.
Additionally, the study found that centenarian offspring who were followed in the study were 81 percent less likely to die than the reference group of similarly-aged patients during the follow-up period. The survival rate is evidence that longevity runs in families, and the results reinforce the notion that there may be physiological and genetic reasons that longevity runs in families.
The identification of genes that influence longevity will lead to drugs that alter genetic regulation in order to produce the same life-extending effects as the right genetic variations provide. Life extending drugs made to act like resveratrol will probably hit the market ahead of drugs made to mimic life-extending genes. I expect drugs that slow aging to have a fairly short-lived run before stem cell therapies and gene therapies eclipse such drugs by repairing and reversing the aging process.
The first aging decelerator drug is already on the horizon. It will get approved for diabetes but many will ask their doctor for it to slow down aging.
Harvard gerontologist David Sinclair, who co-founded Sirtris Pharmaceuticals and first showed resveratrol's effect on mice, says the drug will be inexpensive. Since the company is testing its own formulation as a diabetes drug, it will need to be priced at just a few dollars per dose, competitive with other diabetes treatments. People who use it off-label for other diseases would pay the same price.
I'm tempted to start taking resveratrol now. Anyone want to comment on their experiences using it?
A potential longevity-enhancing drug has passed its final animal testing challenge, pushing closer to reality the dream of all-purpose drugs against diseases of aging.
Mice given the new drug, called SRT1720, gorged on high-fat food for four months without gaining weight or developing diabetes, and ran twice as far on a treadmill as their control-group counterparts. Similar drugs are expected to follow down the pipeline.
SRT1720 targets the gene SIRT1 also targeted by resveratrol while being far more potent.
The drug's side effects aren't yet apparent, but resveratrol has proven safe in animals and — anecdotally, at least — in humans. Since SRT1720 works at doses 1000 times lower than resveratrol, said Lambert, it should prove even safer if effective.
The synthetic drug, called SRT1720, shifted the animals' metabolism into a mode normally seen only when they are calorie-deprived, reported Johan Auwerx, M.D., of the Ecole Polytechnique Federale de Lausanne, and colleagues.
The agent directly activates the so-called SIRT1 pathway, which is believed to account for at least some of the beneficial effects of resveratrol, the health-giving component of red wine.
It would be hard to get a drug such as this approved to slow general aging. But fortunately the benefits against weight gain and insulin resistance mean the drug has very specific clinical benefits that make approval for disease treatment easier.
The drug called SRT1720, which acts through the protein SIRT1, enhances running endurance in exercised mice and protects the animals against weight gain and insulin resistance even when they eat a high-fat diet, the researchers report. The drug works by shifting the metabolism to a fat-burning mode that normally takes over only when energy levels are low.
The findings bolster the notion that SIRT1 may be a useful target in the fight again metabolic disorders, including obesity and type 2 diabetes. It also helps lay to rest a long-standing controversy in the scientific world over the metabolic benefits of the red wine ingredient known as resveratrol. Resveratrol also acts on SIRT1, but its influence on other metabolic actors had left room to question exactly how it works.
Once one of these SIRT1 activators get approved expect to see many people asking for a prescription even if they do not have one of the diseases it treats.
Resveratrol is available now. Whether SRT1720 or another drug which mimics resveratrol will it make it to market remains to be seen. If you want to buy something that might deliver this sort of benefit now resveratrol is the only game in town.
Dr. Deng and colleagues were interested in investigating the relationship among BRCA1, SIRT1 and Survivin. SIRT1 is a protein and histone deacetylase involved in numerous critical cell processes including metabolism, DNA repair and programmed cell death, known as apoptosis. Although SIRT1 has been implicated in tumorigenesis, no concrete role in cancer initiation or progression has been identified. Survivin is an apoptosis inhibitor that is dramatically elevated in many types of tumors. Research has suggested that Survivin may serve to maintain the tumor and promote growth.
The researchers found that BRCA1 functioned as a tumor suppressor by maintaining SIRT1 expression, which in turn inhibited Survivin expression. When BRCA1 was not functioning properly, SIRT levels decreased and Survivin levels increased, allowing BRCA1-deficient cells to overcome apoptosis and undergo malignant transformation.
They went on to show that the compound resveratrol strongly inhibited BRCA1-mutant tumor growth in cultured cells and animal models. Resveratrol is an important constituent of traditional Japanese and Chinese medicine that has recently been shown to inhibit some types of cancer by inducing apoptosis with very little associated toxicity. In the current paper, resveratrol enhanced SIRT1 activity, this leading to reduced Survivin expression and subsequent apoptosis of BRCA1 deficient cancer cells.
These findings identify SIRT1 and Survivin as downstream mediators of BRCA1-regulated tumor suppression and identify resveratrol as a potent inhibitor of BRCA1-mutant cancer cells. "Resveratrol may serve as an excellent compound for targeted therapy for BRCA1 associated breast cancers," says Dr. Deng.
If resveratrol really works in the way described there is a substantial chance that resveratrol might decrease the odds of getting breast cancer in the first place - especially among women who have the BRCA1 mutation that increases the odds of getting breast cancer. Resveratrol appears to substitute for properly formed BRCA1 and enhance SIRT1 which lowers the expression of Survivin. Survivin helps keep cells alive. So less Survivin causes more cancer cells to commit suicide.
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.
I periodically mull over the possibility of taking resveratrol for its various reported benefits. Still haven't crossed over to taking it yet. I expect I'll take it when I get older and my risk of cancer goes up.
Scientifically and health minded chocolate and cocoa eaters take note. Processing of cocoa powder to make it less bitter removes substantial amounts of antioxidants.
Over the past ten years, dark chocolate and cocoa have become recognized through numerous studies for flavanol antioxidant benefits. In a study published this month in the Journal of Agricultural and Food Chemistry, scientists from The Hershey Company and Brunswick Laboratories of Norton, MA report on the levels of antioxidants in selected cocoa powders and the effect of processing on the antioxidant levels. The study, which analyzed Hershey's Natural Cocoa Powder and nineteen other cocoa powders, reported that natural cocoa powders have the highest levels of antioxidants. Natural cocoa powders contained an average of 34.6 mg of flavanols per gram of cocoa powder, or about 3.5% of total flavanols by weight. This places cocoa powder among the foods highest in these types of antioxidants.
The study went on to look at a variety of Dutched (alkaline processed) cocoa powders, which are commonly used by the food industry. New findings showed that the Dutched cocoa powders, especially the light- and medium-Dutched cocoa powders, retained significant amounts of cocoa flavanol antioxidants. In fact, despite the losses created by light to medium Dutch processing, these cocoa powders still were in the top 10% of flavanol-containing foods when results were compared to foods listed in the USDA Procyanidin Database.
This is why Mars sells their Cocoavia line of chocolates that have more retained antioxidants. But it is not clear to me how high the concentration of antioxidants is in Cocoavia versus lightly processed or even heavily processed cocoa powders.
When buying cocoa powders what we need to know is just how heavily processed they have been. The difference between 40% and 10% retention of flavanols is a factor of 4.
In this study, the degree of cocoa alkalization caused a progressive, but not complete loss, of flavanol antioxidants, with about 40% retained in lightly dutched cocoas, 25% retained in medium dutched cocoas, and 10% retained in heavily dutched cocoas.
That USDA Procyanidin Database makes for interesting reading (at least to me). Raw pinto beans are up there with unsweetened chocolate in terms of procyanidin antioxidants and you can eat a lot more pinto beans than chocolate. But cooked pinto beans have about 2 orders of magnitude less of the good stuff. Is that accurate? Blueberries and cranberries are excellent sources. Ditto hazelnuts, pecans, and pistachios. Sorghum is highly excellent. I had no idea. But that's typically cooked. Whereas you can eat the berries and nuts raw. My advice: eat the berries and nuts.
Update: Chocolate contains resveratrol.
In the study, top selling retail products from six categories were tested for the level of resveratrol and its sister compound, piceid. The six product categories included cocoa powder, baking chocolate, dark chocolate, semi-sweet baking chips, milk chocolate and chocolate syrup. Gram for gram, cocoa powder had the highest average amount of resveratrol and piceid, followed by baking chocolates, dark chocolates, semi-sweet chips, milk chocolate and then chocolate syrup. In the products studied, the level of piceid was 3 to 6 times the level of resveratrol.
When the cocoa and chocolate levels were compared to published values for a serving of red wine, roasted peanuts and peanut butter, resveratrol levels of cocoa powders, baking chocolates and dark chocolate all exceeded the levels for roasted peanuts and peanut butter per serving, but were less than California red wine.
My guess: If you want to get a regular substantial dose of resveratrol then best to take pills.
BETHESDA, Md. (Oct. 14, 2008) − The accumulation of fat in the liver as a result of chronic alcohol consumption could be prevented by consuming resveratrol, according to a new study with mice. The research found that resveratrol reduced the amount of fat produced in the liver of mice fed alcohol and, at the same time, increased the rate at which fat within the liver is broken down.
Chronic alcohol consumption causes fat to accumulate and can lead to liver diseases, including cirrhosis and fibrosis of the liver. It can also result in liver failure. The study points to resveratrol as a possible treatment for alcoholic fatty liver disease, and as a way to prevent the disease in those who are at risk, but have not developed it.
Resveratrol is present in grapes, peanuts, berries and in red wine. Other research with mice has suggested resveratrol may have anti-cancer and anti-inflammatory properties. There is also evidence that it has cardiovascular benefits. However, these findings have not been extended to humans.
I'm still waiting for the definitive study on whether resveratrol will lower all-cause mortality. There's a decent chance it will. But at this point I'm still not sure whether resveratrol pills are worth taking.
CAMBRIDGE, Mass., July 3, 2008 -- Sirtris, a GlaxoSmithKline company focused on discovering and developing small molecule drugs to treat diseases of aging such as Type 2 Diabetes, is included among a research team that reported in today's online edition of Cell Metabolism that mice treated at middle-age to the end-of-life with resveratrol showed an overall health improvement, including improved bone health, a reduction in cataracts and cardiovascular dysfunction, and improved balance and motor coordination.
Resveratrol probably works by mimicking the effects of calorie restriction. The big advantage of resveratrol is that most people can't stand to live in constant hunger. Taking a pill is a whole lot easier.
"In this study, we wanted to determine whether or not resveratrol, which imparts many of the same health benefits as caloric restriction in mice, does so by inducing a physiology similar to dietary restriction," says study co-author David Sinclair, Ph.D., a Sirtris co-founder and Harvard Medical School Associate Professor of Pathology. "The data show that resveratrol does induce many similar pathways," says Sinclair, who is co-chair of Sirtris' Scientific Advisory Board. The study was co-led by Rafael de Cabo, Ph.D. at the National Institute on Aging and David Sinclair.
The research team began testing of mice at one year, the mouse equivalent of middle-age, as that is when a small molecule drug mimicking dietary restriction might be given to humans.
Rather than restricting calories by feeding the mice less per day the researchers restrictd calories with every-other-day feeding (EOD). Anyone know why?
The mice were placed on different diets: a standard diet (SD); every-other-day feeding (EOD); and a high-calorie diet (HC). Mice in each dietary regime were divided into treated and untreated subgroups, with some not receiving resveratrol and others receiving different dosage levels of resveratrol.
Surprisingly, resveratrol extends life of those on the calorie restriction diet. I say "surprisingly" because calorie restriction is already causing most of the changes that resveratrol causes. But note that mice on the middle range calorie diet did not live longer as a result of resveratrol treatment.
The study showed that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by dietary restriction, a diet known to slow aging and extend lifespan in rodents and dogs. The study also found a significant increase in lifespan in both the resveratrol treated group on a high-calorie diet and the resveratrol treated group on a calorie restriction diet, but the treatments did not extend lifespan of mice on a standard diet when started at one year of age. This study was funded by the National Institute on Aging.
Maybe on the EOD mice the resveratrol worked by mimicking the effects of calorie restriction on the feeding days?
Resveratrol altered mitochondrial gene expression. I like the idea of delaying osteoporosis, cataracts, and decline in motor coordination.
Specifically, researchers found that resveratrol decreased functional decline often seen in the frail and elderly, such as osteoporosis, cataracts, and motor coordination. For example, in general, femurs from the resveratrol-treated mice trended toward better bone properties, suggested that resveratrol could reduce age-induced bone loss in normal mice. Cataract formation was also lessened by resveratrol in a dose-dependent manner. The mice on a SD treated with resveratrol also showed a significant improvement in balance and motor coordination. The resveratrol treated mice also had improved markers for cardiovascular health. Their arteries were more youthful, and they had reduced aortic stiffness. They also had fewer free radicals and DNA damage.
Even better, I like the idea of reversing the aging process so that we never get osteoporosis, cataracts, cancer, heart disease, decline in motor coordination, shriveling of muscles, graying of all hair, hearing problems, loss of teeth, knee pain, wrist pain, and a great many other things that make aging very undesirable.
My reaction to this study is mild disappointment. Resveratrol did not work nearly as well as calorie restriction in extending life. You still need to starve yourself to assure a longer life.
Resveratrol did not have a significant effect on lifespan in animals fed standard chow, suggesting that the intervention did not affect all aspects of the basic aging process. Mice on a high-calorie diet without resveratrol lived the shortest length of time and mice on an every-other-day regimen lived the longest, regardless of resveratrol treatment. However, for mice on a high-calorie diet, mean and maximum lifespan increased for mice on resveratrol when compared with the control mice. Researchers found that resveratrol's effects on longevity could be completely uncoupled from changes in body weight, meaning that mice on a high-calorie diet with resveratrol did not necessarily lose weight but did experience a longer (and healthier) life than mice on the same high-calorie diet not taking resveratrol. They speculate that improved cardiovascular health and reduced fatty changes in the liver may have contributed to the increased lifespan of resveratrol-treated mice.
I'm still not taking resveratrol yet. But this result makes me lean a little closer toward taking it.
A report in Plos One finds that in mice resveratrol causes a change in gene expression patterns very similar to that seen with calorie restriction diets. Resveratrol might extend life just as calorie restriction does without the need to feel constant hunger or to look gaunt.
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg−1 day−1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.
Biogerontology theorist Aubrey de Grey does not expect calorie restriction (CR) or drugs that mimic calorie restriction to boost human longevity by the same percentage amount that they do in mice. Aubrey expects maybe a year or two extra life from a human as a result of CR. If Aubrey is correct then resveratrol might extend life but not by a decade. However, we still do not know whether resveratrol will lower all cause mortality in humans.
Some of the researchers involved in this effort think this result is important because the dose of resveratrol used is low and makes human use of resveratrol more practical.
"This brings down the dose of resveratrol toward the consumption reality mode," says senior author Richard Weindruch, a University of Wisconsin-Madison professor of medicine and a researcher at the William S. Middleton Memorial Veterans Hospital. "At the same time, it plugs into the biology of caloric restriction."
Previous research has shown that resveratrol in high doses extends lifespan in invertebrates and prevents early mortality in mice given a high-fat diet. The new study, conducted by researchers from academia and industry, extends those findings, showing that resveratrol in low doses and beginning in middle age can elicit many of the same benefits as a reduced-calorie diet.
"Resveratrol is active in much lower doses than previously thought and mimics a significant fraction of the profile of caloric restriction at the gene expression level," says Tomas Prolla, a UW-Madison professor of genetics and a senior author of the new report.
That 4.9 mg per kg means 4.9 mg per 2.2 pounds. So a 180 pound person would take 400 mg of resveratrol per day. Or a 150 lb person would take 334 mg per day. You can easily find resveratrol capsules in the range of 100 to 500 mg per capsule. Though one has to consider the possibility that some of these advertised potencies overstate the quality of the products.
The report is part of a new wave of interest in drugs that may enhance longevity. On Monday, Sirtris, a startup founded in 2004 to develop drugs with the same effects as resveratrol, completed its sale to GlaxoSmithKline for $720 million.
Such drugs will take years to come to market. The clinical trials for these drugs will provide us a clearer picture of whether this effect will provide real health benefits.
Led by Dr. Randall Holcombe, director of clinical research at the Chao Family Comprehensive Cancer Center at UC Irvine, the study followed up on previous in vitro studies showing that resveratrol, a nutritional supplement derived from grape extract, blocks a cellular signaling pathway known as the Wnt pathway. The Wnt pathway has been linked to more than 85 percent of sporadic colon cancers, which is the most common form of colon cancer.
The UC Irvine researchers conducted their study with colon cancer patients. One group was given 20 milligrams daily of resveratrol as a pill; another drank 120 grams daily of grape powder mixed in water; and a third drank 80 grams daily of grape powder.
While the supplements did not have an impact on existing tumors, biopsied colon tissue showed that Wnt signaling in the patients taking 80 grams of grape powder was significantly reduced. Similar changes were not seen in patients taking the higher dose of grape powder or the resveratrol pills.
So excess is not always best and the whole food has advantages over the supplement pill.
Up for a pound of grapes every day?
Eighty grams of grape powder equal a half glass of wine or 1 pound of grapes, which is equivalent to three dietary servings of grapes, according to the USDA.
The wine has alcohol that will increase your risk of some cancers. Grape juice might be more effective.
My general take on studies about specific foods is that they typically are too short in duration and each food has such limited effect that we can't tell whether eating that food for years and years will increase your odds of survival. Remember, you can reduce your risk of a single disease but as a side effect increase your risk of something else. Or maybe you weren't at much risk of, say, colon cancer in the first place.
Whereas studies about whole categories of foods (e.g. vegetables and fruits) typically involve larger groups of people for longer periods of time. So we can state with some confidence that eating lots of fruits and vegetables will increase your life expectancy. But how much of the benefit is coming from particular fruits or vegetables is less clear.
Some of the benefit of fruits and vegetables is probably coming from a displacement effect. The fruits and vegetables displace less healthy foods from the diet. Eat a lot of vegetables and therefore eat less white flour and other refined high glycemic index foods.
WASHINGTON, Oct. 12, 2007 — For the first time, scientists have linked the all-too-human preference for a food — chocolate — to a specific, chemical signature that may be programmed into the metabolic system and is detectable by laboratory tests. The signature reads ‘chocolate lover’ in some people and indifference to the popular sweet in others, the researchers say.
The study by Swiss and British scientists breaks new ground in a rapidly emerging field that may eventually classify individuals on the basis of their metabolic type, or metabotype, which can ultimately be used to design healthier diets that are customized to an individual’s needs. The study is scheduled for publication in the Nov. 2 issue of American Chemical Society’s Journal of Proteome Research, a monthly publication.
Sunil Kochhar and colleagues studied 11 volunteers who classified themselves as ‘chocolate desiring’ and 11 volunteers who were ‘chocolate indifferent.’ In a controlled clinical study, each subject — all men — ate chocolate or placebo over a five day period while their blood and urine samples were analyzed. The ‘chocolate lovers’ had a hallmark metabolic profile that involved low levels of LDL-cholesterol (so-called ‘bad’ cholesterol) and marginally elevated levels of albumin, a beneficial protein, the scientists say.
The chocolate lovers expressed this profile even when they ate no chocolate, the researchers note. The activity of the gut microbes in the chocolate lovers was also distinctively different from the other subjects, they add.
If people who dislike chocolate take cholesterol-lowering statins then will that increase their desire for chocolate? Or does the chain of cause and effect flow in some different direction?
Does this difference have a genetic cause? Just how many of our preferences and desires have genetic causes?
If we turned on a gene that increases longevity and causes cholesterol to get expelled would we crave more chocolate as a result? At least we'd live longer and therefore would gain more time to each chocolate.
The study focused on a gene called SIRT1, which the researchers found prevents cholesterol buildup by activating a cellular pathway that expels cholesterol from the body via HDL (high density lipoprotein or “good cholesterol”).
“SIRT1 is an important mediator of cholesterol efflux, and as such it's predicted to play a role in the development of age-associated diseases where cholesterol is a contributing factor,” said Leonard Guarente, MIT professor of biology and senior author of a paper on the work to be published in the Oct. 12 issue of Molecular Cell.
Drugs that enhance the effects of SIRT1 could lower the risk of cholesterol-related diseases, Guarente said. Potential drugs could be based on polyphenols, which are found in red wine and have been shown to enhance SIRT1. However, the quantities naturally found in red wine are not large enough to have a significant impact on cholesterol levels.
In earlier studies, Guarente has shown that high levels of SIRT1 can be achieved with extreme calorie restriction, but that is unappealing for most people.
Would taking resveratrol increase one's desire for chocolate?
But there is a downside to tuning your metabolism to crave chocolate. Chocolate lovers can be bribed with chocolate.
"Student evaluations of a professor have major influence on what happens to the professor's career - whether a university or college chooses to retain him, give him tenure and even teaching assignments," Youmans said. "We began wondering if outside influences could affect how students rated a professor. People pride themselves in being fair and objective when they are asked to give an assessment of someone else's performance, such as evaluating a professor. But what if they really aren't being objective? What if something else could influence their judgments?"
To test their theory, Youmans visited undergraduate classes with laboratory sections, study sections led by a teaching assistant that drew students from a larger lecture into two smaller groups. In one group, Youmans passed out the evaluations and collected them when the students were finished. In the second group, when it was time for the students to assess their professor's performance, Youmans repeated what was done in the first class, except he offered the students chocolate, saying it was leftover from a prior event, while passing out the evaluations.
Youmans and Jee repeated the experiment in three different classes, and each time the result was the same: The groups that received the offer of chocolate gave their professors higher ratings than the groups that were not offered candy, even though students from either group were rating a class and instructor that they had experienced together.
"I should point out that not everyone in the classes offered chocolate took the candy. Also, we made it clear in all the classes that we were not affiliated with the professor, just 'strangers' asked to pass out and retrieve the evaluations," Youmans said. "But we found that the good feelings brought on by the offer of chocolate from a complete stranger, even in those students who didn't accept the candy, affected the professors' evaluations in a positive way."
So if you need someone to maintain their objectivity be aware of the danger chocolate poses to the human capacity to render objective judgments.
Resveratrol continues to be the supplement which I'm not taking that I most wonder whether I should be taking. Resveratrol appears to confer some protection against prostate cancer.
BIRMINGHAM, Ala. – Researchers at the University of Alabama at Birmingham (UAB) have found that nutrients in red wine may help reduce the risk of developing prostate cancer.
The study involved male mice that were fed a plant compound found in red wine called resveratrol, which has shown anti-oxidant and anti-cancer properties. Other sources of resveratrol in the diet include grapes, raspberries, peanuts and blueberries.
In the study resveratrol-fed mice showed an 87 percent reduction in their risk of developing prostate tumors that contained the worst kind of cancer-staging diagnosis. The mice that proved to have the highest cancer-protection effect earned it after seven months of consuming resveratrol in a powdered formula mixed with their food.
Other mice in the study, those fed resveratrol but still developed a less-serious form of prostate cancer, were 48 percent more likely to have their tumor growth halted or slowed when compared to mice who did not consume the compound, the UAB research team said.
A pair of recent articles from MIT's Technology Review provide a broader look at the science and commercial development efforts around resveratrol. At Harvard Medical School researcher David Sinclair believes resveratrol might extend our lives.
Sinclair's basic claim is simple, if seemingly improbable: he has found an elixir of youth. In his Australian drawl, the 38-year-old Harvard University professor of pathology explains how he discovered that resveratrol, a chemical found in red wine, extends life span in mice by up to 24 percent and in other animals, including flies and worms, by as much as 59 percent. Sinclair hopes that resveratrol will bump up the life span of people, too. "The system at work in the mice and other organisms is evolutionarily very old, so I suspect that what works in mice will work in humans," he says.
Sinclair has co-founded a biotech start-up, Sirtris Pharmaceuticals, to try to develop variations on resveratrol to develop them into drugs.
Sinclair and a few other researchers involved in biotech start-ups around Boston argue that drugs can turn on the same genes that calorie restriction activates and thereby extend life just like calorie restriction does.
Only 20 years ago, aging was considered too complex for pharmacological intervention, involving thousands of genes and pathways. However, geneticists studying model organisms such as yeast and worms discovered several genes that can dramatically extend healthy life span1. There are proaging genes such as IGF-1 and antiaging genes such as SIRT1.
While genes that control aging have only recently been discovered, scientists have known for many decades that a simple change in diet can dramatically slow the pace of aging. "Calorie restriction" (CR), the diet wherein calories are reduced 20 to 40 percent, is the most robust means of extending healthy life span in mammals, and several of the key longevity pathways seem to underlie the beneficial effects of this diet. CR also improves health parameters in higher organisms including humans3.
There is controversy over whether calorie restriction delivers its benefits via SIRT1 activation. Researchers are chasing other genes as activators of CR's life extending effects. But resveratrol might deliver benefits even if it does not do so by emulating CR.
Along with scientists Nanjoo Suh, also of Rutgers, and Agnes Rimando of the USDA’s Agricultural Research Service (ARS), Reddy and his associates conducted a small pilot study to determine the effect of pterostilbene on colon cancer. The study included 18 rats that were given a compound (azoxymethane) to induce colon cancer in a manner similar to human colon cancer development. Nine of the animals were then placed on a balanced daily diet, while the other nine were given the same diet supplemented with pterostilbene (at a level of 40 parts per million).
At the end of an eight-week study period, the rats that were fed pterostilbene showed 57 percent fewer pre-cancerous lesions in their colon in comparison to the control group, Reddy and his associates say. Pterostilbene also reduced colonic cell proliferation and inhibited certain genes involved in inflammation, both of which are considered colon cancer risk factors, the researchers say.
You can read the full paper online: Pterostilbene, an Active Constituent of Blueberries, Suppresses Aberrant Crypt Foci Formation in the Azoxymethane-Induced Colon Carcinogenesis Model in Rats. The full paper reports that pterostilbene has been found in blueberries, cranberries, sparkleberries, lingonberries, and grapes.
Pterostilbene lowers blood lipids and cancer. Some labs report that pterostilbene lowers blood glucose sugar levels as well.
Glucose levels in rats with hyperglycemia induced by streptozotocin were determined after i.p. administration of marsupsin (1), pterosupin (2), and pterostilbene (3), three important phenolic constituents of the heartwood of Pterocarpus marsupium. Marsupsin and pterostilbene significantly lowered the blood glucose level of hyperglycemic rats, and the effect was comparable to that of 1,1-dimethylbiguanide (metformin).
For reasons that are unclear, pterostilbene is not normally found in wine, Rimando says. This may be because it is unstable in light and air, which makes it less likely to survive the wine-making process, she says.
Pterostilbene and resveratrol are both antifungal compounds and they deliver some of same health benefits as each other.
This research provides yet more argument for eating more berries, grapes, and cherries. Eat the full fruit for maximal benefit rather than drinking juice.
ORLANDO, Fla., Feb. 28 -- Drinking a little alcohol every day, especially wine, may be associated with an increase in life expectancy. That’s the conclusion of Dutch researchers who reported the findings of their study today at the American Heart Association’s 47th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.
The researchers found that a light intake of alcohol (on average less than one glass per day) was associated with a lower rate of cardiovascular death and death from all causes. When compared to spirits and beer, consumption of small amounts of wine, about a half a glass a day, was associated with the lowest levels of all-cause and cardiovascular deaths.
"Our study showed that long-term, light alcohol intake among middle-aged men was associated not only with lower cardiovascular and all-cause death risk, but also with longer life expectancy at age 50," said Martinette T. Streppel, lead author of the study and a Ph.D. student in the Division of Human Nutrition at Wageningen University and National Institute for Public Health and the Environment (RIVM) in Bilthoven, The Netherlands. "Furthermore, long-term light wine consumption is associated with a further protective effect when compared to that of light-to-moderate alcohol intake of other types."
Drink, be merry, live longer.
The researchers found that long-term, light alcohol intake of less than or equal to 20 grams per day (1 glass of alcoholic beverage contains 10 grams of alcohol, 1 ounce = ~30 mL of alcoholic beverage) compared to no alcohol intake was associated with a 36 percent lower relative risk of all-cause death and a 34 lower relative risk of cardiovascular death. The average long-term daily intake of the men throughout the 40-year study was six grams based on any alcohol intake of more than zero and up to 20 grams. The long-term average intake of six grams of alcohol is equal to one four-ounce beer, one two-ounce glass of wine or one one-ounce glass of spirits, daily.
When the researchers looked independently at wine consumption, the associated risk reduction was greater. Participants who drank on average half a glass, or 1.5 ounces, of wine per day, over a long period, had a 40 percent lower rate of all-cause death and a 48 percent lower incidence of cardiovascular death, compared to the non-wine drinkers.
Researchers said life expectancy was 3.8 years higher in those men who drank wine compared to those who did not drink alcoholic beverages. Life expectancy of wine users was more than two years longer than users of other alcoholic beverages. Men with a long-term alcohol intake less than or equal to 20 grams per day had a 1.6-year-higher life expectancy, compared to those who consumed no alcohol.
The big question: Why? If wine is more beneficial than other alcoholic beverages then at least part of the benefit comes from something other than alcohol. If so then we can get some of the same benefits by eating foods that contain those compounds. Most obviously, grape juice and grapes. But assorted berries and chocolate contain compounds that are also found in red and white wines. Though resveratrol is found in few other foods besides red wine.
Cancer scientists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have shown that a gene that is involved in regulating aging also blocks prostate cancer cell growth. The researchers, led by Kimmel Cancer Center director Richard Pestell, M.D., Ph.D., hope the newly found connection will aid in better understanding the development of prostate cancer and lead to new drugs against the disease.
SIRT1 is a member of a family of enzymes called sirtuins that have far-reaching influence in all organisms, including roles in metabolism, gene expression and aging.
SIRT1 is the target of the Sirtris Pharmaceutical efforts to develop a more potent and longer lasting variation on resveratrol. High doses of resveratrol turn on the SIRT1 gene. So one obvious implication of this research is that resveratrol might restore the androgen sensitivity of androgen insensitive prostate cancer by turning on SIRT1 which will somehow change mutated androgen receptors and make them no longer stimulate prostate cancer cell growth. That, in turn, would make that fatal form of prostate cancer back into a form that can be controlled with Lupron and other testosterone suppressor drugs.
“We know that sirtuins play a role in aging, and that the risk for prostate cancer increases with aging, but no one has ever linked the two until now,” says Dr. Pestell, who is also professor and chair of cancer biology at Jefferson Medical College.
“We’ve shown that by making a prostate cancer with cells overexpressing a mutation for the androgen receptor, which is resistant to current forms of therapy, we can almost completely block the growth of these cells with SIRT1,” he says. Dr. Pestell and his team report their findings in November in the journal Molecular and Cellular Biology.
Turning on SIRT1 stopped cancer growth.
According to Dr. Pestell, prostate cancer cells can express a mutation that makes patients resistant to current forms of treatment such as hormonal therapy. Such therapy focuses on inactivating the androgen receptor by giving agents that shut off testosterone production.
In one experiment, the scientists took a series of mutations in androgen receptors from prostate cancer patients who are resistant to hormonal therapy and showed that SIRT1 blocks receptor activity, halting cancer growth. “We systematically tested each androgen receptor mutation,” Dr. Pestell explains. “These mutant receptors are resistant to current therapies and are all blocked by expression of SIRT1,” adding that prostate specific antigen (PSA) levels were used to confirm this. Rising PSA levels are frequently an indication of prostate cancer growth or recurrence, whereas falling levels indicate tumor shrinkage.
This result does not suggest (at least not to me) that resveratrol will reduce the risk of getting prostate cancer in the first place. The SIRT1 gene's protein product probably prevents mutated androgen receptors from stimulating an existing prostate cancer. But usually prostate cancer grows with non-mutated androgen receptors in its early stage. Though I can't rule out the possibility that higher activation of SIRT1 (using resveratrol or Sirtris' SRT501 experimental drug or another drug) might reduce prostate cancer risks.
If resveratrol or Sirtris's SRT501 work to restore androgen sensitivity to prostate cancers they will buy prostate cancer sufferers months or perhaps years of additional life. Still, this is not an ideal solution. The testosterone suppressor drugs that would likely still be necessary probably reduce cognitive function, certainly cause muscle mass loss, and cause other harmful side effects. But if cancer cell growth can be stopped by this method the cells might also become more amenable to other treatments such as vaccines and monoclonal antibodies.
Thanks to Robert Silvetz for the heads up on this report. Also see my previous posts on resveratrol: Resveratrol Increases Energy In Humans, Mice and Wine Compound Resveratrol Protects Mice From Obesity Damage.
CAMBRIDGE, MA and Strasbourg, France – November 16th, 2006 – Sirtris Pharmaceuticals and the University Louis Pasteur, Strasbourg announced that in an article published today in Cell, “Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α.” Lagouge et al., Cell. 2006; 127: 1–14, SIRT1 was shown for the first time in a human population to accelerate metabolic rate.
In a human population in Finland, SIRT1 was linked to increased energy expenditure as demonstrated by genetic studies of three variants of the SIRT1 gene. The study also showed that treating mice with resveratrol increased mitochondrial biogenesis leading to increased exercise endurance and protection from diet induced obesity. Activation of SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes, was shown to be the mechanism by which these therapeutic benefits occur.
The doses used in mice, 200 mg/kg and 400 mg/kg, is milligrams per day per kilogram of body weight of the mice. Well, scale that to humans and it becomes clear the dose is very high. A 150 lb human is 68 kilograms. That works out to over 27 grams per day.
Mice were dosed with 200 mg/kg or 400 mg/kg of resveratrol daily in either normal chow or high fat chow. The mice on resveratrol lost weight due to decreased fat, and this was attributed to an increase in the number and function of mitochondria. The resveratrol-treated mice also exhibited improved insulin sensitivity and an increased metabolic rate. Notably, mice treated with resveratrol showed a two-times increase in exercise endurance. These effects were shown to be mediated through SIRT1 and PGC-1α.
The scientists who did the work are at prestigious research universities.
The authors of the Cell article include the teams of the principal investigator Johan Auwerx, M.D. Ph.D., Professor at the Medical Faculty in Strasbourg, at IGBMC (Unité mixte de recherche CNRS, Inserm, University Louis Pasteur), France, and of Pere Puigserver, Ph.D. from Johns Hopkins University School of Medicine in Baltimore (now at the Dana-Farber Cancer Institute/Harvard Medical School in Boston), both members of the Scientific Advisory Board of Sirtris Pharmaceuticals, and Sirtris scientists: Peter Elliott, Ph.D. Senior Vice President and Head of Development, Phil Lambert, Ph.D. Senior Director of Pharmacology, and Jill Milne, Ph.D., Senior Director of Biology.
It would be hard to get regulatory approval for a drug that increased life expectancy because it is a claim that is hard to prove in a clinical trial. But Sitris is chasing a more provable claim: That their modified resveratrol molecule, SRT501, will reduce the symptoms of old age and obesity such as high unhealthy blood lipids and insulin resistance in the form of type II diabetes.
“This work is significant because it shows that a SIRT1 activator can protect against metabolic disease, highlighting the therapeutic potential of sirtuins. Resveratrol a compound found in the skin of red grapes and hence in red wine, could very well explain the French Paradox,” said Johan Auwerx.
Sirtris has initiated a human Phase 1b clinical trial in diabetes with SRT501, a proprietary formulation of resveratrol with improved bioavailability. SRT501 is the first small molecule to enter human clinical trials that is designed to activate SIRT1. Sirtris has applied this scientific discovery to the development of SRT501, which activates SIRT1, for the treatment of diseases of aging such as metabolic and mitochondrial disorders. In addition, Sirtris has a robust pipeline of novel small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol.
“This important work highlights the significance of SIRT1 as a therapeutic target for metabolic disease. Based on the continuing scientific evidence, as shown in this most recent Cell article, we are continuing to advance drug candidates to translate the science of sirtuins into new treatments for diseases of aging, such as diabetes,” said Peter Elliott, Ph.D. Senior Vice President and Head of Development at Sirtris Pharmaceuticals.
“These new human data support SIRT1 as a therapeutic target for metabolic disease. Our broad pipeline of sirtuin modulators have potential in a number of diseases of aging,” said Christoph Westphal, M.D., Ph.D., Chief Executive Officer of Sirtris Pharmaceuticals.
Now for the qualifiers and caveats.
Back in March 2005 Sirtris co-founder David Sinclair of Harvard said that most commercial resveratrol preparations have no active resveratrol in them - with activity measured by the ability to activate the SIR2 enzymes.
Resveratrol is not an easy molecule to protect from oxidation. Most commercially available supplements I have tested have no ability to stimulate SIR2 enzymes.
Longevinex sells resveratrol to many researchers. But their commercial resveratrol preparation has only 100 mg of resveratrol per capsule and costs more than $1 per capsule. But the recent study by David Sinclair and Rafael de Cabo showing resveratrol protected mice from the harms of obesity used a dose of resveratrol that would be the equivalent of 1600 mg for a 150 lb human. Whereas the study above on mice used the equivalent of 27 grams (27,000 milligrams) of resveratrol for a 150 lb human.
Bulk sources of resveratrol from knotweed can be found on the internet. But which of those sources is selling real active resveratrol? Your guess is as good as mine.
Then there's the question of whether this stuff is safe. We do not know. Okay? Really, we do not know. We need a big study of large numbers of people taking a gram of resveratrol a day with all sorts of checks done on them to look for bad signs. My guess is we are not going to see such a study on resveratrol because the money is in making a patentable commercial variation of resveratrol into a marketable drug. That'll take 6, 7, 8 years more and hundreds of millions of dollars.
In the comments section of my post on the David Sinclair and Rafael de Cabo study on resveratrol you'll see a reader who claims he's taking over 1 gram of resveratrol a day with very beneficial effects. He thinks he has a good trustworthy source for large doses.
Where do resveratrol and the Sirtris drug SRT501 fit into the larger picture of anti-aging treatments and life extension? If they work then they probably work by slowing down aging the same way that calorie restriction does. The interest in the Sir1 and similar sirtuin genes comes from studies on calorie restriction's effects on gene expression in yeast and rodents. But we do not know for sure that calorie restriction will increase human life expectancies.
Now, if resveratrol and SRT501 do extend life that's a good thing because they'll help keep us alive until rejuvenation therapies such as gene therapies and stem cell therapies become available. That companies are trying to develop drugs that mimic the effects of calorie restriction is a good thing. I wish them luck and watch their progress closely.
But we still need the rejuvenation therapies and we need even greater efforts to develop rejuvenation therapies. For more on that read about Strategies for Engineered Negligible Senescence (SENS). We won't need to slow the rate of aging when we can reverse aging. Though slowing the rate of aging will still let us go longer between rejuvenation therapy episodes.
Resveratrol, a compound found in highest concentration in red wine, protected mice from the life shortening effects of a high calorie diet.
How the Study Was Done
This 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.
Mice on resveratrol also are more coordinated.
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."
The 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 experiment they did not do: Feed resveratrol to mice on the standard diet. Why we need that experiment: For those of us who are not overweight would resveratrol increase our life expectancy? Maybe. Maybe not. It might emulate the effects of a calorie restriction diet and boost life expectancy even further.
Be careful about taking resveratrol as a supplement. Some preparations are not stable. Also, if you want to get resveratrol then wine made from muscadine grapes is the ticket.
The amount of resveratrol in food substances varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L , depending on the grape variety, whilst white wine has much less - the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, contain more than 40 mg/L.
The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-pound person would need to drink from 1,500 to 3,000 bottles of red wine a day to get such a dose. Whatever good the resveratrol might do would be negated by the sheer amount of alcohol.
That works out to about 1600 mg of resveratrol for a 150 lb human. Even muscadine grapes would give you about 40 milligrams per liter which is slightly more than a quart. The resveratrol supplements on sale that I've seen range as high as 25 mg resveratrol. But at least one scientific paper questions the stability of commercial resveratrol supplements. Does anyone know of recent research on resveratrol potency in commercial supplements?
Gene array studies would be useful here. Give obese mice various doses of resveratrol and see how high the dose has to be to deliver a big protection as measured by changes in gene expression (e.g. in sirtuins). Then do a clinical trial with humans at various doses and do gene expression tests to look for a human dose response curve.
Update: Experimental drug SRT501 is a more potent form of resveratrol and works works by activating the gene SIRT1 which is suspected of increasing life expectancy in animals on calorie restriction diets.
Sirtris Pharmaceuticals, the leading sirtuin therapeutics company, announced today that SRT501, its initial clinical candidate which is a proprietary formulation of resveratrol with improved bioavailability, has been administered to patients with Type 2 diabetes in a human Phase 1b clinical study. Sirtris is studying SRT501 as a drug candidate for Type 2 diabetes, based in part on the scientific evidence that sirtuin activation, by means of compounds like resveratrol, has been shown to have a positive effect on key clinical measures for diabetes. In an article published today in Nature, “Resveratrol improves health and survival of mice on a high-calorie diet,” resveratrol was shown in mice to promote normal cellular function and extend healthy lifespan, including an increase in insulin sensitivity, a decrease in insulin growth factor-1 levels, and an increase in the number of cellular mitochondria. The authors of the Nature article include principal investigator David Sinclair, Ph.D., Associate Professor of Pathology and Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School and co-founder and Board member of Sirtris, and Olivier Boss, Ph.D., Associate Director of Pharmacology at Sirtris.
“This study indicates that SIRT1 is associated with extension of healthy lifespan in obese mice and if this is translated into humans, it could have an enormous impact on medicine.” said David Sinclair. “I believe that the measures of health improvement in this study, such as increased insulin sensitivity and decreased IGF-1 levels, show the potential for sirtuin activation to treat metabolic diseases, such as diabetes.”
SRT501 is the first small molecule to enter human clinical trials that is designed to target SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes. Activation of SIRT1 is believed to be a key pathway by which resveratrol regulates such processes as glucose and insulin production, fat metabolism, and cell survival. Sirtris has applied this scientific discovery to the development of SRT501, which activates SIRT1, for the treatment of diseases of aging such as metabolic and mitochondrial disorders. In addition, Sirtris has a robust pipeline of small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol.
Compounds that slow down the rate of aging will give us more time to wait for actual aging reversal and rejuvenation therapies.