Web Site Tallies Your Risk Of Disease And Tells You What You Can Do About It

Web Site Tallies Your Risk Of Disease And Tells You What You Can Do About It

October 31, 2006; Page D1
The Wall Street Journal
Everybody worries about cancer, heart disease and other illnesses, but most people don't have any idea what their long-term risk for developing a serious health problem really is.

The best place to find out is a Web site called www.yourdiseaserisk.com1. The site, created by the Harvard Center for Cancer Prevention, stands out as one of the best health-oriented sites on the Web. Most Internet sites give users general health information, but the Harvard site has found a way to provide customized information to help patients better understand their personal health and risk for disease. More important, it also spits out a tailored action plan on ways to lower risk for health problems. It does all this using colorful graphics and charts that allow users to grasp how their health stacks up against the rest of the population and how small changes in lifestyle can lower their health risks.

"We started this because people didn't appear to understand how much of cancer or other diseases can be prevented with changes in lifestyle," says Harvard professor Graham Colditz, director of the cancer prevention center and founder of the site. "We're giving you an individualized assessment of what you can do."

Other Web sites offer calculators to help users assess their risk for various health problems. The American Heart Association, for instance, offers a short quiz to help determine your 10-year risk of heart attack. But the calculator isn't easy to find. Go to www.americanheart.org4 and type "heart attack risk assessment" in the search box. But unlike the Harvard Web site, the heart association calculator just focuses on basic statistics like cholesterol and blood pressure, and doesn't factor in healthful behaviors like exercise, fruit and vegetable intake, and regular wine consumption.

Another site, www.cancer.gov/bcrisktool5 from the National Cancer Institute, allows women to calculate their risk for breast cancer. I like this site because it gives a woman her actual risk rather than using scary-sounding relative-risk percentages. For instance, a 60-year-old woman who had children after the age of 30 and whose own mother had breast cancer has a 44% higher risk of getting breast cancer than the average 60-year-old. But this site puts those numbers in perspective, showing her real risk of getting breast cancer in five years is just 2.6%, compared with the 1.8% risk faced by the average 60-year-old woman. But again, the downside of the NCI calculator is that it uses only a few basic questions and doesn't include the variety of factors that influence breast-cancer risk.

The Harvard Web site allows users to calculate their risk for developing 12 different cancers, as well as heart disease, stroke, diabetes and osteoporosis. The site goes beyond the standard questions about age, cholesterol and family history and explores the variety of lifestyle choices, environmental issues and other factors that can influence health risk. The questions are based on risk factors that have been established through credible scientific studies. To create the site, researchers pored through the medical literature, looking for various risk factors that could influence a particular disease, such as age of first period (breast cancer), age of first sexual contact (cervical cancer) and history of steroid use (osteoporosis). Then a committee of Harvard experts met to discuss the quality of the research behind those risk factors and formed a consensus on which risk factors should be used in the Web-site survey to calculate a person's overall risk for various diseases.

"There's no way to completely control everything," says Cynthia Stein, associate director of the Harvard center, who in 2004 helped revamp the site from just a cancer tool to a risk assessment for several diseases. "You can't change your family history or your age. Those do have a huge impact on your risk, but there are things you can do to keep yourself healthier."

At the end of the survey, the site creates a color-coded graphic showing how your risk stacks up against the rest of the population. But the best thing about yourdiseaserisk.com is the next step -- a customized action plan showing how you can alter your risk through lifestyle changes, such as increasing vegetable consumption, exercising more, taking calcium supplements or a multivitamin, stopping smoking or changing alcohol habits. The site allows you to click on those tips, and the color-coded graph changes, showing the user how adopting the lifestyle changes will alter risk.

The site, which receives about 2,000 visits a day, is supported by Harvard, various foundations and research grants. The site is constantly being updated as new health information becomes available.

Substance in Red Wine Appears To Let Mice Live Longer

Substance in Red Wine Appears To Let Mice Live Longer
By DAVID STIPP
Wall Street Jornal
November 2, 2006; Page B1

One day last summer, a researcher at a Baltimore lab gently lowered two mice onto a device resembling a spinning rolling pin. Though the rodents were old and fat, they gamely began walking in place like log-rolling lumberjacks.

Then the device sped up and forced them to run hard until they maxed out and harmlessly dropped off. Trembling like a winded octogenarian, one fell after 81 seconds. The other lasted 144 seconds -- almost twice as long.


Three 15-month-old mice from the study were fed, from left to right, a standard diet, a high-calorie diet and a high-calorie diet plus resveratrol. Although it still got fat, the mouse on the right had a 31% lower chance of dying as it aged than the control mouse next to it.


The animals were essentially twins that had lived under identical laboratory conditions. But the more vibrant mouse had been given daily doses of resveratrol, a substance in red wine that some researchers think may slow the aging process.

The mice were part of a new study showing that resveratrol at high doses can block many of the deleterious effects of high-calorie diets in mice, enabling them to survive significantly longer than they normally would on fattening fare. Results showing how much longer mice taking resveratrol may live aren't yet complete because some of them are still alive. But preliminary findings indicate they may have a lifespan extension of 20%.

The study follows several earlier ones showing that resveratrol can boost lifespan in creatures like fruit flies. It represents the first time a substance shown to slow aging in multiple species of lower animals was tested for similar effects in mammals. The results boost hopes that resveratrol, or drugs like it, may eventually be able to ameliorate many diseases of aging, and possibly to extend human life, but that would be many years and many studies away.

The resveratrol study was conducted by researchers at Harvard Medical School and the National Institute on Aging, one of the National Institutes of Health. "The significance of the study on a scale of 10 is 11 in the aging and longevity field," said Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in the Bronx, N.Y., who didn't take part in it.

But he cautioned that the study didn't prove that resveratrol slows aging. That's because blocking the diseases associated with rich diets isn't the same as retarding general aging, which isn't considered a disease. In the study, the mice lived longer, but it isn't certain whether that's because resveratrol slowed aging or only blocked diseases associated with rich diets.

LONGEVITY RESEARCH



Antiaging Researchers Study Calorie Cutback1
10/30/06The study's authors are now examining whether resveratrol makes normally fed mice live longer. The data on that should be out next year.

The mice in the Nature study were given much higher doses of resveratrol than anyone could get by drinking red wine, which contains only minuscule amounts of the substance. A person would need to drink more than 300 glasses of wine a day to get the amount of resveratrol the mice got, according to a commentary accompanying the study, which was reported online yesterday by the journal Nature.

Dietary supplements containing concentrated resveratrol extracts, mostly obtained from a plant grown in China known as giant knotweed, let people ingest higher doses than they can get from wine. Various companies, such as Longevinex, based in San Dimas, Calif., sell the supplements over the Internet. But it isn't known what number of such pills might induce health-promoting effects in humans like those observed in mice, because resveratrol hasn't been tested in large, rigorous clinical trials.

Sirtris Pharmaceuticals Inc., a biotech start-up in Cambridge, Mass., co-founded by one of the new study's main authors, recently began testing a resveratrol-based drug in patients with adult-onset diabetes, which is closely linked with fattening diets. Within about a year, the early-stage trial may give a preliminary indication of resveratrol's potential for averting obesity-linked disease in humans. Sirtris says its novel prescription drugs are far more potent than dietary supplements containing resveratrol. Definitive clinical-trial data on the drugs' efficacy probably won't be available for at least several years.

Scientists familiar with the new mouse study generally said that not enough is known about resveratrol to warrant taking the dietary supplements right away. For now, wrote the authors of the Nature commentary, University of Washington biologists Matt Kaeberlein and Peter S. Rabinovitch, "we counsel patience. Just sit back and relax with a glass of red wine."

What has sparked controversy but most interests researchers like Dr. Barzilai about the study are signs that the compound engages the same antiaging mechanisms that calorie restriction does.

Calorie restriction, or CR, entails cutting normal calorie intake by a third or so to slow aging. Discovered in the 1930s, it has been shown to extend longevity by 30% to 40% in animals. Monkey and human studies suggest it can probably also extend human longevity. But its hunger-inducing regimen is too demanding for most people. (Thus, the standard joke about it: Even if it doesn't extend your life, it will make it seem longer.)

Several other substances have shown hints of mimicking CR. A widely used diabetes drug called metformin, for example, activates many of the same genes that CR does. But resveratrol stands out for two reasons: It is the first compound shown to boost lifespan in widely diverse species -- there are four so far -- and it is a naturally occurring molecule that people have long ingested, suggesting that it is safer to take than other potential CR-imitating compounds.


An aged mouse in Dr. Sinclair's Harvard lab like those in the study.


Hopes that resveratrol might yield CR's gain without pain were first raised in 2003 by Harvard Medical School biologist David Sinclair, who led a study showing that the compound boosted yeast cells' lifespan by 70%, apparently by mimicking CR. The finding led to speculation that resveratrol's CR-like effects might already be evident in people in the form of the "French paradox," under which France's famously bibulous citizens have anomalously low rates of cardiovascular disease despite their fatty, high-calorie diets.

Dr. Sinclair has become the leading proponent of the idea that resveratrol mimics the effects of CR. His theory is controversial, and some researchers assert that his interpretation of existing data on the issue is wrong and that resveratrol's mode of action hasn't been pinned down.

Studies that followed those on yeast cells have shown that resveratrol has antiaging effects in roundworms, fruit flies and a species of short-lived fish. They set the stage for the new mouse study, spearheaded by Dr. Sinclair.

The researchers put the mice on high-calorie diets designed to mimic the kind of fattening food many Americans eat. The study demonstrated that while the mice gained weight on their rich diets, resveratrol largely protected them from adult-onset diabetes, the buildup of harmful fatty deposits in the liver, heart-muscle degeneration and other fallout from the rich diets. The report "suggests that guilt-free gluttony might not be a fantasy," wrote the authors of Nature's commentary.

Still, the study's findings are "very important" because they suggest that resveratrol and similarly acting drugs may offer "considerable benefits" for people with obesity-linked diseases, said Massachusetts Institute of Technology biologist Leonard Guarente. Dr. Guarente co-founded Elixir Pharmaceuticals Inc., a Cambridge, Mass., biotech company that competes with Sirtris, which Dr. Sinclair co-founded to capitalize on his research.

The study's findings paralleled those obtained in another investigation of resveratrol's effects in mice on fattening diets that Sirtris reported at a recent scientific meeting.

Besides lowering the risk of diabetes, according to Sirtris's rodent data, resveratrol and like-acting drugs may limit weight gains from rich diets. (Sirtris's chief executive, Christoph Westphal, is married to a reporter for this newspaper.)

Resveratrol pills for people haven't been tested in large clinical trials, so their efficacy isn't proven, nor is it clear what dose would yield desired effects. Still, Dr. Sinclair believes that long-term ingestion of relatively small doses of resveratrol via dietary supplements may help lower the risk of various diseases.

Resveratrol is considered safe at the modest doses available in the dietary supplements. But massive doses given to rats induced signs of kidney damage, anemia, diarrhea and other side effects, according to a 2002 toxicity report on resveratrol by the National Institute of Environmental Health Sciences.

The toxic doses were roughly equivalent to a person taking many thousands of resveratrol pills a day. The study noted that there were no observable adverse effects in rats at doses comparable to a human taking hundreds of the pills daily, a dose far higher than that used in the study described in Nature.

Resveratrol can inhibit formation of new blood vessels in mice with skin wounds, according to the federal institute's safety study. That could potentially retard wound healing. But it may also have benefits by blocking tumor growth. Resveratrol may also inhibit blood-clotting, according to some studies, potentially risky for people undergoing surgery.

Several of the new study's findings support Dr. Sinclair's view that resveratrol mimics the effects of CR. One of the most striking results was the dramatic edge in running endurance among mice on resveratrol compared with their undosed peers. The longer mice were on resveratrol, the perkier they got. After taking it for a year beginning in middle age (the rodents generally live two to three years), elderly mice had about twice the running endurance of undosed peers. Such late-life sprightliness is also observed in old mice long subjected to CR.

Last spring, Italian scientists reported similar vigor in aged fish treated with resveratrol. The substance also boosted the animals' life span by more than 50%. Another research group, whose data aren't yet published, has reportedly seen the same effect in mice on high doses of resveratrol.

Recent studies by Dr. Sinclair's group and others suggest one reason why this energizing occurs: Resveratrol and other compounds that stimulate an enzyme called SIRT1 engender new mitochondria, tiny dynamos within cells that churn out energy for everything from moving muscles to sending signals between neurons. CR is thought to do the same thing, says Eric Ravussin, an authority on CR at the Pennington Biomedical Research Center, an obesity research center affiliated with Louisiana State University, and an adviser to Sirtris.

Dr. Ravussin adds that the fresh mitochondria appear to spew fewer damaging "free radicals," molecules whose DNA-fraying action has been linked to aging, than do the older mitochondria they replace. "It's like replacing the engine of a polluting gas guzzler with an efficient, cleaner-burning new one," he says.

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Researchers Seek Key to Antiaging In Calorie Cutback

Youthful Pursuit
Researchers Seek Key to Antiaging In Calorie Cutback
A Controversial Hypothesis Draws Scientists, Investors;
Will It Work in Humans?

By DAVID STIPP
October 30, 2006; Page A1
The Wall Street Journal

In the 1930s, researchers stumbled onto a surprisingly simple way to slow the biological forces of aging: cutting normal calorie intake by about a third. Scientists found it boosts animals' life spans by 30% to 40%, and considerable evidence suggests that calorie restriction, or CR, would slow human aging too.

But only steely ascetics could hack its hunger pangs. So the finding remained a little-known curiosity in the back halls of science.

Now a coterie of scientists and biotech ventures are rekindling interest in CR as they try to mimic its antiaging effects with medicines. It is still a highly speculative quest, and many researchers fret that it hasn't completely shaken its association with centuries of dubious nostrums to slow aging, from inhaling virgins' breath to eating gold to implanting monkey glands.

Much of the new focus is on a substance in red wine called resveratrol. The interest in it started three years ago when a group led by Harvard Medical School biologist David Sinclair reported that it boosted yeast cells' life span by 70% via a mechanism resembling CR. He later co-authored a study showing that it also boosts life span in fruit flies and roundworms. But his tendency to make bold leaps based on tentative data has also sparked intense controversy. One big question: Does he really understand the workings of CR well enough to mimic them in a drug?

Last spring, Italian scientists reported that resveratrol boosted life span more than 50% in a kind of short-lived fish. Intriguingly, fish on resveratrol had much faster swimming speeds as they aged, and spent far more time moving around, than did undosed control fish.

At least two groups of researchers are now testing whether resveratrol can extend life span in mice -- the first such studies in mammals. At a meeting of the American Aging Association in June, Dr. Sinclair and colleagues presented preliminary results from a study showing that resveratrol had "CR-like protective effects" against the buildup of fatty deposits in the livers of mice on high-calorie diets. That suggests that resveratrol could lead to new drugs for diseases of aging associated with rich diets, such as adult-onset diabetes.

A company that Dr. Sinclair co-founded in 2004, Sirtris Pharmaceuticals Inc., of Cambridge, Mass., has begun testing a resveratrol-based drug in diabetic patients. It has raised $82 million from venture capitalists, a hefty sum for an early-stage biotech. (Sirtris's chief executive, Christoph Westphal, is married to a reporter for this newspaper.)

It faces competition from Elixir Pharmaceuticals Inc., also based in Cambridge, which Dr. Sinclair's former mentor, Massachusetts Institute of Technology biologist Leonard Guarente, co-founded in 1999 to develop drugs based on gene variants that slow aging. The niche also includes BioMarker Pharmaceuticals of Campbell, Calif., and LifeGen Technologies of Madison, Wis., both of which focus on mimicking CR with drugs.

The companies hope to develop therapies for diseases, not antiaging pills. One reason is that the Food and Drug Administration doesn't recognize aging as a problem warranting treatment. But if a drug could retard aging, it might delay the onset and possibly the progression of age-related diseases. "When you slow aging," says University of Illinois epidemiologist S. Jay Olshansky, "you push a host of diseases to later ages at one fell swoop -- cancer, heart disease, Alzheimer's, diabetes, as well as everything else that's negative about growing older."

Some researchers believe antiaging drugs could also improve health in late life -- rather than prolong misery -- letting people stay in relatively good shape until a swift demise. Their case rests partly on the svelte, energetic look of old animals on CR. "Often it's hard to identify the cause of death" in post-mortem studies on such animals, says Richard Weindruch, a University of Wisconsin CR researcher. "The only apparent problem is that they died."

THE BATTLE AGAINST AGING


Key antiaging medical advances:
• 1935: Cornell scientists report calorie restriction's antiaging effect in rodents.

• 1956: University of Nebraska researcher proposes that "free radicals" cause aging, indicating that antioxidants may slow it.

• 1989: U.S. and British scientists propose that calorie restriction triggers an evolutionarily ancient "starvation response" to slow aging.

• 1992: University of California at San Francisco researchers find a gene mutation that doubles life span in roundworms.

• 1996: Southern Illinois University scientists report gene mutation that extends life span in mice.

• 2000: MIT's Leonard Guarente and colleagues report that "SIR" genes actuate calorie restriction's antiaging effects in yeast.

• 2003: Harvard's David Sinclair and others report that resveratrol, a substance in red wine, extends yeast life span.

• February 2006: Italian scientists report resveratrol extends life span of a fish species.

Still, some experts on aging doubt that enough is known about CR to guide the development of drugs that mimic its effects. "We know a lot about CR's effects," says Edward Masoro, a leading gerontologist. "But what bothers me is that I don't think we've figured out CR's basic mechanism yet."

Dr. Sinclair's idea that resveratrol mimics CR has come under heavy fire. His main adversaries are two researchers who used to rub elbows with him when they all studied together with MIT's Dr. Guarente. The skeptics maintain that resveratrol's mode of action is still murky; instead, they are looking at other mechanisms that may account for how CR works.

The resveratrol doses used in the life-span-extension studies in animals were far higher than the amount people can get by drinking wine -- they were roughly equivalent to hundreds of glasses a day. Resveratrol is available as a dietary supplement, but to replicate the doses used in the studies, a person would need to take scores of pills a day. (Sirtris says it is developing prescription drugs that work like resveratrol but are hundreds of times more potent.) The dietary supplements haven't been tested in clinical trials, so their efficacy isn't proven, nor is it clear what dose might make people live healthier or longer. And although they seem safe at modest doses, megadoses may not be.

Nevertheless Dr. Sinclair, a 37-year-old Australia native, thinks taking small doses over time may yield health benefits and has been taking the supplements for three years.

The story of resveratrol has its roots in scientists' increased understanding of CR. In 1989 researchers theorized that it activates a "starvation response" whose genetic machinery evolved eons ago to enable survival through periods of food shortage -- such as droughts -- by retarding the rate of aging. The response blocks growth and reproduction in order to free up energy to slow aging. The energy is siphoned to cellular systems that limit damage from harmful "free radical" molecules and other toxins produced as metabolic byproducts in cells.

The theory explained longstanding mysteries about CR, such as the fact that animals on CR become resistant to toxic chemicals and temporarily lose the ability to reproduce. It also had a dismaying implication: Our obesity-fostering, high-calorie diets are putting us in fast-aging-and-reproducing mode. That may be why childhood obesity is closely linked to early puberty, which now begins before age eight in many girls, and why adult obesity is linked to such a wide swath of aging diseases -- cancer, heart disease, diabetes, arthritis, even Alzheimer's.

But an important piece of CR's machinery remained hidden: the activator that senses calorie intake and, when it is low, triggers cellular changes that retard aging. This CR off-on switch is the holy grail of gerontology, the study of aging. In principle, drugs that turn it on could ward off or ameliorate degenerative diseases of aging, just as CR does in animals.

Many scientists are looking for the switch. And to the consternation of some of them, Dr. Guarente, 54, and Dr. Sinclair assert that they know what it is. Further, Dr. Sinclair's research indicates that resveratrol toggles it in order to slow aging. Their shared view on CR's basic mechanism has sparked a furious debate.

Its roots go back to 1991, when Dr. Guarente's lab at MIT began hunting for life-span-boosting mutations in baker's yeast.

The grandson of Italian immigrants, Dr. Guarente grew up in Revere, Mass., a blue-collar town near Boston. In his memoir "Ageless Quest," he recalls that as a child, "I was precocious by local standards -- I quit smoking in third grade."

By the mid-1990s, Dr. Guarente's lab had zeroed in on so-called SIR, or silent information regulator, genes. SIR mutations enabled yeast cells to divide an abnormally large number of times before dying, a form of extended life span. But how they worked wasn't clear until the group made further discoveries, one of which was Dr. Sinclair's first claim to fame.

Dr. Guarente recalls that Dr. Sinclair, who came to MIT in 1995 to do post-doctoral studies, breezed into his lab as if out of a Crocodile Dundee movie, greeting everyone with a cheery, "Hello, mate." The eldest son of parents who both worked in medical diagnostics, he was known in high school as a talented class clown and risk-taker, a kid who aced science classes but got in trouble for setting off minor explosions in chemistry lab. The idea of taking part in unorthodox, high-risk studies on aging suited him.

In a key experiment, Dr. Sinclair showed that yeast cells' machinery for copying chromosomes runs amok as the cells age, eventually killing them. Hailed as a major advance, the discovery got Dr. Guarente on Good Morning America. It also helped him formulate a theory positing that proteins made by SIR genes activate CR's antiaging action. A SIR gene found in mammals, dubbed SIRT1, seems especially important: It makes a protein that Drs. Guarente and Sinclair believe triggers the slowed-aging mode in mammals when calorie intake is low. In their view, it's either the gerontological grail or a crucial part of it -- hence, stimulating it might slow aging.

Drugs that juice up proteins' activity are very rare. But in 2003, Dr. Sinclair, then at Harvard, heard that scientists at Biomol International LP, a Plymouth Meeting, Pa., biotech firm, had observed signs of SIRT1 activation in test-tube experiments with certain plant compounds. The most promising one was resveratrol. That was doubly exciting, for dozens of studies on the red-wine ingredient had previously suggested that it lowered the risks of heart disease, cancer and various other disorders of aging -- just what a substance that slows aging should do.

Dr. Sinclair soon began the study about resveratrol's effects on yeast aging. But a year after it appeared, studies by other researchers cast doubt on the idea that SIR genes are key actuators of CR.

The sharpest questions were raised by two researchers who also studied under Dr. Guarente: University of Washington biologists Brian Kennedy and Matt Kaeberlein. Their data suggest that CR can exert antiaging effects independently of SIR genes, and that other genes are more central to CR -- at least in yeast. "My view is that CR probably has nothing to do" with SIR genes in lower animals, says Dr. Kaeberlein. In short, according to him, Drs. Guarente and Sinclair haven't necessarily found the grail.

Undaunted, Dr. Sinclair joined forces with a researcher at the National Institute on Aging, Rafael de Cabo, to plan one of the ongoing studies of resveratrol in mice. But he had a problem: He lacked the $20,000 needed to buy mice. Then he got a call out of the blue from Tom LoGiudice, foreman at the U4EA ("euphoria") Ranch near Thousand Oaks, Calif. Mr. LoGiudice had phoned on behalf of the ranch's owner, Harman Rasnow, who was considering taking resveratrol pills and wanted to know more about them. When Mr. LoGiudice heard about Dr. Sinclair's problem, he arranged for his boss to talk directly to the researcher. "I have an 85-year-old passion for longevity," says Mr. Rasnow, pinpointing his age. "David sounded like he was really onto something. So I told him, 'I'll send you a check for $20,000.' "

Dr. Sinclair later got another call from Mr. LoGiudice, this time inviting him to make a pitch for funding to one of Mr. Rasnow's wealthy acquaintances, Paul Glenn, a venture capitalist and a longtime supporter of research on aging. After Dr. Sinclair did so, the Glenn Foundation for Medical Research in Santa Barbara, Calif., awarded $5 million to Harvard Medical School to launch a center on the basic mechanisms of aging with Dr. Sinclair as its founding director. Now plans are afoot to expand the center into a leading institute on aging, says Mr. Glenn, with start-up funding of $75 million to $100 million.

Sirtris, the company Dr. Sinclair co-founded, says it has made progress. Test-tube and animal studies suggest that its early-stage drugs may help treat various neurological killers as well as diabetes, says Dr. Westphal. The company plans soon to begin testing a drug in people with MELAS syndrome, a rare metabolic disorder that afflicts youngsters with potentially fatal brain and muscle deterioration.

At a recent meeting on aging research, a Sirtris scientist reported that SIRT1-activating compounds, including resveratrol, dramatically lowered blood levels of glucose and insulin in mice that get diabetes on high-fat diets, as well as helped to keep their weight down -- just as CR does.

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