Still raring to go, Montana resident Walter Breuning turned 113 in September. Just one in 6,000 people lives to be 100, and one in 7 million makes it past 110.   John Moore, Getty Images

 

Scientists can predict who will live past 100 using a subset of 150 genetic variations

MIT Technology Review, July/August 2010, by Emily Singer  –  By analyzing just 150 spots on the genome, researchers can predict who will live to extreme old age with almost 80 percent accuracy, according to a study published online today in the journal Science. Researchers from Boston University employed a widely used genetic-screening technology to find genetic variations that occur more frequently in centenarians–people age 100 and older.

In addition to providing a potential way to predict who might live into their 100s, the findings suggest that genetics play a major role in surviving to extreme old age. And the team hopes that identifying the genes and corresponding molecular mechanisms that promote longevity will give new insight into how to prevent or delay age-related diseases, such as heart disease, Alzheimer’s, and cancer.

“Centenarians are a model of aging well,” says Thomas Perls, director of the New England Centenarian Study at Boston Medical Center and an author of the study. Previous findings from the project, the largest study of centenarians in the world, show that 90 percent of them are free of disability to an average age of 93. “They seem to compress disability to the end of their lives,” says Perls. “I am very hopeful that understanding how centenarians do that will lead to new strategies for therapies.”

Perhaps most surprisingly, preliminary analysis showed that centenarians had just as many genetic variants linked to diseases as did people in the control group. “That suggests that what makes people live long lives is not lack of genetic disposition to disease but longevity-promoting genes,” says Paola Sebastiani, a biostatistician at Boston University and coauthor of the study. “If longevity variants cancel out disease-associated variants, it could open new ways of treating age-related diseases.” The findings also call into question genetic tests now available to consumers that calculate an individual’s risk for a specific disease, such as type 2 diabetes or cancer, based on common genetic variants. “The finding needs to be replicated, but if it’s true, trying to predict risk of disease out of context may be inaccurate,” says Sebastiani. “You need the overall genetic background to make an accurate prediction.”

The researchers used microarrays, chips dotted with specific sequences of DNA, to screen centenarians in the study for about 30,000 common genetic variations. They identified about 30 variants found at significantly higher rates in two groups of centenarians compared to a control group. Each individual variant had little impact, however, so the researchers developed an algorithm to combine the effects of multiple variants acting together. Using a list of the variants that differed most between the control groups and centenarians, they found that the predictive value topped out at about 150 variants; in an independent set of 250 centenarians and 350 controls, the model could accurately predict the centenarians 77 percent of the time. The remaining 23 percent may possess as-yet unidentified genetic factors or be the result of environmental factors not accounted for by the model.

Most centenarians possess a subset of the 150 variants, and the researchers found that their genetic profiles cluster into 19 different genetic signatures. The longest survivors, who live a median age of 108, have the highest number of longevity variants, says Sebastiani. “And some of the signatures correlate with the latest age of onset of age-related diseases, such as dementia or cardiovascular disease.”

“To have about 150 genes involved in exceptional longevity is really very few,” says Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine, in New York, who was not involved in the study. “I think it’s within our power to understand their mechanisms and to start to develop drugs against aging.”

David Altshuler, a geneticist at the Broad Institute, in Cambridge, MA, cautions that the findings need to be repeated, because the study groups and the control groups were drawn from two different populations, increasing risk for detecting genetic differences not linked to longevity. “The authors were very careful in their analysis to address these points, but it will nonetheless be important for independent investigators to confirm the results,” he says.

Scientists haven’t yet looked in detail at the genes implicated in the research; the microarrays used in these studies spotted genetic markers near genes, not the genes themselves. The next step will be to sequence some of the candidate genes in order to figure out what the longevity-linked variants do.

The study did highlight some genes previously associated with longevity, such as a protein involved in cholesterol metabolism and tied to relative risk of Alzheimer’s, as well as genes linked to chromosomal instability and the insulin pathway. “A lot of the genes have no function associated with them as of yet,” says Perls. “We will begin looking at genetic databases to figure out what pathways these genes point toward and maybe start to look at some animal models.”

The researchers caution that the study was limited to people of European descent. “We have to do these investigations all over again for different ethnicities and maybe different environments as well,” says Perls. “If you’re up in Greenland, it probably takes a whole different set of genetic variations to survive in that environment than in Arizona.” His team is already working with a group in Japan that is studying a group of Japanese centenarians.

The findings also raise the possibility of developing a genetic test to predict an individual’s chances of living past 100. But the scientists caution against use of this type of test, at least in the near term. “I think from a social point of view, it’s not ready for prime time. A lot more study has to be done in terms of what physicians can do for people with the results of this test,” says Perls. “If someone has tons of longevity marks, I start to worry about what insurance companies and others would do.”

However, people who have already had their genomes analyzed, through services such as 23andMe, will soon be able to predict their risk score through a free website that Perls’ collaborator is developing. But Perls hopes to head off commercial efforts to market this kind of test. “We are concerned that the marketing [for such a test] will not mention the shortcomings of the test,” says Perls.

“My hope has always been that we would learn much more about how to get lots of people to live to older ages in good health and delay the onset of disease to the end of life,” says Perls. “I do not think this will lead to a treatment that will get people to become centenarians, but rather make a dent in diseases like Alzheimer’s.”

 

A researcher performs a DNA test in a file photo. The test, based on DNA from a drop of blood, can predict exceptional longevity with 77 per cent accuracy, according to an international team that is homing in on genetic elixirs that delay the ravages and disease of aging for decades.

Photograph by: Leon Neal, AFP/Getty Images

Among the key findings of the 2010 Evercare 100@100 Survey: More than 80 percent of the centenarians surveyed say they talk to/communicate with a friend or family member daily.

Photograph by: David McNew, Getty Images

Longevity lab: Harvard’s David Sinclair is testing compounds in mice that could be used to slow down the aging process in humans.
Credit: Rick Friedman/WPN

Can a drug extend good health and postpone the effects of aging?

MIT Technology Review, July/August 2010, by Karen Weintraub  –  Sirtris Pharmaceuticals was, until recently, the golden child of antiaging research. Founded by Harvard biochemist David Sinclair and venture capitalist ­Christoph Westphal, it produced research suggesting something almost too good to be true: that a chemical in red wine could help you live a longer, healthier life. With its young, photogenic founders, the startup was a media darling, the subject of dozens of breathless magazine and newspaper articles. Pharmaceutical giant GlaxoSmithKline was so impressed that it spent $720 million to buy Sirtris in 2008.

David Stipp’s new book The Youth Pill traces this meteoritic rise and other events in the history of antiaging research, detailing how the science and personalities came together at just the right moment to create the successful company. In the mid to late 1990s, Stipp explains, what had been considered a fringe field began evolving into a focused attempt to uncover the biochemistry of aging. Scientists including Cynthia Kenyon at the University of California, San Francisco, and Leonard Guarente at MIT began to find genes linked to longevity in lower organisms such as yeast and worms, prompting a conceptual shift in our understanding of aging. Rather than inevitable decay, their work suggested, aging was a genetically controlled process–and thus one that could be manipulated.

Sirtris was one of the companies to emerge as this view of aging gained currency. At the heart of its drug development program are a class of enzymes called sirtuins: the molecular signals that they send appear to silence aging-related genes during times of starvation. The sirtuins’ role in aging was first identified in 1993 by ­Guarente and his colleagues. (Sinclair would later join the lab as a postdoc.) As Stipp explains, the role of these enzymes in aging made sense to scientists who had known for years that caloric restriction, or nutritionally adequate diets about 30 percent lower in calories than average, could extend the lives of yeast, worms, and mice (the effect was also later demonstrated in rhesus monkeys). Realistically, however, few people can stick to this type of diet. So for more than a decade, the primary goal of antiaging researchers has been to mimic caloric restriction with a pill, a prospect that Stipp describes as “the great free lunch.” Such a drug, he writes, would theoretically postpone aging in people, extending their years of good health and limiting their years of decline.

In 2003, Sinclair made headlines around the world when he announced that the red-wine component resveratrol, which had previously been linked to a reduction in heart disease, extended life span in yeast. He argued that the compound activated one of the sirtuins and proposed that it mimicked the effects of caloric restriction. Sinclair and Westphal launched Sirtris in 2004 with the aim of developing molecules that could stimulate the enzyme much more potently. The company is developing treatments not for aging itself–which the U.S. Food and Drug Administration doesn’t consider an illness–but for diseases of aging, such as diabetes, Alzheimer’s, and cancer.

As Stipp recounts, hopes for antiaging drugs captured media attention and investors’ imaginations. But a different conversation has played out in the academic community. Some scientists doubted whether resveratrol truly targeted the sirtuins. Researchers at drug maker Pfizer also published a study in January questioning whether one of Sirtris’s newer compounds targets the enzyme. The study failed to confirm the health benefits seen in earlier trials. To make matters worse, safety concerns have arisen over one of ­Sirtris’s resveratrol compounds. In May, Glaxo announced that it would not expand a clinical trial for multiple-myeloma patients until it better understood why some participants developed a dangerous kidney ailment.

The field of antiaging research is littered with failures, and the controversy over ­Sirtris’s compounds highlights just how difficult it has been to transform exciting scientific discoveries about the aging process into useful drugs. As Stipp illustrates, many candidates with promising antiaging benefits later failed to work in mammals or showed conflicting results.

Elixir Pharmaceuticals, which was cofounded by Kenyon and Guarente in 1999 to translate their findings on the genetics of aging into a pill, was once “the leading commercial effort to turn research on aging into antiaging drugs,” says Stipp. But the company has been far less successful than ­Sirtris in generating funding and excitement; today it employs just a handful of people, who are still pursuing sirtuins but have also moved on to developing other types of drugs. (Both Kenyon and Guarente have since left Elixir. Guarente joined Sirtris’s scientific advisory board in 2007.) Peter S. DiStefano, chief scientific officer of Elixir, is no fan of the rival company, accusing it of weak science and overzealous claims. “While Sirtris was way more successful than Elixir from a business perspective, at least I have my scientific integrity and can look at myself and say I did the right thing the right way,” he says.

Even if Sirtris’s compounds don’t pan out as safe, effective drugs, the enzymes behind them have great medical potential, says Matt Kaeberlein, an assistant professor in the pathology department at the University of Washington, who is another former student of Guarente’s and a consistent critic of some of Sinclair’s work. These enzymes have been highly conserved through evolution, appearing in worms, flies, mice, and primates, and they play a central role in the biochemistry of the cell. Guarente says, “If the whole world gave up on sirtuins, I would still start another company for the next generation of sirtuin drugs based on what I know.”

But some scientists doubt that sirtuins hold the key to life extension; for one thing, sirtuin activation hasn’t been shown to extend life in healthy animals. A number of other molecular mechanisms are also under close scrutiny for their effects on aging. Kenyon, director of the Hillblom Center for the Biology of Aging at UCSF, points to a different drug, called rapamycin; as Stipp explains, one way it appears to lengthen life is by slowing the production of the proteins needed for cell division. As more proteins are produced, so are more defective proteins, which can accumulate in cells and contribute to the symptoms we see as aging.

Though rapamycin has not gotten nearly the attention or money that sirtuins have, some put far more faith in its age-slowing effects. “I’ve been in this area for about 35 years, and I honestly have never thought that in my lifetime there would be something like a pill that you could take that would have this impact on aging,” Arlan Richardson, director of the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center at San Antonio, says of the drug. Aging “may not be as intractable a problem as I thought,” he says. Rapamycin even worked on adult mice equivalent in age to 60-year-old people.

So why isn’t rapamycin more talked about? “The scientists involved with the rapamycin studies have been much less inclined to make bold claims,” Kaeberlein says. “That may be in part due to the fact that the mouse rapamycin studies were done as part of [a government] testing program, so there’s no commercial interest involved in selling a story.” But if sirtuins and rapamycin don’t work, researchers say, there are plenty of other possibilities to explore, from insulin signaling to mitochondrial function.

Stipp and others are confident that a “youth pill” is on the horizon–whether it comes from Sirtris or not. But some researchers are far less optimistic. Thomas Perls, for one, thinks it’s reckless to suggest that science is anywhere close to such a drug. “I think people just don’t get how incredibly complex aging is,” says Perls, an associate professor of medicine at Boston University’s School of Medicine, who for the last 16 years has run a study on centenarians. “Delivering the message that antiaging works, and that we’re now in prime time in producing substances that work, is incredibly irresponsible.”

Karen Weintraub is a freelance writer based in Cambridge, MA. She is the former Deputy Health/Science Editor at the Boston Globe.

Copyright Technology Review 2010 

Protecting the brain: Alzheimer’s disease is characterized by the buildup of protein plaques, shown here, in the brain. A genetic variation that boosts levels of “good” cholesterol appears to protect against the disease.   Credit: Cecil H. Fox / Photo Researchers

Drugs that mimic the molecular effect are under development

MIT Technology Review, by Emily Singer  –  A genetic variation previously linked to longevity may also protect against the development of Alzheimer’s disease and other types of dementia, according to a new study. The variant affects cholesterol metabolism, boosting levels of high density lipoprotein (HDL), also known as “good” cholesterol, but it’s not yet clear how it could promote healthy aging in the brain. The new findings are likely to heighten interest in finding ways to chemically enhance good cholesterol–experimental drugs that mimic the molecular effects of the genetic variant are already in clinical tests for heart disease.

In a previous study of Ashkenazi Jews, researchers at Albert Einstein College of Medicine, in New York, found that a specific variation in a gene that codes for a protein called cholesteryl ester transfer protein (CETP) is more common in very long-lived people. Those older people who carried it also tended to have better cognitive function. (Ashkenazi Jews are often studied in genetic research because they originate from a relatively small founder population and possess less genetic complexity than other groups, making it easier to identify meaningful genetic targets.)

The new research, conducted by the same group on a more diverse sampling of people, found that those with two copies of the protective variant had a 70 percent lower chance of developing Alzheimer’s and other dementias, as well as a significantly lower rate of memory decline. “That’s a huge reduction,” says Richard Lipton, senior author of the study. “I’m not aware of other genetic factors that have that effect.” The research was published today in the Journal of the American Medical Association.

“It’s a striking reduction in the incidence of Alzheimer’s disease and dementia that they observe,” says Benjamin Wolozin, a neurologist at Boston University’s Alzheimer’s Disease Center, who was not directly involved in the research. “I think there is increasing evidence that factors that protect the cardiovascular system also protect against dementia.” Still, he cautions that other studies examining the same gene have had mixed results, so the findings are not yet conclusive.

The new findings are part of the Einstein Aging Study, an ongoing examination of a diverse group of people age 70 and older living in the Bronx. All were free of dementia when they enrolled in the study. Participants undergo regular cognitive testing, as well as annual medical and neurologic exams.

The frequency of the protective CETP variant in the general population is not well known. But Lipton says that his team’s previous studies have found that about 5 percent of 60-year-olds had it, and approximately 25 percent of centenarians–those age 100 or older. “It’s one of the more robust longevity genes we have identified,” says Lipton. The Einstein researchers are now trying to replicate the findings in another group. They also hope to find other genetic variants that protect against Alzheimer’s disease.

People with the protective variant produce a less active version of CETP protein, which in turn raises levels of HDL, or good cholesterol. HDL plays an important role in the membranes of nerve cells in the brain, but it’s not yet clear what role the genetic variation plays in the brain. “It may also cause particle sizes of certain lipoproteins in blood to be larger,” says Amy Sanders, a physician at Einstein and lead author of the paper. “But exactly how that helps isn’t known.”

“My speculation is that it helps get blood into the brain,” says Wolozin. “We do know that reduction in blood flow is one of the earliest changes in dementia, and anything that preserves blood flow to the brain is helpful.”

The findings support the link between cholesterol levels and dementia. Another genetic factor previously linked to Alzheimer’s risk, a gene called Apolipoprotein E (APOE), also affects cholesterol metabolism; a variant known as APOE4 substantially increases the risk of developing Alzheimer’s, while a much rarer version called APOE2 reduces the risk.

Pharmaceutical companies are already developing drugs, called CETP inhibitors, that mimic the effect of the protective variant in hopes of preventing heart disease. (Raising HDL has long been thought to protect the heart, though that link has yet to be conclusively proven.) The first CETP inhibitor to be tested in humans–a highly hyped drug from Pfizer called torcetrapibturned out to be a multibillion-dollar failure. Rather than helping heart health, it appeared to increase blood pressure, and testing was halted in 2006.

Scientists have since determined that the negative effects were likely due to the molecule itself rather than its method of action. A handful of other CETP inhibitors are now in clinical trials, including compounds from Roche (dalcetrapib) and Merck (anacetrapib). Both appear to raise good cholesterol without increasing blood pressure, though their long-term safety and effectiveness in preventing heart disease is not yet clear.

“Ultimately, I think people who are developing these drugs to raise HDL may end up adding cognitive measures to their studies to see if there is a protective effect on cognition,” says Lipton. Previous research on mice that were engineered to mimic Alzheimer’s found that CETP inhibitors provided modest protection against the disease.

Anders Olsson, a physician and researcher at the University of Linkoping, in Sweden, is testing Roche’s CETP inhibitor in people with heart disease. He says that these patients probably aren’t the best subjects to tests cognitive function. “But this type of finding suggests these end points should be included,” he says.

While there are a number of drugs available to treat Alzheimer’s disease, none are approved to prevent the onset of the disease. “But given that there are four million Americans with Alzheimer’s and the number is likely to skyrocket as the population ages, there is a huge societal and public health need to develop agents that will prevent the disease,” says Lipton.

 

96-year-old Eric Brown still delivers meals on wheels and

says all of his customers are younger than he is.  He’s still raring

to go!    Photo: Anthony Johnson