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Longevity quest moves slowly from lab to life

Research on centenarians plus laboratory work with yeast, worms, flies and rodents scientists closer to understanding what causes aging and how to delay it.
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At 104 and counting, Sadie Kaplan has achieved the lifespan so many of us say we want, without ever popping a pill or lifting a finger to pursue longevity.

The secret behind her long, healthy life remains a mystery to the New York matriarch, belle of the local Jewish senior center, who still lives in her own apartment and likes to sneak past well-meaning neighbors for a solo dinner at the nearby Popeyes chicken joint.

“I keep myself so occupied, I haven’t time to get old,” she tells her children.

Daughter Fran Marton says family members feel blessed, but a little surprised, to have had Kaplan around so long. “It started to dawn on me when she was in her 90s that she was unusual,” says Marton, the youngest of five siblings who range in age from 62 to 80. “She has survived just everybody, miraculously.”

But to researchers who have studied Kaplan and other centenarians, her longevity is less a miracle than the key to a scientific puzzle. When Kaplan agreed four years ago to enroll in the Longevity Genes Project run by the Albert Einstein College of Medicine of Yeshiva University, she joined the oldest of the old willing to supply some answers.

In March, for instance, Kaplan’s biological information was part of a study that showed short women may have a genetic mutation linked to long life. (In her prime, Kaplan was 5 feet, 2 inches; now she barely tops 5 feet, her daughter says.) The researchers, who are studying some 450 Ashkenazi Jews ages 95 and older, also have found that centenarians and their offspring have far more HDL cholesterol — the "good" kind — than other people, and that the size of their HDL proteins is larger than normal. And they've used genes from Kaplan and others to detect longevity markers that not only allow people to live longer, but appear to increase mental agility and protect against dementia.

Human studies of people like Kaplan plus laboratory work with yeast, worms, flies and rodents are propelling scientists closer to understanding what causes aging, how to delay it — and how to translate such progress from the lab to real life.

Biologically, it could be possible one day to extend the average nearly 80-year human lifespan by five to 10 years, and eventually, perhaps, to 110 years, says Dr. Nir Barzilai, a professor of medicine and molecular genetics and director of the Institute for Aging Research at Albert Einstein. Even more important, lives could become not only longer, but healthier, thanks to a medical midlife intervention.

“We are in an accelerated area in science,” Barzilai says. “I want to have something you take when you are 40 and then take for 50 years.”

No one’s promising such an anti-aging drug any time soon, says Dr. Evan Hadley, director of the geriatric and clinical gerontology program at the National Institute on Aging in Bethesda, Md. For one thing, it would take decades to conduct trials to confirm safety and effectiveness of such drugs in humans. For another, no current research comes close. “We’re not seeing any of those that will produce any quantifiable increases in lifespan,” Hadley says. Still, anti-aging is a fertile field for research, he notes.

Surprisingly, potential anti-aging tools that have received considerable public attention — stem cell replacement therapy, injections of human growth hormone and testosterone, tissue engineering — don't rank high on the list of most promising techniques cited by Hadley, Barzilai and others. Barzilai's research, for instance, shows that lower — not higher — levels of a protein that correlates with HGH are linked to long life.

Public imagination has been sparked by researchers such as Aubrey de Grey, the British scientist who claims that aging is an "engineering problem" that can be solved by identifying basic causes of aging and creating nuts-and-bolts medical and biomedical solutions. These may include growing new organs or tissues for use in aging bodies, or other techniques promised by the burgeoning field of regenerative medicine. But some scientists who study the underlying causes of aging say such benefits aren't likely to extend lifespan in the near future.

"It's easy to say that aging is an engineering problem, but we're pretty elaborate pieces of engineering," says longevity researcher Brian Kennedy, an assistant professor of biochemistry at the University of Washington in Seattle.

Nonetheless, leading anti-aging researchers are pursuing several approaches that they hope may one day extend lifespan. Here are the top candidates, according to scientists:

Eating way, way less
Known as caloric restriction, or CR, the practice of reducing food intake by at least 30 percent and as much as 70 percent has been regarded for decades as the gold standard for boosting longevity. It’s the single therapy reliably shown to extend lifespan and reduce disease in yeast, worms, flies and rats and to promise the same for primates and, perhaps, people.

Peter Voss, 54, of Los Angeles, has been practicing CR for more than a decade. At a little over 5 feet, 10 inches, he limits himself to 1,850 calories a day, about 300 calories less than recommended for a man of his stature. The lure of a longer, healthier life was the primary motivator for Voss, who won’t even guess how long he might live.

“Ask me that again in a hundred years, I’ll have a better idea then,” he says.

CR proponents report reduced cholesterol, disappearing cardiac risks, lower levels of infection and inflammation, plus other benefits prompted by the process that appears to alter vital metabolic enzymes that create new proteins and remove damaged ones. 

The downside, of course, is that it requires substantially reducing food intake. As Dr. Lenny Guarante, a molecular biologist at the Massachusetts Institute of Technology notes, people who follow CR might live longer, but they’ll seem “unusually miserable.”

That certainly was the case for Micky Snir, 42, of Redmond, Wash., who combined CR with strenuous weight lifting and other exercise for a few years, hoping to extend his life by at least 10 percent. But he found that subsisting on 2,200 calories a day — about 800 calories a day less than recommended for someone at his activity level — left him shaky, edgy and obsessed with food and thoughts of death.

After a difficult divorce, Snir gave up CR, began eating more and seeking new ways to cultivate happiness. He still pursues a healthy diet and regular exercise, but he’s more at peace with the process. “I decided that spending my life in that state was no good,” Snir says.

Also, some scientists worry that the effects of CR on the immune system are unknown and that it may be possible for humans to grow too thin.

Early results from the first clinical trials in humans, conducted at the Washington University School of Medicine in St. Louis, Mo., and Louisiana State University in Baton Rouge, support claims of protection against heart disease, high blood pressure and high cholesterol, but they also show it may be difficult and impractical for people to maintain the practice over time.

CR copycats
Drugs or supplements that mimic the effects of CR without requiring starvation would be a boon, researchers say. But there’s one big problem: “There are a lot of theories, but the actual mechanism by which CR works is not known,” Hadley says.

So far, the most promising candidates appear to be those that affect a series of proteins known as sirtuins, which may influence the processes that govern cell metabolism and death. In humans, one of the most important seems to be SIRT1, a gene that appears to help regulate the metabolic pathways linked to aging, particularly those linked to diabetes and obesity.

“SIRT1 is a gateway to drugs that would be calorie-restricted mimetics,” says Guarante.

That could include drugs like SRT501, a proprietary formulation of the sirtuin-booster resveratrol, a natural substance found in the skin of red grapes and in trace amounts in red wine. Last year, SRT501 was unveiled by Sirtris Pharmaceuticals as a promising treatment for Type 2 diabetes. Drugmakers emphasize that it would be developed only to treat that disease, but scientists say doctors and patients likely won’t ignore possible effects on aging.

Such drugs work by activating SIRT1 in mammals, apparently reproducing the positive effects of CR at a cellular level. They appear to be safe and well-tolerated in early clinical trials in people with Type 2 diabetes in India, Guarante says.

“I’m absolutely excited. The benefits are going to hit the market in one to two years,” he says. “It’s farther along. It’s close to having actual molecules that we could use.”

Not everyone is convinced. Kennedy and his research partner Matt Kaeberlein, an assistant professor of pathology at the University of Washington, are among scientists who say that sirtuins have been overhyped and that more study is needed to determine whether they increase longevity and moderate disease in healthy, normal rodents, let alone humans.

“The story is not as clear and put together as we would like it to be,” says Kaeberlein.

Researching resveratrol Uncertainty also surrounds resveratrol itself. In 2006, researchers reported that resveratrol protected obese mice from the effects of a high-fat diet and dramatically extended the rodents’ lives as well. The news sparked a huge demand for resveratrol supplements, which began flooding the health-food market almost immediately.

Barzilai says that when he asked for volunteers to help study the supplement, he got 250 candidates in one day.

Missing in the excitement was the acknowledgment that the substance had a lifespan-enhancing effect only in obese rats. The benefit has not been reproduced in normal-weight animals, scientists say.

“Right now, we’re nowhere near a basis to say taking resveratrol makes you live longer,” Hadley says. More study of resveratrol’s long-term effects on people is needed, he says.

In the meantime, scientists caution those eager to try it to be aware that most of the products marketed as resveratrol might include only minute amounts of the supplement — or none at all.

Tinkering with growth pathways in cells
Scientists also have experimented with altering the pathways that regulate growth and nutrition in cells. Two promising options appear to be the insulin/insulin-like growth factor 1 pathway, known as IGF1, and the mammalian target of rapamycin pathway, known as mTOR.

IGF1 governs a series of hormonal signals that trigger growth in childhood, and, to a lesser extent, throughout life. Mutations that decrease insulin/IGF1 signaling and impair growth have been shown to increase significantly the lifespan of worms, flies and mice. It was information about the levels of insulin/IGF1 in Sadie Kaplan and her daughters that contributed to Barzilai’s recent findings that such mutations may link shorter stature and increased longevity in humans as well.

The mTOR is a protein involved in the signaling responses of cells and its activity may account for the lifespan extension found in CR. “By tinkering with those pathways, it’s possible we can alter the cells’ aging processes,” Kennedy says.

Research on mTOR by Kennedy and Kaeberlein was recently boosted by the discovery of 25 shared genes that regulate aging in yeast and worms, organisms separated by 1.5 billion years of evolution. Equally remarkable, researchers found that 15 of those genes are present in humans.

“It’s exciting because there are human diseases we can model in worms,” Kennedy says. “If we intervene with aging, we can affect the disease.”

Altering mTOR activity has been found to slow aging in yeast, worms and flies, but Kennedy acknowledges that it’s still a long way from the lab to practical therapies in humans.

Telomeres, antioxidants and stem cells
The same might be said of other scientific research touted as potential routes to longevity. Take telomeres, the chemical caps of DNA that keep our strands of chromosomes from fraying. Like a string of beads losing a pearl at a time, telomeres shorten with aging. When the telomere caps become too short, cells die. Researchers have experimented with an enzyme called telomerase that aims to preserve or lengthen the strand, but the results remain preliminary, Hadley and other scientists say. 

It’s a similar story with antioxidants, natural substances regarded as antidotes to the damage that occurs as tissue ages. Vitamins E and C, zinc, selenium, manganese and certain foods all have been thought to buffer or reverse harm caused by so-called “free radical” molecules that contribute to disrepair.

“Most results with antioxidants have been negative,” Hadley says.

Stem cell transplants, frequently mentioned as a possible aging therapy, are in that category, too, researchers say. Restrictions on and controversy over the use of embryonic stem cells are one problem. But much work remains before it's clear how stem cells might renew aging tissues and extend life, scientists say.

"We're far away on telomeres, and in stem cells, we're even farther away than that," Barzilai says.

Despite the hopes of an aging world, the prospect of extending longevity — or even adding a few extra years to lifespan — remains elusive, scientists say. People have to keep in mind that human longevity is increasing, but incrementally. In the U.S., average life expectancy has inched up during recent decades, from less than 60 years in 1930 and nearly 71 years in 1970 to nearly 78 years in 2005.

“Scientists and people in general want single answers, but biology is complicated and aging is complicated,” Kaeberlein says. “I don’t think there’s anything that’s going to revolutionize medicine in the next five years, unless resveratrol turns out to be a miracle.”

Until then, the scientists remind us, the best hopes for promoting a long life aren’t found in the lab at all. Not everyone can be like Sadie Kaplan, who was always active but never a health nut, and who has avoided most medical care because she's a little wary of doctors, her daughter says.

"Her hearing is impaired, but she refuses to get a hearing aid," says Fran Marton. "She's only had one mammogram in her life."

Clearly, something in Kaplan's make-up has allowed her to live so long, says Marton, who expects to celebrate her mother's 105th birthday on June 18. Part of it might be a certain spirit — "She has lived life as if she were not going to die," Marton says. But the Longevity Genes Project has shown there's almost certainly a genetic basis as well.  

Until scientists tease out the mysteries of longevity genes, or until they mimic the effects with drugs, most people need to rely on practical — albeit boring — interventions like regular exercise, avoiding obesity and limiting dangerous habits, experts insist.

Marton says she tries to eat right and stay fit because she doesn't know whether she takes after her mother or her father, who died at the more typical age of 80. She's not even sure she'd want to live to be older than 100, given the losses of family and friends and no guarantee of good health.

"It's mixed, certainly," Marton says. "But it's nice to feel you have an option."