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UNLOCKING THE KEY TO LONGEVITY

The Baltimore Sun

Antonio Zamora, a lean 64-year-old computer scientist from Bethesda, suffers none of the chronic diseases that afflict people his age. "I haven't been sick for a long time," Zamora said. "Last year, my medical bill came to $20 - for my co-pay for my yearly medical exam."

His secret: a variant of an ultra-low-calorie diet known to extend the lives of animals and protect humans from age-related diseases.

Known as calorie restriction, or CR, the Spartan diet is one of several avenues researchers are exploring in their quest to understand and delay aging. They're also interested in genes that appear to play a role in getting older, along with a variety of chemical compounds, including one found in red wine, that may possess life-extending properties.

But assembling the clues to solve the aging puzzle is no easy feat.

"We know a lot more than when Ponce de Leon was wandering around Florida looking for the Fountain of Youth," said Cynthia Wolberger, a Johns Hopkins University professor of biophysics. "But these things are tied together in ways that aren't completely understood."

Even so, paragons of self-control such as Zamora are forging ahead, as are scientists intent on developing anti-aging therapies.

Last week, Harvard University researchers announced a link between aging and two human genes that seem to play a role in the longevity of the cells that compose our bodies. Scientists said the discovery might help explain the health benefits of caloric restriction, which can extend the life of a number of organisms - including rats and primates - by up to 30 percent.

"We've found a gatekeeper of cell survival and potentially the aging process itself," said David Sinclair, a Harvard molecular geneticist and lead author of the paper.

Outside experts praised the study, published in the journal Cell, as an important, scientifically rigorous step in understanding why cells die. But they cautioned that the link to human aging was speculative.

"It's certainly very good, solid science, and it's obviously fascinating," said David Finkelstein, a molecular biologist and program administrator at the National Institute on Aging in Bethesda. "But to extrapolate from that to human aging is a big step."

This is the latest in a string of high-profile discoveries Sinclair has made in his efforts to understand cellular mechanisms of aging and develop drugs to foil them. In 2003, he made headlines after finding that resveratrol, a compound in red wine, could lengthen the life span of yeast cells by up to 80 percent. The compound has since been shown to also extend the lives of worms and flies.

Last year, Sinclair reported that high doses of resveratrol counteracted the ill effects of an unhealthful, high-fat diet fed to laboratory mice. The study also found that resveratrol activated SIRT1, a gene that produces one of a class of enzymes known as sirtuins.

Sinclair believes sirtuins also play a key role in calorie restriction. "Your hamburger could be turning off your longevity," he said. "But there may be ways to turn on the body's genes and to still protect you from diseases of aging."

Sinclair's latest experiment was an attempt to mimic in the laboratory the stresses that near-starvation might put on the cells in a person's body. Cells starved of oxygen and nutrients were better able to protect themselves against DNA damage and cell death, Sinclair said, by activating two more of the seven sirtuin genes humans carry, SIRT3 and SIRT4.

He said Sirtris Pharmaceuticals, a publicly traded company he co-founded in 2004, is focusing on sirtuins in its efforts to develop anti-aging drugs. "I am absolutely certain that within my lifetime we will see a drug that is capable of slowing down the aging process," he said. "I just don't know if it will be five years or 30 years."

Longevity drug

Sirtris is conducting a clinical trial to see whether a compound that activates a sirtuin gene is effective at treating age-related diabetes. Sinclair said the compound activates the sirtuin genes 1,000 times more effectively than resveratrol, the substance found in red wine.

"It's not going to be sold as a longevity drug," Sinclair said of the compound, which has not received FDA approval. "But we might have a drug that could work on multiple diseases of aging."

Other scientists contend that the link between CR and sirtuins is still murky, and that other mechanisms may be at work. "The whole trick is trying to figure cause and effect," Finkelstein said. "Sirtuin genes are something to keep your eye on, but if it's not just one master switch [that slows aging], it's going to be difficult to figure it out."

Although no one knows exactly why CR makes animals live longer, evidence is building that drastically cutting calories protects humans from age-related diseases.

A Johns Hopkins study published last week found that during Cuba's economic crisis from 1989 to 2000, Cubans' health improved drastically. Their average calorie intake dropped by 36 percent to about 1,860 per day and they had to walk more because of fuel shortages. As a result, obesity rates were cut in half and the country recorded substantial declines in cardiovascular disease, Type 2 diabetes and death from all causes.

The U.S. National Institute on Aging is also exploring the phenomenon. In 1987, it began a study of CR in rhesus monkeys and so far, the monkeys appear healthier than those fed a normal diet. That suggests the skinny primates will also live longer.

It's also conducting a two-year study on a group of people who've chosen to follow a CR diet, to see whether they experience immediate health benefits.

"They don't have much muscle and their sex drive may be down," Finkelstein said. "But if you look at every risk for cardiovascular disease, these people look very, very healthy."

Zamora, who follows a less-extreme version of a CR diet than some, understands there is no guarantee he will live longer. "The biggest attraction is health, more than longevity," he said. "The health aspects are well documented."

'I don't feel hungry'

He started eating less about five years ago, after his sister noted that he'd gained weight. At the time, he weighed about 167 pounds, which for his height (5 feet 8 inches) was slightly overweight according to the National Institutes of Health. He also had high cholesterol and was at risk for heart disease. "Everything pointed to the fact that I was not in good shape," he said.

He determined that he was taking in 2,500 calories per day, about 300 calories more than the U.S. Department of Agriculture recommended. "I never passed up a doughnut or a sticky bun," he said. "I was eating basically good food, but got fat from eating all these desserts."

After doing some research, he decided to go on a mild version of a CR diet, cutting back to about 2,000 calories, or 9 percent below the USDA recommendation for men his height. He carefully rations his calorie intake at each meal and exercises for about 30 minutes a day.

"I now have a very standard way of eating," he said. "I feel great, and I don't feel hungry."

He cautioned that it took willpower to give up on the desserts he so enjoyed. "Not everybody can keep on a nutritious diet," he said. "They are always tempted by all these fancy things they see in the grocery store and on television."

"I just got my Medicare card," he added. "And one thing I realized is I'll probably be paying for other people - because I'm not going to need it."

chris.emery@baltsun.com

Caloric count

Here's a look at what Antonio Zamora eats in a typical day:

Breakfast: Zamora has a half-cup of granola, a tablespoon of yogurt and two scoops of protein powder. (about 700 calories)

Lunch: Zamora has a milkshake made with one and a half cups of milk, blueberries and strawberries, more protein powder, and some flaxseed oil and grapeseed oil. Sides include two Brazil nuts and a fish oil capsule. (about 600 calories)

Dinner: Zamora might eat a turkey leg and a big salad, followed by a "little square" of dark chocolate for dessert. (about 700 calories)

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