Monday, June 12, 2006

Back to School: I Become a Student at the Harvard Medical School

The seminar at the Harvard Medical School is free and open to the public. It is entitled, “Aging Well: Finding Keys to a Longer, Healthier Life.” The moderator and two presenters are professors at Harvard Medical School.

So, having a pulse, I get to go to Harvard. So much for Ivy League standards.

The moderator is Lewis A. Lipsitz, MD, director of the HMS Division on Aging and Chief of the Gerontology Division, Beth Israel Deaconess Medical Center. Dr. Lipsitz' research focuses on falls and syncope in the elderly, blood pressure regulation, orthostatic hypertension, and clinical geriatric syndromes.

This geriatric guy and his wife have a front row seat, thanks to a prevalent but under-appreciated and understudied phobia called Front Row Syndrome. Sufferers are afraid to sit in the front row; they will do so only at gunpoint. An apprehensive wife, obviously in the early stages of the disorder, has to be coaxed into the empty front row.

Why does no one care about FRS?

Dr. Lewis says the purpose of the seminar is to bring a “little bit of medical school to the public.” The full house of mostly older people will hear the same information and research findings on aging and human longevity that medical students are getting, and from the same professors.

“Aging used to be viewed as a long period of decline,” Dr. Lewis says, “leading to death. But now we recognize that for many people, aging is actually a period of vitality, of self-actualization. It can be a positive thing in which people maintain a high quality of life until the day they die.”

Dr. Lewis said that one simple fact of demography overshadows all else in aging and health care today: people are living longer and 13% of the population – those 65 and over -- “consume most of our medical resources.”

Presenting first is David Sinclair, PhD, of the HMS Department of Pathology. Dr. Sinclair's research focuses on finding small molecules and genes that can delay or prevent diseases caused by aging. He has recently published major new findings in the prestigious journal Nature, describing a “master regulatory gene” and extending lifespan in lower organisms. He is founder of SIRTRIS Pharmaceuticals, a company seeking to develop drugs to combat diseases of aging such as cancer and diabetes.

Dr. Sinclair is boyish, with a full head of light brown hair, looking far too young to be a professor at Harvard Medical School and a leading researcher in the field of aging and longevity. He apologizes for the Australian accent he has not been able to shake despite several years in Boston.

He begins by saying that human beings today face a barrier of 100 years of age, mainly because of the death toll taken by major chronic diseases such as cancer, heart disease, and stroke.

“Is there an underlying cause of each disease?”

There is a perception, Dr. Sinclair said, that “when a few of us get it, it's an illness; when disease occurs in more than 50% of the population, it is part of aging.” But the fact is, Dr. Sinclair said, we can do a lot to delay aging. “Within 15 years we will have a pill that will slow down the processes of diseases.”

In all animals, he said, aging is slowed down by an extreme diet known as calorie restriction. “I tried it for about a week and gave up. You're hungry all the time. It was too tough for me.” But he emphasized that severe calorie restriction works in all laboratory animals, from worms to rats.

A gerontologist who did pioneering research showing that a low-calorie diet could prolong life and increase vigor was Dr. Roy Walford. His most famous subject was himself.

For the last 30 years of his life, Dr. Walford adhered to a diet of about 1,600 calories a day, far below the 2,000 to 2,800 calories recommended. Eating mostly fruits, vegetables, fish, and lean meat, he kept his weight at about 130 pounds. He stood 5-foot-9.

Dr. Walford experienced major health benefits: lower blood pressure, reduced blood sugar, better cholesterol, more energy and greater zest for life. In research with other people, he demonstrated similar results.

“His work really established the sub-caloric diet as a valid way of increasing longevity,” said Dr. Jonathan Braun, the chairman of pathology and laboratory medicine at the David Geffen School of Medicine at U.C.L.A.

In 1991, Dr. Walford's restricted-calorie diet was put to the test on a national scale when he become one of eight researchers to seal themselves in Biosphere 2, a three-acre self-contained greenhouse in the Arizona desert. Shortly after shutting themselves in, they discovered that they were short of food.

With food scarce, Dr. Walford put the group on a severely restricted diet. When the door of Biosphere 2 was opened two years later, the group emerged with drastic weight loss and improved health.

But the restricted diet could not save Dr. Walford from amyotrophic lateral sclerosis, or Lou Gehrig's disease. He died of the disease in the spring of 2004 at the age of 79, victim of the greatest barrier to human longevity today – chronic disease.

“Life expectancy and life span are not the same,”Dr. Sinclair said. “Life expectancy is the number of years a new baby can expect to live. In 1900, life expectancy was 47 years. Today it is 77.4 years. Life span is the number of years a human being is capable of living. Some say that is 100. Over the last few decades, this number has been creeping upward.

"Maybe this is good, maybe it's not so good. What we should all want is for life expectancy to perfectly match life span. That means we would all live happily to the fullest [the maximum human life span] and then drop dead.”

People are surprised to learn that much of Dr. Sinclair's research centers on simple yeast cells. “Yeasts are organisms who have a life,” he said. “They take nourishment, find mates, reproduce, and have a life span.”

In short, he said, yeast have the essential characteristics found in the animal kingdom, plus a short life span, which makes them suitable for the study of the aging process; the shorter the lifespan studied, the faster answers can come.
Every animal has an intimate relationship with food and this is true of simple organisms like yeast, Dr. Sinclair said.

If yeast have enough food, "they are happy, want to grow fast and want to reproduce. If food is scarce, the yeast become stressed and undergo bodily changes to protect themselves. They pull back from reproducing. Their actions seem to be saying, 'Why reproduce if the offspring are just going to die?'”

This defensive action seems intended to reduce damage to the body, Dr. Sinclair said. It also slows the metabolic rate which has the effect of shifting the body down to slow motion.

“What appears to be happening is that the body is being tricked and mounts defenses,” Dr. Sinclair said. “A car doesn't fix a scratch, but we do. We have little cellular mechanics that spring into action during times of stress and fix us.”

In 1990, the first longevity gene was discovered in a worm. It was a single gene. “That told us that aging can be regulated and that a single gene is the master regulator,” Dr. Sinclair said. The process starts with the diet, which activates the master regulator gene, which changes metabolism and slows the aging process, Dr. Sincalir explained.

When Dr. Sinclair and his team applied severe calorie restriction to yeast, the organism reacted just this way. He and his team found that a single gene, the master regulator, is the engine of the process. The name of the gene is Sir2. Dr. Sinclair reported this remarkable finding in the May 2003 issue of Nature.

Another important finding from Dr. Sinclair's lab quickly followed. Having learned about the controlling role of Sir2 in the aging process in yeast, the scientists searched for a means to activate the master regulator gene without first nearly starving an organism to death.

They succeeded in finding the means in a specific molecule. But where they found the molecule came as something of a shock. They found it in, of all things, red wine.

“I almost fell out of the chair,” Dr. Sinclair said.

The molecule, resveratrol, extends the lifespan of lower organisms by activating an anti-aging pathway. This finding was also reported in Nature, August 2003. Since then, Dr. Sinclair has been introducing resveratrol to a variety of lab organisms and has found that it significantly extends the lifespan of every organism. It doubles the lifespan of yeast, for example.

“We were very sad when those old yeast finally died,” Dr. Sinclair said.

What next?

“The goal now is to design drugs to slow down the aging process.” Dr. Sinclair smiled coyly. “I have a scoop for you, something that hasn't been published but will be soon. Almost certainly this will work in a person.”

So long and keep moving.


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