SEPTEMBER / OCTOBER 2005

FORUM

Unraveling the secrets of aging: Scientists seek the key to a healthier old age

Aging is a fact of life. It is also becoming a global issue, as the rising proportion of elderly threatens to overwhelm the world’s health care systems. The percentage of people over age 65—particularly those over 85—is rising rapidly, fueling an impending wave of chronic non-communicable diseases, such as cardiovascular disease, diabetes, Alzheimer’s, and forms of cancer, as well as musculoskeletal problems and other conditions related to aging.

Roger McCarter: “There has never been a time which has been more exciting in the history of aging research.”

Fortunately, awareness is spreading that a change is needed, says Dr. Roger McCarter, professor of the Genetics Center at Pennsylvania State University’s Department of Biobehavioral Health. He should know. He is also president of the International Biogerontology Resources Institute, and chair of the North American Committee of the International Association of Gerontology. In these roles he’s observed that “governments are recognizing that something has to be done to minimize disease and disability in old age and keep people living independently for as long as possible,” he says. In other words, we might think of aging as a disease, and go from there to determining to what extent it is a treatable one.

McCarter, who has been studying the mechanisms of aging for the past three decades, says the field has suddenly exploded. More money is being channeled into longevity studies, and scientists are making new discoveries every day. As a result, he says, “There has never been a time which has been more exciting in the history of aging research.” And contrary to popular belief, most of this research is not intent on extending the human life span. It is devoted to creating healthier old people, who can remain independent and able-bodied longer in life. It’s a two-pronged goal. From a health systems perspective, it is imperative to do all that is possible to minimize the burden of the elderly, as their numbers rise, on health care systems. The other obvious objective is to extend quality of life into the golden years, to foster a healthier—and happier—elderly population.

Within the pursuit of a healthier old age, there are two broad categories. Experimental researchers are deciphering the mysteries of aging. Meanwhile, translational researchers are putting into practice what is understood today.

In this HMI World Forum, two scientists at the forefront of each branch of aging research discuss how they and their colleagues are approaching the concept of aging—as both a health care issue and as a process that occurs in our bodies. Dr. David Sinclair, associate professor of pathology at Harvard Medical School and director of the school’s Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, is known for his groundbreaking molecular research. And Dr. Lewis Lipsitz, chief of gerontology at Beth Israel Deaconess Medical Center, vice president of Academic Medicine at Hebrew SeniorLife, and professor of medicine at Harvard Medical School, is using complexity theory to understand why so many older people suffer dizziness and falls.

That which doesn’t kill you makes you stronger

Experimental scientists want to know why people age, how people age, and what can be done to slow the process. To answer these questions, they are studying a variety of life forms, including yeast, fruit flies, nematodes, mice, and primates in search of clues they can apply to human aging. As they examine the genes, cells, and organs involved in aging, they are delving ever deeply into the body’s mysteries.

Science has known for more than 70 years, for example, that severely restricting calories extends the life span of mice and rats by preventing them from getting many of the diseases of aging. But to date, nobody understands precisely why or how the process works. Many scientists are developing theories and trying to mimic the effects of calorie restriction without putting people on a starvation diet. One of the best known and most single-minded of these is David Sinclair.

David Sinclair: Drugs to treat Alzheimer’s and other aging-related diseases could be right around the corner

Sinclair has been working on this calorie restriction puzzle for a decade. In that time, he has fine-tuned a theory of how it works. He calls his hypothesis “xenohormesis.”

Xenohormesis comes from the word xeno, which means “between organisms” (plants and animals, in this case), and hormesis, meaning “a little bit of stress can be good for you,” he explains. Beyond its philosophical implications, the theory of xenohormesis proposes that organisms have evolved to respond to stress signaling molecules produced by other species in their environment. In this way, organisms can ready themselves for a deteriorating environment or loss of food supply.

“Plants make compounds in response to adversity, such as too much sun or not enough water or food,” Sinclair explains. “It’s our belief that our bodies have evolved to pick up on these chemical cues from the plant world. When we ingest the compounds, they turn on our own bodies’ defenses against adversity, and the upshot of that is less disease and hopefully, a longer lifespan.”

Sinclair and his colleagues have extracted these compounds (or molecules) called polyphenols from plants such as onions and grapes (to be more precise, red wine made from grapes), though small quantities of them exist in most foods. When the scientists gave the molecules to yeast, worms, and fruit flies, the organisms lived longer. When the molecules were fed to mice, they prevented cancer, diabetes, and Alzheimer’s disease.

Today, Sinclair’s lab is reengineering the compounds and turning them into drugs. How do these miracle molecules work? You can think of the body as being like an automobile. Most people think that, like a car, the body wears out and breaks down. But increasingly scientists believe that if the body is like a car, it has the equivalent of internal mechanics and body repair technicians who fix damage as it occurs. “In the last few years,” says Sinclair, “we’ve figured out how to get these guys up earlier in the morning and working to keep our bodies in a more pristine state.”

The secret to resetting the mechanics’ alarm clocks lies in a family of enzymes called sirtuins. These sirtuins—which are found in almost every species including plants and fungi as well as mice and humans—protect cells from damage and keep them alive.

When yeast and worms are fed a restricted calorie diet, the activity of the sirtuins increases. This increased activity extends the organisms’ lifespan. Amazingly, the same thing happens when they are fed polyphenols from stressed plants.

Sinclair and his colleagues predict that eventually they will find a bounty of medicinal molecules in stressed plants that will stimulate the activity of the seven human sirtuins involved in aging (SIRT 1-7).

“ If we’re right about our theory,” Sinclair asserts, “the development of these drugs will represent a turning point in medicine, one that could have as big an impact on society as antibiotics.”

He acknowledges, however, that this crossroads is most likely many decades away. In the interim, however, he expects the research to yield a drug that will successfully treat a single disease of aging, such as diabetes or Alzheimer’s disease, within the next 5-10 years.

Aging is complex
While scientists like Sinclair investigate the mechanisms of aging, another group of researchers is focusing on the aged. In other words, they are interested in the problems, diseases, and difficulties that face elderly people. One of the pioneers in this area is Dr. Lewis Lipsitz, whose research focuses on abnormal blood pressure regulation and its relationship to falls and fainting in older people. Lipsitz was the first to identify postprandial hypotension, the excessive decrease in blood pressure that many older people experience after a meal, and to link it to fainting and dizziness.

Rather than study the diseases of aging individually, Lipsitz is interested in the syndromes of aging. Syndromes such as falls, fainting, and confusion can be caused by hundreds of different diseases and sometimes multiple diseases in the same person, Lipsitz explains. For example, confusion could be caused by Alzheimer’s disease, but it could also be a side effect of certain drugs, the result of thyroid problems, or a symptom of depression.

To explore these complex relationships, Lipsitz and other scientists working in this area have adapted a mathematical theory called “complexity theory” from the field of nonlinear dynamics. “Typical science is very reductionistic,” Lipsitz explains. Most scientists tend to think in terms of “one symptom/one disease.” But functional problems—such as an inability to pay the bills effectively or walk to the market—are rarely caused by a single disease. “They are usually due to a combination of diseases and age-related vulnerabilities, as well as medications, social problems, economic problems, and psychological problems,” says Lipsitz. “It’s a complex system. That’s why we use complex systems to study it.”

The question of why older people fall and faint is one area of particular concern. Studies show that 35 percent of community dwelling elders everywhere fall each year. Meanwhile, 50 percent of nursing home residents fall each year; a tenth of these falls can result in serious injury; and 4 percent can result in fractures. The estimated cost of fall-related problems in the U.S. is $20 billion a year, a number that could reach $32 billion by 2020. In other words, preventing falls would save money and improve people’s lives.

In their studies of falls, Lipsitz and his colleagues discovered a number of changes in the cardiovascular system and the brain that are partially responsible. One of the changes is a dip in blood flow to the brain, causing microstrokes (or microvascular disease). These show up frequently on MRI scans in older people.

Microstrokes used to be considered part of normal aging, says Lipsitz. But recently they have been linked with cardiovascular risk factors like hypertension, diabetes, and high homocysteine levels. Now Lipsitz’s team has shown that they are also associated with slow walking, slow thinking, and depressive symptoms—all of which can lead to falls and fainting.

The upshot, says Lipsitz, is that risk factors such as hypertension, high cholesterol, and diabetes, long thought of as being connected with heart attacks and strokes are also risk factors for falls and functional loss in older people—providing yet another reason to take care of yourself in middle age.

Other areas of inquiry include the relationship between falls and other cardiovascular risk factors, falls and pain (particularly arthritic pain), falls and foot disorders, and whether vibrating insoles that help balance can improve function and prevent falls as well.

The future
Further study is needed to clarify how caloric restriction works and to determine whether drugs that mimic its effects might be safe and effective for humans. But the day when those questions will be answered is coming closer. Meanwhile it has become increasingly clear that aging is a complex assortment of interdependent processes, some physiological, some, social, some environmental. Over time, scientists will untangle this bundle and gather even more information about how and why we age. These discoveries may lead to longer life spans, better health, less disability, and greater independence as we enter our golden years.

In the meantime, evidence is mounting that one of the keys to healthy aging is to live healthfully regardless of how old you are. “The take-home message from our work and so many other studies,” says Lipsitz, “is that aging is something that is happening all your life.” That means managing your risks while you are young could affect your ability to function later on.

And it’s never too late to take longevity-building steps like treating hypertension, quitting smoking, and performing weight-bearing exercises. “The whole notion of ‘use it or lose it’ is quite relevant,” says Lipsitz. “And it applies to the brain as well as the body.”

Copyright 2006 Harvard Medical International