Is Frailty Inevitable? Some Experts Say No

By GINA KOLATA

octors know them when they see them, or so they say. They call them the frail elderly. The assumption is that frailty goes along with aging, as inevitable as white hair and wrinkles. It is the price to be paid for living to an advanced age.

But now some researchers are questioning this assumption. Why, they ask, should frailty be inevitable? And what, they ask, is frailty? Are there physical signs and symptoms that define the condition? Are there biochemical markers? If so, can frailty be reversed or prevented by correcting biochemical abnormalities?

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The result, said Dr. Evan Hadley, an associate director at the National Institute on Aging, is a fresh approach to an old problem. Frailty, he said, is no longer seen as just part and parcel of growing old. Instead, he said, it is newly recognized as a real disease in its own right.

Dr. Lewis A. Lipsitz, chief of gerontology at the Beth Israel Deaconess Medical Center in Boston, likens the changing view of frailty to the change in the way Alzheimer's disease was perceived.

"Thirty years ago, Alzheimer's was thought to be an inevitable consequence of aging; we called it senility," he said. "It was not until people began to recognize the specific proteins that deposit in the brain that we began to realize that it may be treatable or preventable. The same is true of frailty. It's a syndrome, and there probably are some physiologic underpinnings."

One thread of the work had its origins in a question, raised two decades ago, by a few gerontologists: what, exactly, is frailty?

"We were taking care of frail older adults, but we really didn't have much clarity about what frailty was," said Dr. Linda Fried, who directs the Center on Aging and Health at Johns Hopkins Medical Institutions. "Everyone said, `I know it when I see it,' but what I see may not be what everyone else sees. It became very important to me to figure it out."

She and her colleagues began by questioning other gerontologists, surveying 60 of these specialists at seven medical centers and asking them to define what, to them, were the hallmarks of frailty. What emerged was a consensus definition. Frailty, they agreed, was characterized by muscle weakness, fatigue, declines in activity, a slow or unsteady gait and weight loss. People with at least three of these symptoms were considered frail.

"These are pathologies that hadn't been recognized as discrete disease processes in their own right," Dr. Hadley said. But they were every bit as debilitating as well-known diseases of aging like osteoporosis. For example, he said, "Everyone knows about osteoporosis, but quite parallel to it there is a tendency to lose muscle with age." Until recently, he added, "that was considered normal aging."

With their definition of frailty, researchers could then ask about its incidence, and, in this case, the Johns Hopkins investigators realized they had an opportunity. They were participating in a national study, the Cardiovascular Health Study, that would be following about 5,000 people ages 65 to 90 for a decade, starting in 1990. If they inserted questions about frailty in the medical exam, they could learn how many were frail at the study's start and how many developed the disease in the ensuing decade.

They asked specific questions. For walking speed, the investigators timed how long it took participants to walk 15 feet at their usual pace. The slowest 20 percent were considered to have this indicator of frailty. They tested grip strength, asking the participants to squeeze a device that measured their grip and counting the weakest 20 percent as having this frailty indicator.

For weight loss, they asked whether people had lost 10 pounds or more in the past year. They learned about fatigue by asking the participants if they felt that everything they did was an effort and that they could not get themselves going.

To learn about activity levels, they asked whether the participants had done any of 18 activities in the previous week, and, if so, how often they did them and for how long. From there they calculated the number of calories expended in exercise. Those in the bottom quarter had this frailty indicator.

The result, reported in 2001, was that 7 percent of the study participants were frail — they had three or more of the frailty indicators — and the incidence of frailty increased rapidly with age. Just 3 percent of the people aged 65 to 69 were frail, but 20 to 30 percent of those aged 80 or older were considered so.

Last year, the investigators reported that those who had started down the path to frailty, with one or two signs, were likely to develop the full-blown syndrome soon. Once someone was frail, he had a twofold to fourfold increased risk of falling, becoming disabled or dying in the next three years. Frailty, said Dr. Fried, "is a high-risk condition."

But if frailty is an independent disease, the researchers asked, what underlies it? They looked for biochemical abnormalities in the blood, and, in a paper published on Nov. 11 in The Archives of Internal Medicine, they reported that frailty was associated with increased levels of three proteins that are linked to chronic inflammation, a sort of low-grade response to an infection or irritation of body tissues.

One of these, C-reactive protein, is a measure of inflammation. The others, fibrinogen and Factor VIII, are blood-clotting proteins that are activated by inflammation, Dr. Jeremy Walston, one of the Johns Hopkins researchers, explained.

While these proteins also can be elevated in people with heart disease or diabetes, the frailty link was independent of these other chronic diseases. People who were not frail but had these markers of frailty were at the highest risk for becoming frail, the investigators report.

Researchers stress that patients should not expect to have blood tests for frailty; the biochemical abnormalities are not sufficiently specific, occurring whenever there is inflammation. Instead, they say, the blood tests can give them clues to understanding the events that conspire to result in frailty.

Dr. Lipsitz said more and more chronic diseases appeared to be linked to a state of chronic inflammation. Ulcers, for example, now known to be caused by a bacterial infection, are accompanied by inflammation. There also are hints that heart disease and Alzheimer's may be tied to inflammation. So if frailty also has hallmarks of inflammation, that would seem to fit the pattern, Dr. Lipsitz said.

"This adds to the body of evidence that frailty is not an inevitable consequence of aging but is due to specific biologic mechanisms," he said. "This adds to evidence that it is a definable syndrome."

Dr. Ronenn Roubenoff, an associate professor of medicine and nutrition at Tufts and a senior director of molecular medicine at Millennium Pharmaceuticals in Cambridge, Mass., said the findings fitted well with new and unpublished data from a study in Framingham, Mass. Dr. Roubenoff, an investigator in this long-running investigation of the health of more than 5,000 Framingham residents, said increased levels of inflammatory proteins predicted a loss of muscle mass, one signal of frailty.

Some people, Dr. Walston and others said, seem to be pushed into a cycle of increasing debilitation, ending in frailty, by a chronic illness like heart disease. Others simply become frail, raising the question, Is frailty preventable? The answer, Dr. Hadley said, is "we don't know."

Many, like Dr. Lipsitz and Dr. Roubenoff, hold out high hopes for exercise. Dr. Roubenoff points to the problem of muscle loss, for example. "Muscle loss happens to everyone," he said. But, he added, if people exercise regularly, they can go into old age with a reservoir of muscle that may protect them from slipping over the edge into frailty.

They note that even when frailty has already developed, or is well on the way, it may be possible to reverse it. Numerous studies have shown that even very old, very weak people can gain strength and mobility through modest strength training.

The question, however, is whether such programs will work for everyone or whether there are people who, for genetic reasons, simply do not respond, growing frail despite attempting to exercise.

"There certainly is a variability in response to exercise," Dr. Roubenoff said. "How much of that is motivation and how much is biology we don't know."

Dr. Walston agreed. "There are people who exercise like crazy and still get frail," he said.

Dr. Lipsitz said that while he strongly encouraged people to keep active and to exercise regularly, no one could guarantee that those who followed such advice would be protected from becoming frail. "We don't want to portray an elitist attitude about aging, that if only you were better behaved you would avoid these things that accumulate with age," he said.

Dr. Hadley said the continuing research offered hope for new interventions in addition to exercise. "This is now looking ahead and speculating a little bit," he said. "We don't know yet if these inflammatory and blood clotting factors are consequences of frailty or if they contribute to it. But if it's the latter, that would suggest drug therapies."