The Face of Frailty

By Mat Edelson

To find out why aging people go downhill physically, Linda Fried spent a decade sending researchers into the homes of 7,000 older women and men.

Seventy-eight-year-old Lillie Mae Jones doesn't look frail. She stands ramrod straight, offers a firm handshake and looks out from behind her gold-rimmed glasses with curious—and, one senses, slightly mischievous—clear brown eyes. Not only doesn't Jones look frail, she doesn't act frail. In the course of just a few minutes she demonstrates that she can—without any assistance—lift a gallon jug of water over her head, stand easily from a sitting position and walk down a hallway. The Baltimore resident's golden years appear to be treating her kindly. But in her case appearances may be deceiving, a possibility that explains why Jones is involved in the Women's Health and Aging Study. The most comprehensive, complex, expensive and lengthy study of older women ever designed, the investigation is the brainchild of Hopkins researcher Linda Fried.

On this day, Lillie Mae Jones is having her fourth encounter in eight years with Fried's team of researchers. Over the course of five hours, Jones will participate in a session in which her functions are assessed from head to toe in Hopkins' General Clinical Research Center. She'll chuckle as she's laid out horizontal on an exam table to have her bone density checked by a Dexascan. "They'll be a time," she chides the ceiling, "when I'll be like this for good." And she'll express frustration when she can't figure out how to put a hypothetical group of prescription drugs into a time-stamped pillbox, a necessity if she travels away from home for even a day. "I'm not gonna fool with it," she'll tell the examiner, quickly backing away from the plastic pillbox as if it were a sleeping snake. "It's getting me nervous and upset."

Before she leaves with a boxed lunch and certificate of appreciation for her time and spirit of volunteerism, Lillie Mae Jones will have answered several hundred precisely worded questions, and her interviewer will have entered each answer into a Dell laptop computer. Her habits, health, medications, balance and mobility will have been probed to depths unheard-of in geriatric studies. And instead of settling for simple yes and no answers, the interviewers will have elicited from Jones detail after detail about how she compensates for age-related difficulties. Their goal is to uncover the often silent clues that can predict the onset of frailty, the condition that is thought to put older people at high risk for disability.

Even in the sprightly Jones, the clues are there, like pieces of a wind-scattered puzzle. She's moved to an assisted living facility. She walks fine but maybe not quite as fast as before. She can climb stairs but chooses always to take the elevator in her building. She can make oatmeal in the microwave but in general, cooks little. She suffers from several chronic diseases. She wears glasses. She can't balance for long in certain standing positions. Like evidence at a crime scene, each piece of information alone may mean little, but together they're beginning to form a powerful picture: pixels of individuals that eventually could lead to treatments aimed at slowing or halting the onset of frailty and then disability.

To the untrained eye, Linda Fried's studies of older adults can appear to be simple research projects—measurements of this, notations of that, yielding still more papers for the archives of medical literature. In Fried's case, though, the information she's gleaned is laying the groundwork for a whole new medical approach to treating older people. The questions and the tests that Lillie Mae Jones and thousands of other men and women have gone through took years of painstaking preparation by Fried, a geriatrician and epidemiologist who founded and directs the Johns Hopkins Center on Aging and Health.

In 1992 , Linda Fried embarked on a study of 1,000 older women and was funded by a whopping $1.7 million grant from the NIH.

Working with a team of collaborators plus hundreds of nurses and phlebotomists and other testers and supported by more than $20 million in grants from the National Institute on Aging, Fried has studied the gamut of conditions that debilitate older women and men. She's provided insight about such precise topics as how vision problems lead to falls and how diseases combine to speed up the disability process. Perhaps most important, she's come up with a working model for frailty, the physical falling off that takes place so often during old age. That model, published last year in the Journal of Gerontology, could change the way geriatricians practice.

"There's not even a listing for [the term] 'frailty' in the medical dictionary," Fried says, "even though caring for frail older adults is the raison d'Ítre for geriatrics." Without such a scientific definition, internists and even geriatricians have fallen back on instinct and experience to spot frail patients. If their determination is accurate, countless medical decisions from then on can potentially affect that person's outcomes: the dosage of medications the doctor prescribes and the assessment of the person's ability to tolerate certain treatments. But until Linda Fried came up with a definition of frailty, what the term meant was guesswork.

Today, frailty has a face. Fried's research demonstrates that men and women suffering from this condition may look gaunt, having dropped at least 10 pounds or 5 percent of their body weight in the past year. They've probably also slowed down—walk with difficulty and have little strength. And they may well admit to weakness and exhaustion, often exacerbated by their inactivity. Exhibit three or more of these conditions, and, according to Fried, you're frail. And you're also at higher risk for falls, disability, the inability to carry on activities of daily living, hospitalizations—and finally death.

All this from a physician who never intended to specialize in geriatrics in the first place. As an M.D., with a master's in public health, Fried was a beginning researcher studying cardiovascular risk factors in the mid-1980s, when, as she jokes, she was "geriatricized" by Hopkins' pioneering specialist in the medical problems of older adults, William Hazzard. Refocusing her research on the elderly was an easy choice. From a career viewpoint, gerontology was in its infancy with little existing literature. Fried would be free to blaze a trail that in an established field would have been well-worn. And with the nation's over-65 population expected to top 20 percent by the year 2020, research into the ravages of aging would become a national priority.

The idea of working with older people struck a personal chord for Fried. This was a population that had been chronically underserved by the medical establishment—in a sense shunted aside. There was tremendous potential here for promoting effective health practices. For Fried, who has a passion for not wanting to see people "waste their abilities," that message hit close to home. Her mother, Adrienne Fried-Block, by the age of 13, knew her aspirations reached far beyond those her family held for her as a girl. Fried-Block went to night school while working and raising a family. "She got her doctorate in musicology the day after I graduated from medical school," says her daughter. "She came to my graduation and then I went to hers."

By late 1988, though only a beginning investigator, Linda Fried's research career had taken off. Drawing on her earlier training in preventive cardiology, she had just designed a study examining how cardiac disease develops and progresses in older adults, when the National Heart and Lung-Blood Institute sent out a call for bids on a multimillion dollar multicenter study on just that topic. Persuading her senior colleagues to let her lead the proposal, Fried—to everyone's shock, given her junior status—won the grant.

One of the biggest single NIH-funded studies in the nation at that point, the Cardiovascular Heart Study began in 1989 and still follows more than 6,000 older Americans. The information it has yielded on heart disease and stroke in men and women over 65 has changed preventive approaches to those conditions across the nation. The study also revealed that the association between age and mortality diminishes when factors such as a person's level of activity and treatable diseases are considered.

But even as the cardiovascular study got under way, a larger question was forming in Fried's mind. From her work in the clinic, she knew that many of her older patients became disabled. What happened, she wondered, before they ever got to the clinic that led to that disability? Was it one factor, one disease or many? Was it a slow, long descent or a single catastrophic event? For that matter, was disability a state that a person could never return from once entered?

For all its scope, Fried's original Cardiovascular Heart Study couldn't answer such broad questions. She needed another large-scale investigation, "Where," as she says, "you...look at what really causes disability, all the diseases that could play a role, to see which ones are most important and how they conspire together." An important element would be to choose subjects whom she could follow long enough to witness their decline—or their improvement.

This project would become Fried's Women's Health and Aging Study. The National Institute on Aging's chief of epidemiology, Jack Guralnik, who administered her grant application, remembers: "Linda had to make me believe she could do it. She did that well. We found her application superior."

To grasp the myriad of factors that lead to disability, Fried had decided to follow companion groups of women. In the first group, the subjects would have already begun to go downhill and could need assistance in their daily life. Many would be one step removed from a nursing home, but their mental faculties would be intact.

The second group, though parallel in age, would be women who still functioned on their own. For whatever reasons, they had remained healthy and independent. Some would be in what Fried refers to as "a preclinical state"-they would show signs of early functional decline, but they would have no difficulty in doing tasks like walking and taking care of their homes.

To find her subjects, Fried looked not in doctors' offices but in homes all over Baltimore. Into these private residences she proposed to bring all the measuring yardsticks normally found in a hospital clinic. For five hours, a team of two nurses would go over every relevant aspect of each subject's health and functioning. With the disabled women, the researchers would conduct the same examination all over again every six months. The better-functioning group would be re-examined every 18 months.

Some of Fried's colleagues said such lengthy exams would exhaust older women. They thought the studies were too complex to carry off. Fried's experience as a geriatrician told her otherwise. "One of life's tasks for today's seniors is to give back, to leave a legacy, to contribute," she says. "The chance to improve health care is a bequest people care about a lot."

And so, beginning in 1992, Linda Fried turned more than 1,000 homes, belonging to senior women of every ethnic group and income level who had volunteered to become study subjects, into mini-laboratories. Into apartments, row houses, and cottages, interviewers and nurses hauled questionnaires and more than 125 pounds of equipment to test heart rates, hand dexterity, blood-hormone and protein levels, visual acuity, lung function, walking speed and climbing strength. They measured everything.

"By the end," Fried recalls, "these women would be sitting there with a Holter heart monitor on, a metronome going, raising their legs in rhythm to the height of the six, 12- and 18-inch steps we brought in, all with a blood pressure cuff on."

The first phase of the study on the most debilitated women ran until 1995. By the time it ended, it had provided the first glimpse into the physiological changes that lead to disability. Meticulous clinical measurements showed that nearly two-thirds of women approaching a "disabled"state couldn't lift or carry 10 pounds of groceries, had difficulty manipulating their upper extremities and were capable of only limited mobility. Most couldn't crouch easily or bend, and they had trouble walking a quarter mile.

Since then the research team has gone on to identify multiple causes for frailty and disability, including minimal strength and reduced hormone levels. More recently, the study has begun pinpointing possible genetic disability. The researchers learned how people compensate for limitations. One of Fried's favorite stories is of a woman with osteoarthritis and its resulting leg weakness who claimed she had no problem climbing stairs. After probing questions, what came out was that she accomplished that task by sitting down and pushing herself backward up the stairs. Other women pushed off from a table to stand or asked their neighbors to open jars for them. All these were early indicators of functional decline.

The raw data was eye-opening. Specialists across the medical spectrum had never had access to so much baseline information on older adults. As Fried was funded for the second and then third phase of the study, more findings emerged. She showed linkages between disease states and the mechanisms that lead to those states—"causal pathways," she calls them. One thread followed nutritional deficiencies that affect vision, which then can lead to devastating falls. Another looked at how disease combinations like arthritis and visual impairment, heart disease and arthritis, stroke and high blood pressure may magnify each other's symptoms and lead to dependency.

Fried's scientific explanation of the cycle of frailty.

One exciting finding had to do with the connection between a hormone called IGF-1 that's related to human growth hormone and a decrease in muscle strength. As IGF-1 and human growth hormone naturally decline with age, that decline may start the cascade that leads to muscle loss—sarcopenia—which could well be a key player in disability.

Today, Fried and her team are following dozens of these pathways. The next phase of the Women's Health and Aging Study will attempt to trace some of them back to their genetic and biological roots, to find out if perhaps there are genes that act as precursors to frailty. The proteins called Interleuken-6, for instance, are key players in inflammation, which typically increases with aging. By isolating the gene that creates IL-6, she suggests, it may be possible to identify therapies that slow inflammation and its consequences, one of frailty's prime culprits. Variants of the 'strength' gene, myostatin, also might someday be manipulated to ward off the muscle wasting associated with age.

A Fried collaborator, geriatrician Jeremy Walston, meanwhile, wants to understand how different physiological mechanisms go awry with age. Blood drawn from women during phase one will continue to be analyzed to look for clues to this and other phenomena of aging. Blood-clotting factors, for instance, tend to increase with age at the same time our ability to handle sugar decreases, a combination that could lead to cardiovascular disease, diabetes...and ultimately frailty.

"The field is so very young," Fried says. "To translate results into improved patient care, there's a whole cycle of research you have to go through. The fight is finally on, though. We've put a map for prevention on the agenda for our aging population."