Columbia’s Linda P. Fried: Robust Research on Frailty

Scientist Interview: January 2011

Linda Fried
Photo: Manuello Paganelli

It was thirty years ago that a committee of the Institute of Medicine first concluded that the Baby Boom generation constituted a huge, if not perhaps insurmountable, challenge to the American health care system. And little, regrettably, has changed since then.

Americans have grown ever older as a society, baby boomers have begun moving into their twilight years, and medical advances have continued to push the limits of our longevity. The challenge now to physicians and researchers is how to make those extra years productive ones— to minimize frailty, extend the benefits of a healthy life, and lessen the growing burden on health care.

“The fact that the world’s population is aging is a great success of public health and medical science,” says Linda P. Fried, an epidemiologist and geriatrician at Columbia University, “but we now have to figure out how to reap the benefits by keeping people healthy as they do age.” Fried herself has dedicated 25 years to this goal, and her efforts have led to major advances in geriatrics and gerontology, as well as to her high ranking in this publication’s recent survey of the most-cited researchers in the field over the last decade (Science Watch, July/August 2010). Fried’s March 2001 article in Journals of Gerontology Series A – "Frailty in older adults; Evidence for a phenotype” – has been cited 570 times, a striking number for the relatively small field of geriatrics and gerontology (see table below). Of her papers published since 2000—many on risk factors predicting disability and mortality in older women—17 have been cited more than 100 times each.

Fried, 61, received her bachelor’s degree in history from the University of Wisconsin in 1970 and her medical degree from Rush Medical College in Chicago nine years later. In 1985, she obtained her Master’s degree in Public Health from Johns Hopkins University and then went on to hold joint faculty appointments in the JHU School of Medicine, the School of Hygiene and Public Health, and the School of Nursing. She also served as director or co-director of geriatric medicine and research centers aimed at studying the epidemiology of aging and the relationships between aging and health. In 2008, Fried moved to Columbia University, where she is now dean of the Mailman School of Public Health and a professor of epidemiology and medicine.

Fried spoke to Science Watch from her office in New York City

SW: How did you first get interested in studying geriatrics?

When I came to Hopkins to study internal medicine and epidemiology, I started working in prevention and cardiovascular disease. I worked as a fellow on a small project with Bill Hazzard, who was a world leader in geriatrics. We became intrigued by issues of preventing cardiovascular disease in older adults, and at that time there was not a lot of data, even though half of people with cardiovascular disease and half the people who die from it are older than 60 or 65. It seemed like an area where prevention is really needed. One day Bill persuaded me—and it was not a hard sell—that the major issue of the 21st century was going to be the aging population and that I might have something to contribute. I changed my career the next morning.

SW: Much of your early research was dedicated to the Cardiovascular Health Study, which you set up. What did you learn from that?

I’ll give you a few headlines. One is that about a third of older adults have clinical cardiovascular disease, a third have subclinical disease, and a third have neither. And people who have neither are at very low risk of developing cardiovascular disease. So, in screening and in targeting interventions to prevent cardiovascular disease, the group you want to worry about is the one that already has subclinical disease.

We’ve learned a lot about a whole long list of physiologic markers and risk factors, and we’ve learned that hypertension, diabetes, smoking, and physical inactivity still matter as risk factors into the oldest ages. Elevated LDL cholesterol matters in terms of the development of subclinical disease. This means that the potential for prevention remains high even into advanced age.

We were also able to put a lot of measures of disability itself into that study, and to show how a number of diseases and subclinical diseases conspire in combination to cause disability. At that time, I was clinically active running the geriatric assessment center at Johns Hopkins and was learning a lot from the patients. They got me thinking about the issue of frailty and what it was, and I initiated a long line of related work, including hypotheses, which I got to address in the Cardiovascular Health Study.

SW: How are you defining frailty, and what were the hypotheses?

Well, at the time geriatricians thought frailty was simply the kind of thing that you knew when you saw it. They thought it was the state of high risk, and by “they,” I mean me, too. People are frail. They’re vulnerable. They don’t tolerate stressors well, like getting sick, or being in extremes of heat or cold, or being hit by a car and ending up in the hospital. A lot of clinical interventions were developed to deal with frailty, but a lot of studies were showing no evidence of benefit, even though doctors felt that people were benefitting.

SW: So what was causing this disconnect between appearance and reality?

One problem was that there was no standardized definition of who was frail. A linchpin of science, of course, when you’re going from a clinical observation to an actual investigation, is to be able to define exactly what you’re talking about.  And I spent a lot of time looking at patients, thinking about this in regards to frailty itself, and finding definitions of frailty written in the 1980s that were all over the map. There was little coherence. And none seemed to match what I saw in my patients. Some traits occurred frequently in patients who seemed frail, and I thought these might be used for a definition.

The patients had lost weight and were thin; they were kind of slow, not so physically active; they didn’t have much energy and seemed weak. Shakespeare talked about the “shrunk shank” of old people, meaning people who had lost muscle mass and couldn’t do what they once did.

Selected Highly Cited Papers by Linda P. Fried and Colleagues, Published Since 2000
(ranked by citations)

Rank Paper Citations
1 L.P. Fried, et al., "Frailty in older adults: Evidence for a phenotype," J. Gerontology Series A – Bio. Sci. & Med. Sci., 56(3): M146-56, 2001. 570
2 C.M. Boyd, et al., "Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: Implications for pay for performance," JAMA, 294(6): 716-74, 2005.   338
3 L.P. Fried, et al., "Untangling the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care," J. Gerontology Series A – Bio. Sci. & Med. Sci., 101(33): 12130-5, 2004. 269
4 L. Ferruci, et al., "Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: A consensus report," J. Am. Geriatr. Soc., 52(4): 625-34, 2004.  183
5 S. Volpato, et al., "Cardiovascular disease, interleukin-6, and risk of mortality in older women: The Women’s Health and Aging Study," Circulation, 103(7): 947-53, 2001. 173
SOURCE: Thomson Reuters Web of Science®.

SW: Did this tell you something about the etiology of frailty? A fundamental cause other than aging itself?

Well, that was the question. Why on earth would these characteristics, these symptoms, tend to occur together? I couldn’t figure that out. I spent years reading everything in the literature, trying to think about the biology, the possible pathways that would link these characteristics together.

Finally, one day I had one of those “Aha!” moments, when I realized that biologically they might all be linked in a vicious cycle. And I think we’ve now now provided support for a phenotype, this vicious cycle, and shown that when a critical mass of signs and symptoms of frailty are present, it points to a new clinical syndrome and a certain underlying etiology.

We now have a lot of evidence to support the theory that this phenotype is truly a marker of people who are very vulnerable for short-term mortality, for disability and falling, and that this is a group with many physiologic systems that are dysregulated. And these physiological systems are, it would seem, highly interconnected. So they mutually regulate each other. And we’ve been reporting on these dysregulated systems in a painstaking manner for the last ten years.

SW: Can you give us an example of what kind of systems you’re talking about here and how they’re dysregulated?

Well, many hormones in the hypothalamic-pituitary-adrenal axis, glucose tolerance, inflammation, immune function, anemia—they all mutually affect and regulate each other. Recently we’ve demonstrated that glucose intolerance and other components of the Metabolic Syndrome are very much associated with frailty.

We’ve shown this most recently in the Women’s Health and Aging Study. We have fairly remarkable new data showing that in women in their 80s and 90s, rates of insulin dysregulation and glucose intolerance are incredibly high, and it goes along with this picture of increasing dysregulation of multiple physiological systems with aging. Our theory is that when there is a critical mass of systems dysregulated, the ability of the human organism to maintain homeostasis is impaired—the physical safety net, so to speak, is frayed. And the person has great difficulty in returning to normal in the face of a stressor; they have difficulty maintaining homeostasis, tolerating extremes of heat and cold, recovering from an illness.

Frailty emerges, in effect, as a product of the dysregulation of a critical mass of systems. We have demonstrated that the relationship is nonlinear, consistent with the emergent property of a complex system.

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