ABSTRACT: Frailty is a medical condition that is increasing in prevalence as we see our worldwide populations age. Defined as a state of increased vulnerability to psychological and multisystem stressors, faility is a clinical syndrome with multiple pathologies. A collaborative approach between primary care practitioners, and specialists in cognitive impairment, neurological dysfunctions and genetics, is needed to define the criteria, diagnosis and treatment for the condition. 

By 2025, there will be 1.2 billion frail individuals in the world, 75% of which live in developing nations, according to WHO data.¹ As such, frailty is evolving into a medical care challenge that will increase dramatically within a single generation. In the United States, individuals over the age of 80 represent the fastest growing population segment.¹ 

WHAT IS FRAILTY?

Frailty is defined as: “A state of increased vulnerability to stressors that result from decreased physiological reserves and multi-system dysregulation, limited capacity to maintain homeostasis and to respond to internal and external stressors. Fragility is an aggregate expression of risk resulting from age or disease related physiologic accumulations of subthreshold decrements affecting multiple physiologic systems resulting in adverse health outcomes.”² 

Frailty is a clinical syndrome characterized by multiple pathologies: weight loss, fatigue, weakness, low activity, slow motor performance, and balance and gait abnormalities. Central to the frailty definition is the concept that multiple systems must be involved—including neuromuscular, endocrine, and immune systems—in an aging individual. Low-level inflammation, sarcopenia, nutritional, and environmental stresses can be involved. 

While there is no single consensus on the number or the intensity of the charactersitics of fraility, there are enough insights on the disease to plan treatment strategies and examine risk factors contributing to the diagnosis. Clinicians use a “I’ll know it when I see it” approach.

The loss of muscle mass and strength with aging—referred to as sarcopenia—is highly prevalent and predicts several adverse outcomes. Increased levels of apoptosis have been reported in elderly animal studies, as well as an increased focus on the role of mitochondria.³ Caloric restriction and physical exercise may be therapeutically beneficial treatment options to be tested in a controlled study. 

CAUSES OF FRAILTY

• Chronic inflammation has been proposed as an underlying biological mechanism responsible for the physical function decline in the elderly. These inflammatory markers include C-reactive protein (CRP), insulin-like growth factor-1 (IGF-1), chemokines, cytokines, and lymphocytic cell subtypes.⁴ Genetic factors and telomerase activity may play a yet to be defined role.⁴ 

• Aging is the product of an interaction among genetic, environmental, nutritional, and lifestyle factors—each of which contribute to longevity and the development of frailty. 

• Low grade elevations in the levels of circulating pro-inflammatory markers, including tumor necrosis factor alpha (TNF-α) and interleukin (IL-6), are strong independent risk factors of morbidity in the elderly.⁵ Frailty in elderly may represent the complex and inter-relational expressions of a variety of stressor effects. For example, women with IL-6 levels in the highest quartile have an increased mortality, and have significantly greater limitation in walking and disability in mobility tasks than those without this risk factor.⁶ 

One prospective study, InCHIANTI, followed 1,020 subjects aged 65 years and older to identify risk factors for late-life disability.⁷ The results demonstrated that high levels of IL-6 and CRP were associated with poor physical performance and muscle strength.

ASSOCIATIVE CONDITIONS

Cardiovascular disease. The role of frailty in cardiovascular disease (CVD) patients has been discussed recently.⁸ A study of over 54,000 cardiovascular disease patients with a 6-year follow-up has increased the odds ratio for the development of frailty in this patient subset. It appears that CVD disease and frailty may have mutual causative factors and share certain risk factors, but more research is needed. 

The association between frailty and CVD was initially noted in the Zutphen Elderly Men’s Study of 450 elderly community dwellers.⁹ CVD was identified in 62% of the men who were frail vs. 28% deemed to be non-frail (odds ratio: 4.1; 95% confidence interval: 1.8 to 9.3).⁹ 

The Cardiovascular Health Study followed 4,735 community-dwelling elders and found that prevalent CVD was associated with a three-fold increase in prevalent frailty (odds ratio: 2.79, 95% confidence interval: 2.12 to 3.67).¹⁰ In addition CVD abnormalities noted on echocardiogram, hypertension, carotid intimal-media thickness, and evidence for stroke were all associated with frailty. Cumulative survival at 7 years was 12% in frail patients vs. 43 % in nonfrail patients (odds ratio: 1.63, confidence interval: 1.27 to 2.08).¹⁰ 

The robust correlation between frailty and CVD is associated with similar biomarkers. This may provide an insight into a common biologic pathway to explain the clinical findings. 

Insulin Resistance. A relationship between insulin resistance (IR) and frailty appears likely, since there is evidence that aging is associated with both entities. The incidence of both IR and faility rise with aging, and IR is a risk factor for lipid metabolism, increased inflammatory state, impaired endothelial functioning, a pro-thrombotic state, the metabolic syndrome, and atherosclerotic heart disease.¹¹

The role of many of these same risk factors in both CAD and cognitive impairment, both of which have been linked to frailty has been described elsewhere.¹²

Nutrition. Nutrition has long been recognized as an important component of healthy living, development of children, and aging. One of the phenotypes associated with frailty is loss of muscle and total body mass wasting. Indeed previous definitions of frailty use weight loss of varying severity and duration, as well as inactivity and a low BMI, among their diagnostic criteria. The activities of daily living also include cooking and meal preparation among their criteria. Since IR may be linked to frailty, dietary adjustments can help control and avoiding insulin resistance in most cases.

LESSONING THE IMPACT OF FRAILTY

Since the development and progression of frailty is a marker for increased morbidity and mortality, it is import to evaluate the economic impact in the end-of-life (EOL) time frame. A study of 577 frail older patients treated within an integrated healthcare system compared expenditures and health care service use between decedent (in their last year of life) and survivors.¹³ In-home interviews were conducted by home care nurses at baseline, and at 6 month intervals for an 18 month period. Cost data were collected directly from providers and Health Care Financing Administration for the 12 months immediately before death and for the first 12 month follow-up for survivors. After controlling for baseline differences, significant differences in expenditures of survivors (n=450) and decedents (n=127) were found. 

Compared with survivors, frail older decedents were 7 times more likely to have had any hospital admission and 8 times more likely to have had 30 or more physician visits. On average, the total expenditure for decedents were 276% higher than for survivors.¹³ 

An important insight into the economics of such therapeutic decisions was examined by NIH-funded investigators who studied the health care costs in the last week of life. Life-sustaining medical care of terminal patients at EOL is costly. Of the 603 participants, 188 (31.2%) reported EOL discussions at baseline. A matching group of 415 patients did not differ in sociodemographic characteristics.¹⁴ Patients with EOL discussions reported $1,876 vs. $2,917 for patients who did not have an EOL discussion (P=.002) patients with higher costs had worse quality of death in their final week. (P=.006.).¹⁴

There is no single entity that is either necessary or sufficient for the diagnosis of frailty, but we do know of redflag contributors. All too often an individual will be burdened with more than one of these morbidities, in a variety of combinations. Primary care practitioner should recommend that the patient consider a level of exercise consistent with anginal threshold or athritic knees; a referal to a exercise consultant, may be useful.

FUTURE RESEARCH

To plan for preventive and therapeutic approaches, the first step is to formally agree on the criteria—including risk factors and clusters of impairment—for frailty. This involves collaboration between several clinical domains including cognitive impairment, neurological dysfunctions, and genetics. The next step would include the development of appropriate animal models and the application of large, prospective, controlled, population-based studies of significant duration to determine the genetic and multifaceted dysfunctions underlying the development of frailty.

Currently practitioners do not have many options for treating frailty beyond addressing co-morbidity. Future treatments could include caloric restriction and physical exercise. Physicians need to be aware that frailty is an increasing common complication and that they are the first line to solicit any patient queries on improving diet and exercise behavior. ■ 

References

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11. Abbatecola AM, Paolisso G. Is there a relationship between insulin resistance and frailty syndrome? Curr Pharm Des. 2008;14(4):405-410.

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14. Zhang B, Wright AA, Huskamp HA. Health care costs in the last week of life. Arch Intern Med. 2009;169(5):480-488.

David T. Nash, MD is a Professor of Medicine at the State University of New York in Syracuse. He specializes in internal medicine and geriatric care.