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GERIATRIC SYNDROMES

CME ARTICLE

Risk Factors for Frailty in the Older Adult

Sara E. Espinoza, MD, and Linda P. Fried, MD, MPH

Dr. Espinoza is Assistant Professor of Medicine, Division of Geriatrics and Gerontology, The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Sciences Center at San Antonio, and Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX. Dr. Fried is Professor of Medicine, Epidemiology, Health Policy and Nursing, Director of the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, and Director of the Center on Aging and Health, Baltimore, MD.

At the conclusion of this activity, participants should be able to: 1. Describe the conceptualization that frailty represents a geriatric syndrome associated with increased risk for adverse health outcomes. 2. Identify the physical characteristics of frailty. 3. Identify possible risk factors associated with frailty. 4. Discuss the current field of frailty research.

INTRODUCTION
Geriatricians and physicians caring for older adults recognize frailty in older patients. There is now increasing evidence that such frailty is a geriatric syndrome characterized by a clinical presentation of a critical mass of identifiable components, thus syndromic, with progressive decline, increased vulnerability to stressors, and increased risk for adverse health outcomes. As the U.S. population of those over age 65 continues to grow, recognition of frail older adults is important so that targeted intervention and prevention, medical care, and/or palliation, as appropriate, can be implemented. This review focuses on specific facFULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The authors report no relevant financial relationships. No faculty member has indicated that the presentation will include information on off-label products. DISCLAIMER STATEMENT The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

ACCREDITATION
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

CREDIT DESIGNATION STATEMENT

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Release Date: July 1, 2007 Expiration Date: September 30, 2007 Estimated Time to Complete: 1 hour

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tors that may put older adults at risk for the development of frailty, complementing a previous discussion of specific interventions for frailty.1 By understanding and targeting key risk factors for amelioration, it may be possible for clinicians to improve the overall health of older patients.

mobility2-5; some have also included cognitive or psychological components, such as cognitive impairment and depression.6,7 Although frailty research is still in its infancy and there is no one universally accepted gold-standard definition,8-11 one of the most validated models of frailty is one that was operationalized in the CarFRAILTY DEFINITIONS diovascular Health Study (CHS).3 Building on a Most definitions of frailty describe a syndrome of broad consensus that frailty is a biologic syndrome loss of muscle mass and strength, energy and exercise of decreased reserve and resistance to stressors, retolerance, and decreased physiologic reserve with sulting from cumulative declines across multiple sysassociated increased vulnerability to physiologic tems, causing vulnerability to adverse outcomes,3 stressors, such as acute illness, hospitalization, or these investigators proposed a standardized, pheextreme heat or cold. Most of these definitions notypic, clinical presentation of frailty consistent include measures of strength, low energy, low physwith both geriatricians4,12,13 and patients recogical activity, inadequate nutrition and unintentional nition of markers. Fried et al3 characterized frailty weight loss, slowed performance, and decreased as the presence of three of five central components: unintentional weight loss, slow walking speed, Disease Environment Chronic Medications self-reported exhaustion, undernutrition Disease Medications low energy expenditure, Aging-related changes and weakness. They theorized that the compoCycle of frailty Total energy expenditure Sarcopenia nents of this phenotype were etiologically related Insulin sensitivity to each other in a viOsteopenia Resting Activity metabolic cious cycle of dysregurate lated energetics that, Walking speed Strength VO max and power when at least three were present, identified frailty Disability Immobilization Impaired balance (Figure 1) and could be Falls and Dependency self-perpetuating. 3,9,13 injuries Those identified as frail by these criteria were Figure 1. Cycle of frailty.3,9,13 shown to be at increased Fried LP, Walston J. Frailty and failure to thrive. In: Hazzard WR, Blass JP, Ettinger WH Jr, et al, eds. Prinrisk for falls, hospitalizaciples of Geriatric Medicine and Gerontology. 5th edition. New York, NY: The McGraw-Hill Companies; tion, worsening mobili2003;1487-1502. Adapted with permission of The McGraw-Hill Companies. Copyright 2003. ty and activities of daily

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living (ADLs) disability, and death.3,11,14 Furthermore, these factors were additive in a dose-response fashion, such that those individuals with one or two of these factors (considered intermediate frail) were at increased risk for the adverse health outcomes mentioned when compared with those without any of these factors (non-frail), but were at less risk than those with three or more (frail). This model has recently been cross-validated in a longitudinal cohort of older women, the Womens Health and Aging Studies (WHAS), in which this definition of frailty again strongly predicted ADLs and instrumental activities of daily living (IADLs) disability, permanent nursing home entry, and death.11 This study also showed that this frailty model is consistent with being a medical syndrome,
TA B L E

in which no one of the five components carries more weight than the others in terms of predicting these adverse outcomes. It has been further cross-validated in a study by Woods et al,14 which found that baseline frailty status was, again, strongly predictive of ADL disability, number of hospitalizations, hip fracture, and death at 3 years in the Womens Health Initiative (WHI) Observational Study. It is important to note that individuals who are classified as frail may certainly have disability, multiple comorbid illnesses, and advanced age, but frailty may be present in the absence of these. These factors may predispose one to the development of frailty. This review shall examine several potential risk factors of frailty. Beyond that, Fried et al3 have hypothesized that the clinical presentation marks those at risk of adverse outcomes because it results, itself, Possible Risk Factors for Frailty from dysregulation of multiple physand Summary of Supporting References iologic systems, leading to characterI. Physiologic istic clinical manifestations as well as A. Activated inflammation15 16,17 attendant vulnerability. B. Immune system dysfunction
C. Anemia18 D. Endocrine system alteration19 E. Underweight or overweight14,15,21 F. Age14 II. Medical Illness/Comorbidity A. Cardiovascular disease14,18,26 B. Diabetes14 C. Stroke14 D. Arthritis14 E. Chronic obstructive pulmonary disease14 F. Cognitive impairment/cerebral changes6,26 III. Sociodemographic and Psychological A. Female gender3,14,30 B. Low socioeconomic status21,26 C. Race/ethnicity3,14,30 D. Depression3,14 IV. Disability A. Activity of daily living disability3,14

RISK FACTORS FOR FRAILTY

In order to identify risk factors for a specific illness or syndrome (in the case of frailty), observational studies, especially prospective ones, provide essential insight. Frailty research is an emerging field, and much of what we know about potential risk factors for this syndrome must be obtained from cross-sectional observational studies. In this article, we will review the findings from the study by Woods et al14 described above, the largest and most comprehensive study to date that has examined potential risk fac-

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tors for frailty in a prospective fashion, as well as from other cross-sectional studies on potential risk factors for frailty. This review is organized into categories of potential risk factors: physiologic, medical illness/comorbidity, sociodemographic and psychological, and disability (Table).

Physiologic Factors
A number of physiologic alterations have been associated with frailty. Continuing research suggests that frailty is a distinct physiologic entity with characteristic changes in physiology, including activated inflammation, decreased immune function, anemia, endocrine system alterations, and musculoskeletal alterations. Walston et al15 studied several markers of inflammation in the CHS in relation to frail and non-frail status, and found that those subjects classified as frail by the criteria described above had increased mean levels of C-reactive protein, a reliable marker of inflammation, as well as increased markers of coagulation, including factor VIII and D-dimer. These findings suggest that frail individuals are in a chronic state of upregulated inflammation and are perhaps more prone to coagulation as a result. Altered immune function is also associated with frailty16; this may potentially lead to activated inflammation.17 Specifically, Leng et al17 found that frail individuals, when compared with non-frail controls, have decreased ability to proliferate their peripheral blood mononuclear cells (PBMCs) when stimulated with the endotoxin lipopolysaccharide, as would occur with some acute bacterial infections, and that the PBMCs of frail individuals have increased production of interleukin-6, a marker of inflammation. Other studies have found that frail individuals are more likely to be anemic,18 potentially also re-

sulting from activated inflammation, and are more likely to have endocrine system alterations, including decreased levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEAS).19 A decrease in both of these hormones is associated with decreased lean muscle mass, or sarcopenia, which has been hypothesized to be a central component of frailty.9,20 Although weight loss is one of the components of the frailty model proposed by Fried et al3 and inadequate nutrition is commonly recognized clinically as a marker of frailty, subjects in the CHS categorized as frail included both a subset who were underweight and a subset with higher body mass index (BMI) consistent with obesity.15,21 This information suggests that decreased lean body mass can predispose individuals to the development of frailty even in the presence of obesity. In fact, sarcopenic obesity is a term that has been used to describe this mismatch between lean muscle mass and fat and resulting metabolic derangement. Research in this area shows that it is a physiologic state with adverse consequences such as physical disability, including disability in ADLs.22 Obesity itself is thought to contribute to altered glucose metabolism and insulin insensitivity, as well as activation of inflammation,23 which are physiologic alterations that have been associated with the development of sarcopenia and the frailty syndrome.15 Consistent with these observations, the WHI study found that both underweight and overweight women had increased risk for the development of frailty, suggesting a U-shaped relationship between BMI and frailty.14 The aging process itself has been characterized by a decline in normally functioning physiologic systems and loss of redundancy in normal feedback mechanisms; it has been hypothesized that frailty

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results from reaching a threshold of decline resulting from an aggregate severity of dysregulation in multiple systems.9,10 Aging itself could contribute to this through many mechanisms, potentially including such pathways as age-associated accumulation of oxidative stress and associated cellular damage due to the generation of oxygenderived free radicals over time.10 Perhaps in support of these age-related mechanisms, increased chronological age has been associated with frailty cross-sectionally, even after adjustment for medical comorbidities.21 The WHI frailty study found that individuals age 70-79 years at the time of screening were at increased risk for becoming frail at 3-year follow-up when compared to those age 60-69 years14; similarly, the CHS evaluation indicated a stepwise increase in prevalence with increasing age over 90.3 These data may indicate that increased age is a risk factor for frailty. The physiologic alterations that have been associated with frailty are complex, and there are like-

ly interactions between specific systems that increase the risk of frailty, such as inflammation and endocrine dysregulation10 (Figure 21). This is congruent with the hypothesis that frailty is a physiologic syndrome of multisystem dysregulation and decline, which leads to vulnerability to adverse health outcomes and the clinically manifest syndrome itself.3,9,24 Although inadequate nutrition, increasing age, and physiologic changes that occur with age may lead to sarcopenia and resultant increased risk for frailty, there is evidence that this is modifiable. An innovative and landmark randomized, controlled trial by Fiatarone et al25 showed that strength training increased lower-extremity strength, gait velocity, and stair climbing power in frail older adult residents of a nursing facility. Furthermore, their finding that individuals randomized to strength training also had improvements in mobility and spontaneous activity suggests that increased muscle strength may break the cycle of frailty by stimulating increased activity.

Figure 2. Physiology of frailty. DHEAS = dehydroepiandrosterone sulfate; IGF-I = insulin-like growth factor-I; IL-6 = interleukin-6; CRP = C-reactive protein.
Espinoza S, Walston JD. Frailty in older adults: Insights and interventions. Cleve Clin J Med 2005;72(12):1105-1112. Adapted with permission. Copyright 2005. Cleveland Clinic Foundation. All rights reserved.

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Medical Illness/Comorbidity
Frailty has been associated with selected diseases in cross-sectional studies, and cardiovascular disease, in particular, has been shown to be related to frailty cross-sectionally18,26 and longitudinally.14 The frailty phenotype has been associated with both clinically diagnosed cardiovascular disease, with diastolic blood pressure, and with selected noninvasive tests of cardiovascular function, such as carotid wall thickness measured by ultrasound, infarct-like lesions on brain magnetic resonance imaging (MRI), abnormal left ventricular wall motion measured by echocardiography, and major electrocardiogram abnormalities.26 In addition to its findings that a prior diagnosis of cardiovascular disease was independently associated with baseline as well as incident frailty at 3 years, the WHI study found that prior diagnosis of stroke, diabetes, hypertension, arthritis, cancer, and chronic obstructive pulmonary disease were predictive of incident frailty.14 Thus, specific chronic diseases are risk factors for frailty. In fact, some conceptions of frailty posit that the accumulation of medical illnesses and other deficits, such as geriatric syndromes, predispose to adverse health outcomes with advancing age, and this predisposing vulnerability is frailty.27,28 This is a different formulation of frailty, which does not consider frailty as a syndrome with distinct clinical presentation or etiologic factors. In contrast, a prior survey of geriatricians led to the combined perspective that, while comorbidity may certainly predispose one to the development of frailty, it does not appear to be synonymous with the distinct medical syndrome of frailty.29 Central nervous system (CNS) function and cognitive impairment have been hypothesized to be either components of frailty or risk factors,5,6,10 but

this has not been extensively studied. It is thought that cognitive impairment could directly contribute to the development of frailty as a result of decreased food intake,6 which could then lead to weight loss and sarcopenia, providing a means of entry into the cycle of frailty.3 However, one study suggests, inferentially, that CNS alterations present in frail individuals could result from cerebrovascular disease.26 Newman et al26 found that, when compared to non-frail persons, frail individuals had a higher prevalence of infarct-like lesions and white matter changes, as examined by cerebral MRI. It is plausible that these changes are the result of cerebrovascular disease secondary to upregulated inflammation, either resulting from frailty or contributing to frailty15; however, further studies are needed in order to better characterize these relationships.

Sociodemographic and Psychological Factors

Female gender has been associated with frailty, as women have been more likely than men to be characterized as frail in several studies.3,14,30 This finding may be related to sarcopenia, with women having less muscle mass than age-matched men, which may confer an intrinsic risk for the development of frailty.3 Lower socioeconomic status (SES), as measured by low education and/or low annual income, has been associated with frailty in several cross-sectional studies.21,26 CHS studies found that higher educational status and higher income were associated with disease-free survival at 3-6 years31 and with lower mortality.32 It is likely that high SES does not intrinsically confer less risk for frailty, but that this relationship between SES and frailty is modified by lifestyle factors that are likely to co-exist with low SES. For example, it appears that low income and

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education are predictive of frailty at 3-year followup, but this association is attenuated (although it persists) after adjustment for BMI, ethnicity, tobacco use, alcohol use, self-reported health, and comorbid conditions, suggesting that differences in health status and risk factors may explain at least part of the increased risk for frailty.14 This may also be operant in the case of race and ethnicity, as several studies have shown a higher prevalence of frailty in non-white individuals.3,14,26 While the contribution of psychologic factors has not been extensively studied in relation to frailty in older adults, psychological well-being has long been associated with the idea of successful aging,33 and depressive symptoms have been shown to be associated with the syndrome in cross-sectional analyses.3 The WHI study found a strong prospective relationship between depressive symptoms and the onset of frailty, suggesting that depression may contribute to the etiology of frailty.14 The hypothesis that depression or the presence of depressive symptoms leads to frailty is biologically plausible, given that individuals with depression often lose weight, become less active, and can therefore lose muscle mass, strength, and exercise tolerance, and may be more prone to acute illness. All of these may, additionally, be related to an increase in circulating inflammatory cytokines.34 Self-reported health has also been associated with frailty. The WHI study found that the likelihood of being frail increased in a step-wise fashion as selfreported general health went from very good, good, to fair/poor.14

whether frailty is theorized to be a distinct physiologically-based clinical syndrome or as the aggregation of comorbidities, it is not synonymous with disability, which is the difficulty or dependency in tasks of daily life. Consistent with this, only 27% of individuals in the CHS who were disabled in ADL tasks were also characterized as frail.3 Rather, frailty is predictive of disability, as baseline frailty was strongly associated with ADL disability at 3year follow-up in the WHI study,14 in the CHS study,3 and in the WHAS study.11 Each of these studies concluded that the frailty phenotype3 was able to identify a group of older adults who were at substantially increased risk for adverse health events, death, and future ADL disability. These data support the hypothesis that frailty may be a physiologic precursor to disability.3 It is also possible that disability itself, through secondary decreased physical activity, could itself lead to frailty.

CONCLUSION
Frailty is a syndrome of physiologic vulnerability and progressive decline that is likely multifactorial in etiology. The potential risk factors presented in this review are meant to give an overview of the state of frailty research and to aid clinicians in identifying frail patients so that appropriate intervention and medical care can be identified. Potential interventions span a large range, from exercise intervention to specific geriatric assessment models to end-of-life care for those with end-stage frailty, and have been discussed in further detail elsewhere. While some of the potential risk factors discussed here, such as race and SES, may not be modifiable, it may be possible to modify some of the factors associated with frailty, including strength and exercise tolerance, as well as comorbid illness and disability. In the future, new research will provide in-

Disability
The overlap of frailty with disability is similar to its overlap with comorbidity.29 While it is clear that many individuals who are frail are also disabled,

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sight into the utility of pharmacologic approaches to addressing physiologic risk factors. The research reported in this article is supported by the National Institute on Aging T32AG000120. Dr. Fried is a Cosner Scholar. Support comes through the Johns Hopkins Center for Innovative Medicine.
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1. 2. Espinoza S, Walston JD. Frailty in older adults: Insights and interventions. Cleve Clin J Med 2005;72(12):1105-1112. Chin A Paw MJ, Dekker JM, Feskens EJ, et al. How to select a frail elderly population? A comparison of three working definitions. J Clin Epidemiol 1999;52(11):1015-1021. Fried LP, Tangen CM, Walston J, et al; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56(3):M146-M156. Ferrucci L, Guralnik JM, Studenski S, et al; Interventions on Frailty Working Group. Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: A consensus report. J Am Geriatr Soc 2004;52(4):625-634. Studenski S, Hayes RP, Leibowitz RQ, et al. Clinical Global Impression of Change in Physical Frailty: Development of a measure based on clinical judgment. J Am Geriatr Soc 2004;52(9):1560-1566. Morley JE, Perry HM 3rd, Miller DK. Editorial: Something about frailty. J Gerontol A-Biol Sci Med Sci 2002;57(11):M698-M704. Rockwood K, Stadnyk K, MacKnight C, et al. A brief clinical instrument to classify frailty in elderly people. Lancet 1999;353(9148):205-206. Rockwood K. What would make a definition of frailty successful? Age Ageing 2005;34(5):432-434. Fried LP, Hadley EC, Walston JD, et al. From bedside to bench: Research agenda for frailty. Sci Aging Knowledge Environ 2005;2005(31):pe24. [Erratum in: Sci Aging Knowledge Environ 2005;2005(41):er24.] Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54(6):9911001. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty: Characterization in the women's health and aging studies. J Gerontol A Biol Sci Med Sci 2006;61(3):262-266. Studenski S, Hayes RP, Leibowitz RQ, et al. Clinical Global Impression of Change in Physical Frailty: Development of a measure based on clinical judgment. J Am Geriatr Soc 2004;52(9):1560-1566. Fried LP, Walston J. Frailty and failure to thrive. In: Hazzard WR, Blass JP, Ettinger WH Jr, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th edition. New York, NY: The McGraw-Hill Companies; 2003;1487-1502. Woods NF, LaCroix AZ, Gray SL, et al; Womens Health Initiative. Frailty: Emergence and consequences in women aged 65 and older in the Women's Health Initiative Observational

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