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a Center for the Study of Aging and Human Development, Duke University Medical Center, and the Veterans' Administration Medical Center, Durham, North Carolina
Harvey Jay Cohen, Center for the Study of Aging and Human Development, Box 3003, Duke University Medical Center, and the Veterans' Administration Medical Center, Durham, NC 27710 E-mail: harvey.cohen{at}duke.edu.
Decision Editor: John E. Morley, MB, BCh
IN recent years, the concept of frailty has emerged as a central and critical aspect of geriatrics (1). Although this concept is difficult to define precisely (in fact, Stedman's Medical Dictionary fails to list it), it is increasingly becoming acknowledged as an important conceptual framework around which a great deal can be learned regarding age-related changes, their antecedents and consequences, and, it is hoped, preventive interventions (2). As our understanding of this concept has evolved, it is now recognized that frailty is contributed to by, at least, chronic and acute diseases, the physiological decline that occurs during the aging process, and a dysregulation of systems that also appears to accompany aging (1) (2). It may be that the latter is the most critical, allowing for the negative interplay of several key systems, especially the muscular, neuroendocrine, and immune systems, to create a downward spiral that we eventually recognize as frailty. The potential adverse outcomes resulting from frailty have been well outlined by Fried and Walston (1) and include problems such as falls, injuries, susceptibility to acute illnesses, ultimate hospitalizations, or frank disability and dependence, and, potentially, institutionalization and death. These are obviously among the outcomes that contribute not only to the burden of medical care for older people, but also to the economic burden involved. A better understanding of the mediators of this pathway should be extremely valuable in suggesting methods for prevention and amelioration (3).
It is in the realm of potential precursor pathways that the role of inflammatory mediators and, in fact, the entire inflammatory process has been suggested. It has been suggested that a low level of chronic inflammation results from actual stimulation of the immune system through chronic infectious processes, such as periodontal disease, chronic pulmonary disease, diverticula, chronic renal disease, and urinary tract infections (2) (4). However, it is possible that at least some of this apparent chronic inflammation may be a failure of the immune system to be properly regulated during the aging process, resulting in a continued, albeit low, level of effect over time (2) (5). Such an age-related dysregulation might be analogous to that seen when an idiopathic monoclonal gammopathy results from dysregulation in the same system that would ordinarily produce antibodies reactive to an infectious process (6). The markers of inflammation most studied with respect to aging have been the cytokine interleukin 6 (IL-6) and the acute phase reactant C-reactive protein (CRP) (7) (8). A number of studies have demonstrated the cross-sectional association of increased levels of these proteins with increasing age and associations of increased levels with markers of frailty; in particular, basic and instrumental activities of daily living (ADLs) (5) (8). We have shown this to occur independent of disease and have suggested an age-related dysregulatory phenomenon as the underlying pathophysiology (5). It is of interest that the well-recognized age-related decline in thymic function is accompanied by increased production of IL-6 by the thymic epithelium and that IL-6 induced thymic cortical atrophy (9). Others have shown correlations of IL-6 with the subsequent development of disability, determined by basic and instrumental ADLs, as well as subsequent mortality (10) (11) (12).
So, it may seem that the report in this issue by Taaffe and colleagues (13) of a lack of cross-sectional correlation of IL-6 and CRP with physical performance measures and a failure to predict subsequent decline in measures of physical performance contradicts these previous reports. This is not necessarily true, however, for a number of reasons. First, the authors do confirm the prediction of mortality (i.e., those with increased IL-6 and CRP had shorter survival when compared with those with lower values, in concert with other previous studies) (12). Second, one must remember that this study assesses only physical performance measures as an outcome. This is only one, and indeed an intermediate, measure of frailty. That is to say that although physical performance tests may correlate with the end point (frailty), they are not the only contributors to that end point. Actual outcomes that are intrinsic aspects of frailty are those activities in which the older person can actually engage in real life, as described by them or by others. Thus, strength, balance, speed, endurance, and range all play a role, along with desire, cognition, fatigue, and interest (14). The measures of physical performance used in this study only assess a part of this spectrum, whereas basic and instrumental ADLs, which were reported in other studies, measure other components of this spectrum (15). The failure to show correlation of inflammatory markers with change in physical performance tests suggests that since cytokines are known to correlate with the broader indicators of frailty and are predictors of them as subsequent outcomes, they may operate by mechanisms other than on direct physical performance measures alone. Our previous report of the association of IL-6 with depressive symptoms in an elderly population is one example of other pathways involved (16). Moreover, there has been a preliminary report from the same MacArthur population studied by Taaffe and colleagues showing that IL-6 does predict decline in cognitive function (17).
It is also possible that effects on direct physical performance measures may be seen at different points in the pathway, which may not be reflected in the Taaffe study due to the restricted disability of the population being studied. This is another reason why this study may appear to be in conflict with other studies. As the authors have pointed out, this study is of the MacArthur population, a subset of the larger Established Populations for the Epidemiologic Studies of the Elderly (EPESE) population, which was selected from the highest functioning one third of the population, thus severely limiting the population heterogeneity and limiting the generalizability of these results to a broader population. Moreover, as noted previously, it may limit the effect size seen in an outcome marked by fairly severe impact on function.
Of course, another reason for lack of longitudinal association is the likelihood that IL-6 and CRP are not the only important mediators of such outcomes. Other pathways (i.e., other cytokines, inflammatory molecules, and mediators) are likely to be involved. For example, we have previously suggested that markers of coagulation, as well as of inflammation, might be involved in functional change and that they might interact to do so (18). It has been clearly established that the inflammatory and coagulation processes both can contribute to outcomes in certain systems; in some cases, interacting to do so, although acting independently in other cases. Thus, in the generation of atherosclerosis as marked by cardiovascular disease outcomes, both CRP and markers of coagulation, such as fibrinogen and D-dimer, are important predictors (19) (20) (21). It has been suggested that atherosclerosis results from an interplay of inflammatory and coagulation phenomenon (22). We have previously demonstrated the correlation of D-dimer with function in the MacArthur population (18) and with aging and function in a broader EPESE population (23). In recent studies of the EPESE population, as yet unpublished, we have shown that both IL-6 and D-dimer are predictive of mortality and, to some degree, of functional decline, but that the most impressive prediction of functional decline is seen when both markers are considered together. In this case, the pathways appear to be acting independently, but additively, and also independent of other disease states. Thus, it may be that the full story will involve interactions of systems that operate both independently and interactively leading to a final common pathway of frailty. It is not surprising then that assessing any one given marker and any one given outcome might fail to show significant correlations when evaluation of a broader set of mediators and outcomes might well reveal important insights.
It is also of interest that the study by Taaffe and colleagues noted that those who are more physically active had lower IL-6 and CRP (13). In concert with our previous finding of high IL-6 in those with poor physical function (5), this suggests, though certainly does not prove, a role for these mediators in producing at least certain aspects of frailty and suggests that exercise training may be one possible way to ameliorate some of them. This concept is certainly amenable to experimental assessment through prospective clinical trials, some of which are currently under way. Ultimately (as has previously been pointed out) (11), observational studies will be limited in explaining causality. We will need not only prospective, but interventional, trials to do so. Evidence has regularly accumulated that exercise can ameliorate some aspects of frailty (2) (24), but there has been no direct evidence of changes in cytokines and other inflammatory mediators preceding such improvements. There is some evidence for exercise producing changes that result in more favorable versus unfavorable cytokine profiles (with respect to atherosclerosis generation), but further studies are needed to more accurately assess the potential linkages (25). Other interventions directed specifically at altering cytokine profiles, such as anti-inflammatory drugs, specifically targeted anticytokine or anti-cytokine-receptor antibodies, will provide even more direct ways of addressing this issue. The impact of such therapies on one component of frailty—fatigue—has already been demonstrated in trials for the treatment of rheumatoid arthritis (26). On an even broader front, studies addressing the interface of the cytokine networks and neuroendocrine system should prove quite valuable in increasing our understanding of frailty, which may prove to be a central tenant in geriatric care (27) (28). This is an area in which geriatricians have a great deal to contribute, both in the development of our basic understanding of the phenomenon and in providing clinical care for affected patients.
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Acknowledgments |
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Received July 31, 2000
Accepted July 31, 2000
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  H. E. Whitson, J. L. Purser, and H. J. Cohen Frailty Thy Name Is ... Phrailty? J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2007; 62(7): 728 - 730. [Full Text] [PDF]
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 F. Lally and P. Crome Understanding frailty Postgrad. Med. J., January 1, 2007; 83(975): 16 - 20. [Abstract] [Full Text] [PDF]
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 M. Barbieri, L. Ferrucci, E. Ragno, A. Corsi, S. Bandinelli, M. Bonafe, F. Olivieri, S. Giovagnetti, C. Franceschi, J. M. Guralnik, et al. Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E481 - E487. [Abstract] [Full Text] [PDF]
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W. M. Bortz II A Conceptual Framework of Frailty: A Review J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): M283 - 288. [Abstract] [Full Text]
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 J. K. Kiecolt-Glaser, L. McGuire, T. F. Robles, and R. Glaser Psychoneuroimmunology and Psychosomatic Medicine: Back to the Future Psychosom Med, January 1, 2002; 64(1): 15 - 28. [Abstract] [Full Text] [PDF]
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