Sci. Aging Knowl. Environ., 28 January 2004
Frailty--The Search For Underlying Causes
The author is at the Center on Aging and Health in the Division of Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. E-mail: firstname.lastname@example.org://sageke.sciencemag.org/cgi/content/full/2004/4/pe4
Key Words: frailty weakness fatigue inflammation cytokine IL-6
Practitioners of geriatric medicine have long recognized the existence of a subset of older adults who are frail. The members of this frail subset are more vulnerable to a host of poor health outcomes than are other individuals of the same age. The biology that underlies frailty has been difficult to study for a number of reasons. Until recently, there have been no standardized and validated clinical criteria to identify frail older adults for studies (1). Because these adults often have high burdens of disease and disability, it has been difficult to separate the biology of disease and the clinical characteristics of disability from frailty. Although disability caused by specific disease states might make an individual look frail, and disability and frailty frequently overlap in the same individual, it is increasingly apparent that disability and frailty are not the same clinical entity (1, 2). In addition, although it is clear that high burdens of acute and chronic disease and the medications used to treat some diseases might trigger frailty, there is emerging evidence that disease alone is not completely responsible for the development of frailty (1-3).
In order to further the understanding of the biology of frailty, and in order to move toward the identification of underlying etiologies of frailty, we have developed a hypothetical "cycle of frailty" that illustrates how disease, medications, and age-related changes might trigger frailty and how disability might evolve from this condition (Fig. 1). This figure also illustrates how the loss of muscle mass, altered energy expenditure, and declines in nutritional intake might provide entry into this cycle of decline (4).
In order to study the physiology and biology of frailty more carefully, screening exams based on common clinical features observed in frailty, including weakness, weight loss, fatigue, and low levels of activity, have been developed (1, 5). In these studies, rigorous criteria were used to exclude individuals with conditions, such as Parkinson's disease or a past history of stroke, that cause disability or frailty-like symptoms. Even when individuals with these conditions were excluded, about 7% of the population over age 65 was found to be frail, with the percentage increasing to over 20% in those over 80 years of age (1). In validity studies designed to determine whether the diagnosis of frailty predicted poor outcomes, those deemed frail were found to be the most vulnerable in that they experienced increased hospitalization, more falls, and higher mortality rates as compared to individuals in the same age group who were not considered to be frail (1). Using these screening exams as starting points for biological research, investigators have begun to characterize the physiology that correlates with frailty, which in turn may provide leads toward etiologic discovery. Understanding the etiology and pathophysiology of frailty will be important for the development of interventions to either prevent frailty or to improve the quality of life for the frail older adult.
Alterations in Multiple Physiological Systems Likely to Contribute to Frailty
Investigators have previously hypothesized that multiple interrelated physiological system changes might underlie frailty. Buchner and Wagner first proposed declines in neurological processes, musculoskeletal functioning, and energy metabolism as key to the development of frailty (6). Lipsitz and Goldberger proposed a loss of dynamic response to stressors in multiple physiological systems, including the endocrine, nervous, and cardiovascular systems, as crucial to the development of frailty (7). Lipsitz later suggested that the "complexity" (a concept from nonlinear dynamics) of the response of the cardiovascular and nervous systems changes dramatically with aging, and that frailty might be caused in part by the loss of this ability to respond appropriately to stressors (8). Bortz has proposed a loss of cellular energy production as a key underlying biological process that leads to the altered physiology of frail older adults. He further proposed that frailty is a body-wide set of linked deteriorations including, but not confined to, the musculoskeletal, cardiovascular, metabolic, and immune systems. He also maintains that frailty is largely separable from the process of aging and should therefore be susceptible to active intervention and reversal (2, 9). All of these writings have helped investigators to develop hypotheses about multiple system declines and have led to progress in characterizing the physiology of frailty.
Physiological Correlates of Frailty: Pointing the Way Toward Discovery of the Mechanisms Behind Frailty
Several recent studies have helped to establish sarcopenia, inflammation, activation of blood clotting pathways, hormonal depletion, and lower than normal serum concentrations of hemoglobin as important physiological correlates of frailty. Using a screening exam that consisted of measurements of grip strength, walking speed, weight loss, fatigue, and activity levels to identify frail older adults, as well as exclusion criteria designed to distinguish between frailty and Parkinson's disease, advanced dementia, depression, and acute viral syndromes, Leng et al. established a correlation between frailty and lower than normal concentrations of hemoglobin and higher than normal amounts of the inflammatory cytokine interleukin-6 (IL-6) (10) (for information about the aging immune system, see "Immunity Challenge" and Wollscheid-Lengeling Perspective). Using the same screening exam, increased amounts of certain acute phase reactants (substances whose concentrations increase after injury or inflammation), including C-reactive protein and the clotting factors fibrinogen and factor VIII, were established as correlates of frailty (3). In the same study, correlations were also identified between increased concentrations of the clotting breakdown product D-dimer (derived from cross-linked fibrin blood clots) and frailty, supporting the hypothesis that clotting pathways are activated in the frailty syndrome. All of these correlative relationships remained highly significant even after individuals with cardiovascular disease and diabetes were eliminated from the analyses. Both diseases are associated with increased amounts of inflammatory markers and are very common in older adults. More recent association studies have identified inverse correlations between frailty and serum concentrations of insulin-like growth factor 1 (IGF-1) and the weak androgenic steroid dehydroepiandrosterone sulfate (DHEA-S). IGF-1 is an important messenger molecule whose production is stimulated by growth hormone and is known to be important in muscle mass maintenance (see Hepple Perspective and "Renaissance Woman"). In addition, the IGF-1 signaling pathway has been linked to the regulation of life span in several organisms (see, for example, Sonntag Perspective, "One for All," and "Power to the People"). DHEA-S is an adrenal androgen that is also important in muscle mass maintenance (11). The etiology of the declines in the concentrations of these hormones remains unclear, as does the potential causality of many of these associations.
It appears that no one system change characterizes frailty. Instead, mounting evidence suggests that several physiological systems--including inflammatory, skeletal muscle, endocrine, clotting, and hematological systems--are modestly altered in frail older adults. Most of these systems interact with each other and have the potential to influence the health and well-being of the entire organism. Despite the identification of potential interactions between altered systems, no unifying causal mechanism has yet been established.
Can Declines in Multiple Physiological Systems Provide Etiologic Clues?
The evidence presented above suggests that alterations in multiple physiological systems characterize a frail older adult. To date, there is no obvious etiology that triggers alterations in each of these systems. However, the physiological characterization of the frail older adult has helped to generate testable etiologic hypotheses and might help lead to the identification of specific molecular triggers for frailty. Fig. 2 illustrates a hypothetical causal pathway that includes the observed physiological changes reviewed above (12). It also illustrates how a number of potential causal factors might trigger physiological changes similar to those observed in frail adults. Some disease states, certain forms of genetic variation, and molecular changes related to aging trigger similar but distinct physiological alterations across systems.
Genetic Variation and Frailty
Thousands of genes can potentially affect a complex syndrome such as frailty, and ample evidence suggests that one or several might influence the frailty phenotype. For example, given that increased inflammation, as characterized by increased serum concentrations of the cytokine IL-6, is associated with frailty, one could hypothesize that variation in the IL-6 gene might contribute to frailty. A previously identified polymorphism in the human IL-6 gene promoter at position 174 has been demonstrated to increase the expression of IL-6, leading to higher than normal concentrations of this inflammatory cytokine (13). When the "g" allele is present in individuals with preexisting inflammatory triggering conditions, such as Sj�gren's syndrome (an immunological disorder) or a history of open heart surgery, it is more likely that these individuals will go on to have higher than normal serum concentrations of IL-6 as well as more serious disease complications (14, 15).
The expression of certain alleles might be more strongly influenced by age-related physiological changes than the expression of other alleles, and such differences might play a role in frailty. For example, estrogen plays an important role in suppressing IL-6 expression and hence in the suppression of inflammation. As estrogen production wanes with aging (see Holmes Perspective), IL-6 expression is no longer suppressed, and the effects of variations in the promoter region of the IL-6 gene are uncovered, leading to greater potential for increased IL-6 expression in those with the 174 promoter variant (16). Similarly in frailty, one could hypothesize the existence of gene variants across the genome that have the potential to trigger alterations in several physiological systems; these gene variants might not manifest any particular phenotype until advanced age or some specific disease state triggers an altered expression pattern.
The Molecular Biology of Aging and Frailty
In the past few years, great progress has been made in the understanding of molecular processes related to aging (17) (see "Aging Research Grows Up"). Much of the research centers on mechanisms that lead to multiple cumulative cellular injuries and the gradual loss of the ability to repair and regenerate. Major theories that aim to explain why aging occurs invoke mechanisms that include (i) cumulative oxidative damage from the increased generation of free radicals (see "The Two Faces of Oxygen" and Pratic� Review); (ii) cumulative DNA damage coupled with declines in the ability to repair mutations (see Sinclair Perspective); and (iii) cellular senescence, a state in which cells no longer divide (see Hornsby Perspective). In addition, the loss of telomeres with resulting alterations in cell division and protein production may also influence physiological change (see "More Than a Sum of Our Cells" and Heist Perspective). Although much of this progress has been made using cellular or animal models, these discoveries have provided important clues that can help inform research into frailty in humans. Also, some human studies exist that have yielded results important to frailty research. For example, Cawthon et al. recently reported a strong association between telomere shortening and increased mortality in individuals over 60 years of age (18) (and see "When Tips Disappear, the End Is Near"). In this study, those with the shortest telomeres had a threefold increase in cardiovascular mortality and a more than eightfold increase in mortality from infectious diseases as compared to individuals with the longest telomeres. Although it is not clear what physiological mechanisms connect the shortened telomeres to these clinical outcomes, these findings provide support for the hypothesis that underlying molecular changes make the older human more vulnerable to a host of poor clinical outcomes, including frailty. The findings are notable because there is presently little evidence connecting results from basic research to human subjects.
As new findings about the molecular basis of aging emerge in the coming years, parallel progress in translational research programs will be necessary to connect these findings to the complex clinical phenotype of the frail older adult. The development of animal and cellular models will be critical for studies of causality and for the study of potential interventions. Very large-scale genetic studies with thousands of individuals will be necessary to identify important genotypes and haplotypes that are either deleterious or protective against frailty. In addition, biostatistical and genetic epidemiologic approaches will need to be improved in order to maximize the ability to detect important genotypes or haplotypes. Improved assays to quantify molecular changes associated with aging will also be needed in order to connect these changes to clinical conditions such as frailty. The quantitative polymerase chain reaction assay used for measuring telomere length as reported by Cawthon et al. is a good example of a biological assay that might one day have important clinical utility and play an important role in frailty research (18). In addition, new serum markers that help to identify at-risk older adults may help with both prevention and etiological studies (see Miller Perspective). Finally, a bigger systems-wide biological approach may help to bring together seemingly disparate pieces of the biological puzzle. Models incorporating ideas such as allostatic load (cumulative physiological changes in the body in response to stressors), or further generations of that concept based on more recent epidemiological and basic biological studies, will be needed in order to identify plausible biological pathways that span multiple systems and could influence frailty (19). As more and more individuals live into their 80s and 90s, it will be a critical societal priority to keep older adults healthy, vibrant, and independent. Basic biological discoveries may well be the key to identification of the next generation of treatments for the symptoms and prevention of frailty.
January 28, 2004
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