Frailty in Older Persons

Luigi Ferrucci, MD, PhD Chief, Longitudinal Study Section Clinical Research Branch National Institute on Aging (NIH)

Linda P. Fried, M.D., M.P.H. Professor, Medicine, Epidemiology and Health Policy Director, Center on Aging and Health Director, Division of Geriatric Medicine and Gerontology The Johns Hopkins Medical Institutions

the buffering effect of this phenomenon is negligible compared to the massive increase in the prevalence of disability that results from the disproportionate increase of older people in the population and improved survival after disability due to better social and medical care. prevention of disability has become one of the most important objectives of medical research. The traditional medical system is confronted with an increasing number of persons surviving beyond the age of 80 or even 90 years. especially. have not been consistently confirmed in different populations and surveys. in spite of the fact that they are affected by severe chronic diseases and. Therefore. The progressive expansion of the older portion of the population has strong effects on the economy and presents challenges to political and social institutions that are completely novel in human history. these findings.The need for an operational definition of frailty The population of most countries in the world is rapidly aging. need help in performing basic activities of daily living (2). The cost of medical care and social services for the elderly is already a major concern and some economists predict that it will grow in the future above any previous expectations (1) . bad news for older persons and for the financial health of the health care systems. therefore. when observed. to substantially improve quality of life and functional status in late life. 2 . are mostly limited to the decrease in declines among those at the medium to high level of physical function (4) . In fact. There is crude contrast between our ability to improve survivorship even at older ages and our relative incapacity. to date. Expansion of disability is . Claims of ongoing “compression of disability” that propose that the incidence rate of disability is declining (3) at least in the industrialized countries. Even assuming that some “compression of morbidity and disability” is occurring. There is solid evidence that disability is the critical factor that negatively influences both quality of life and health care cost in the elderly (5-6) .

therefore preventing severe health outcomes such as myocardial infarction. For example. Investigators have also pointed out that a favorable social environment. While we have been very successful in the identification of risk factors for disability. environmental exposures. However. no preventive effects on disability and dementia were detected. including health behaviors.13) . the Systolic Hypertension in the Elderly trial clearly demonstrated that treatment of hypertension is associated with reduced risk of stroke.In the last three decades. and even for this interve ntion we lack definitive answers since no clinical trial with an adequate sample size and follow -up time has ever been conducted. Since it is well known that these medical events are powerful predictors of disability. a number of large epidemiological studies have focused on aging-related issues in large samples representative of the general population (7-10) . In particular. it is surprising to discover that virtually none of the publishe d therapeutic trials demonstrated a sizeable effect on disability prevention and active life expectancy. Pharmacological and non pharmacological interventions are now available that effectively decrease disease risk factors. Some authors suggested that methodologic biases intrinsic to the design and conduct of these studies might account for these findings (18) . it has been suggested that older 3 . supervised physical activity is the only single risk factor intervention that has shown some effectiveness in preventing disability or delaying disability onset. diseases and life-events (11. In practice. Analyses conducted on the rich databases of these studies have identified a wide range of risk factors for disability which are potential targets for preventive interventions. coronary events and congestive heart failure. better socio-economic status and emotional vitality may buffer the effect of risk factors and thus reduce the risk of disability (14-15). stroke or hip fractures (16-17) . intervention studies that targeted these same risk factors for disability prevention have been mostly disappointing.

for example. Incidence and prevalence of most diseases increases with age. regardless of the age of the host. comparison across the age-span may not be completely fair because they assume that the intrinsic pathophysiology of the diseases remains the same. This may not be a true assumption. the estimated prevalence of myocardial infarction at age 45 is less than 1%. major diseases in young age are “exceptions” . The occurrence of an infarction at younger ages is an extremely rare event that jeopardizes the life of an individual and triggers a complex. wide series of diagnostic procedures that are aimed at identifying the genetic. On the other hand. predisposing factors. However. There is overwhelming evidence that aging is associated with increased susceptibility to diseases. This does not mean that interventions targeting specific risk factors or that act on selected pathophysiologic steps in the causal pathway to diseases are useless in the elderly. anatomical or environmental characteristics that may account for such an anomaly. making the disability outc ome selectively not detectable. and suggestions of possible methods to minimize the effect of these biases from selective loss to follow up. the approach to prevention of disability should consider an entirely new paradigm that focuses on non disease-specific pathways of homeostatic equilibrium. informative censoring is not the only possible explanation. Rather. likely genetic. we suggest the hypothesis that. this suggests special. functional ability and compensation. in this particularly challenging population. Another possible interpretation is that the modification of the natural history and clinical evolution of diseases is not adequate for disability prevention.persons who develop disability are likely to drop out from a study. However. when the 4 . In other words. Potential approaches to correct for this that have been proposed recently in the geriatric and epidemiological literature include evidence taking “informative censoring” into account in analyses that use disability as the main outcome.

From the perspective of progressive frailty as an age-associated phenomenon. after long periods of cumulative risk factor exposure. which has been attributed to a long latency period. because of the multi-systemic nature of frailty. it is known that there is affected regulation of inflammatory and immune systems with age. which could affect multiple organ systems and contribute to development of multiple aging-related diseases. stroke. We will define such a core biologic dysregulation as “frailty”. Hypothetically. Three concepts are important in this context: 1) Diseases emerge in the clinical picture when the functional or anatomical damage trespasses certain. there may be other causative factors at play. For example. However. it is possible that there are primary biologic dysregulations which affect fundamental mechanisms aimed at maintaining the biological homeostasis or the anatomical integrity of the organism. a central cause of health status deterioration with aging could be the dysregulation in homeostatic equilibrium. 5 . although in only some of them may such a dysfunction be clinically evident. pre-defined thresholds. Thus. arthritis . most physiological systems are dysfunctional. the latter permits diseases becoming manifest in old age. comorbidity that is often present with age could represent specific diseases being indirect markers of the extent to which the severity of the global. sarcopenia and osteopenia. In addition. this could contribute to development of coronary heart disease. The ageassociated increase in disease is seen with most major diseases (with very few exceptions). The pattern of comorbidity can be different in different individuals because of previous impairment or because of genetic or non-genetic susceptibilities.same diseases occur in older age. biological dysregulation is reflected in specific physiological systems.

Accordingly. some recent lines of research suggest that physical activity improves mechanisms that are supposed to play a role in the genesis of frailty. without any substantial modification of resulting disability. This could explain why many studies have demonstrated a favorable effect of an exercise program in improving the symptoms of major chronic conditions . Changing the clinical evolution of diseases may not affect the underlying frailty and. disease and functional consequences may be. such as the scavenging of free radicals (19) . This raises the question as to whether benefits that have been seen from exercise could be via impact on frailty. have inadequate impact on the prevention of disability. we have proposed that the same aging-related mechanisms of progressive dysregulation and dysfunction of the biological mechanisms that maintain a stable homeostasis may also be responsible for the progressive decline of physical function with aging. This may explain why acting on single disease in terms of prevention and cure may be only pa rtially effective in preventing and/or reversing functional limitations and disability. congestive heart failure and peripheral neuropathy. to some degree. regardless of the presence of specific diseases (Figure 1). However. the production of pro-inflammatory cytokines (20) and the sensitivity of cell membrane-bound receptors such as insulin (21) and IGF-1(22) . However. this could offer a key to design new effect ive interventions for improving the health and quality of life of older persons. If so.2) The primary dysregulation in the mechanisms that maintain the homeostatic equilibrium may have a direct negative impact on physical and cognitive status. therefore. 6 . 3) The biological basis for the age -associated increased susceptibility to disease is unclear. parallel outcomes of frailty. chronic respiratory diseases. including peripheral artery diseases.

Thus. While some have looked at specific diseases. the disadvantage of this method is the low level of specificity. Functional limitations that influence lower extremity performance may select for specific diseases. These findings are now thought to indicate that poor lower extremity performance may be used as a proxy marker of frailty to identify older persons who are most likely to benefit from interventions for disability prevention. For example. knee osteoarthritis or stroke may be associated with problems in balance and/or gait regardless of any impairment. a more comprehensive definition with greater specificity is desirable. even within the context of functional measures. easy to obtain and available for immediate interpretation. the use of performance measures for screening purposes is appealing. Performance measures are fast. 7 . Thus.Frailty and the prevention of disability A limited number of studies suggest that the prevention of disability is feasible and potentially effective. may have considered functional limitations as potent markers of vulnerability. However. especially for first line screening in the community and in the primary care setting. especially when interventions are targeted to frail individuals at high-risk of disability (23) . However. in the other physiological systems. such as osteoarthritis of the knees. anatomical or functional. Guralnik and colleague s found that a simple test of lower extremity function provides information that strongly predicts disability. criteria that should be used to identify such a population at high risk of disability remain unclear. mortality and institutionalization (24-25). Subsequent studies showed that lower extremity function also predicts hospitalization and health care resources utilization (26) . inexpensive. There is a trade -off between a simple definition of frailty based on performance measures and a more extensive definition that takes into account the multi-systemic nature of the syndrome.

c) poor exercise tolerance. After adjusting for significant confounders. 2) poor grip strength. by limiting mobility and physical activity. individual components are associated with the classical geriatric syndromes (e. falls. urinary incontinence and functional impairment) and are strong and independent risk factors of disability and death. hospitalization and death. (24-25) In 1999. and 5) low physical activity. participants with 3 or more of these characteristics were at significantly increased risk of disability. d) unstable balance. Additional validation of these criteria is highly desirable and should be used as the basis for future clinical trials of disability prevention. 4) slow walking speed. However. and sarcopenia (loss of lean body mass). Fried and Walston developed an interpretive framework that combines the elements of the “body composition” and “mobility” domains of the frailty syndrome into a pathophysiologic pathway where sarcopenia and poor muscle strength. Validity of these factors as critical elements of the frailty syndrome is provided by studies showing that in older. which. we lack 8 . The work of Fried and Walston demonstrates that aggregating measures in the domains of physical function and body composition is an effective initial basis for developing screening criteria for intrinsic vulnerability that have predictive validity. such as lower extremity performance and gait abnormalities. e) factors related to body composition.g. symptomatic depression. non-disabled persons. and weight loss. Using data from the Cardiovascular Health Study the elements of the pathway were operationalized as: 1) unexplained weight loss. in turn. b) muscle weakness. without understanding the pathophysiologic pathway that leads to frailty as a syndrome and justifies the aggregation of the domains proposed by Fried and Waltson. lead to weight loss and further aggravate sarcopenia (27). reduce total energy expenditure and nutritional intake. such as undernutrition. 3) self-reported exhaustion.There is now consensus that the basic clinical features of the frailty syndrome should include the following domains: a) mobility.

therefore. 5. The frailty syndrome may be initiated by a number of different causes but once activated it is sustained by circular signaling and metabolic pathways that act independently of the triggering cause. it may be useful to enlist some of the features that. either in the intracellular environment or (more likely) at the whole organism. 3. 4. although initially the multisystemic involvement may not be clinically evident or could emerge as comorbidity. at least theoretically. biological causes of the syndrome. 2. Frailty develops more often in older individuals and. is facilitated by normal aging. To improve our understanding and to identify direction for research. The next step: understanding the biology of frailty The pathophysiologic mechanisms embedded in the layer underlying the phenomenology of the frailty syndrome still elude our understanding. Frailty has a direct impact on mobility and physical function but may exist and may be detectable in persons who are not disabled. 9 . should be characteristic of this syndrome: 1. multi-cellular level. The pathophysiologic mechanism that causes the frailty syndrome is important for normal functioning of multiple physiological systems. and are yet to identify the primary.the critical information to envision any serious attempt to prevention and cure. At the core of frailty is a primary dysregulation of some fundamental biological mechanisms responsible for the maintenance of homeostasic equilibrium. In other words. we are still in the phase of defining the “consequences of frailty” on a superficial layer.

such as IL-6.Based on these characteristics. central nervous system. Inflammation modifies the secretion of many hormones: for example. 4. It has been demonstrated that these substances damage the proteins. 2. the 10 . including bones. Such changes are important for the maintenance of integrity and function of many physiologic systems contributing to mobility. there is clear evidence that high circulating levels of inflammatory markers. the synthesis of IGF -1 is down-regulated in diseases characterized by inflammatory status such as rheumatoid arthritis. which are highly reactive molecules generated in mit ochondria in the context of energetic metabolism. It is interesting to note that these systems are highly interconnected. 3. joints. Dynamic equilibrium between the sympathetic and the para-sympathet ic systems . Examples are: 1. impair signal transduction in many hormone receptors (29) . joints. have detrimental effects on muscles. these are responsible for many of cardiovascular reflexes that maintan adequate perfusion in the vital organs during challenging conditions. hematopoiesis. The circulating levels of many soluble markers of inflammation tend to increase with age. cognition. DNA and other macromolecules. it is reasonable to assume that the intrinsic cause of frailty should be searched for in common pathways for multiple impairments. Inflammation. Hormones.(28) Additionally. bone. and play an important role in many diseases that are highly prevalent and frequent causes of disability in older persons. The examples in the literature are so numerous that only a few can be mentioned here. TNF-alpha and CReactive Protein. The circulating levels of many hormones change with age even in healthy individuals. energy production and delivery. For example. Equilibrium between the production and scavenging of free radicals.

Conclusions Frailty is an exciting area of research that opens a complete new perspective on the possibility of better understanding of aging and health in older persons. The possibility of identifying interventions that reduce the burden of frailty in older persons is hampered by our poor understanding of the biological basis of this age-associated syndrome. This suggests that the benefits of exercise may go far beyond the strength– and conditioning–enhancing effects on disability heretofore considered. improves the function of the autonomic system. stimulates the production of free radical scavengers and. interact with the effect of hormones and create an imbalance between the activity of the different arms of the autonomic systems (30) . It is important to note that physical exercise. as mentioned above. Beyond the many controversies. exercise increases the level of anabolic hormones such as testosterone and DHEAS. in some instances.production of TNF-alpha from the fat tissue is responsible for insulin peripheral resistance in obesity. Clearly. Free radicals may directly trigger an inflammatory response. has a positive effect on all these modulatory systems and is also the only intervention for which we have some evidence of disability prevention. more research is needed in this area. the operational definition of frailty is ready to be translated into clinical practice for the identification of patients who need intensive and “holistic” care and for the screening of older persons at high risk of disability who may benefit the most from interventions for disability prevention. Because of these many and complex interrelationships. the emergence of self sustained cycles that ultimately lead to frailty is a real possibility that warrants evaluation in future research. 11 . In fact. substantially reduces the circulating levels of inflammatory biomarkers (31) .

4) Freedman VA. 6) Cohen HJ. Borhani NO. Gardin JM. Steverink N. 3) Fries JK. Disability and the future of Medicare. Wallace RB. 1996. Manolio TA. Aging. The assessment of ADL among frail elderly in an interview survey: self-report versus performance-based tests and determinants of discrepancies. Pennypacker L. Aging Clin Exp Res. Martin LG. Brodkin K. Deeg DJ. Schoeni RF. Hamdy RC. 5:27-37. 2002. Lemke JH. Newman A. Recent trends in disability and functioning among older adults in the United States: a systematic review. Blazer D. 1993. 335:744-6. Lyles KW. Ann Epidemiol. Scherr PA et al. 8) Cornoni-Huntley J. Ainslie N. N Engl J Med. Feussner JR. McMurtry C. Kohout FJ. N Engl J Med. natural death.Bibliography 1) Callahan D. 5) Kempen GI. Evans DA. J Geront Psychol Sci 1996. Enright P. and the compression of morbidity. Phibbs C. Kuller LH. Carnes M. 1991. 51B:P254-60. Controlling the costs of health care for the elderly--fair means and foul. Lavori P. 1:263-76. Furberg CD. The Cardiovascular Health Study: design and rationale. 349:1084-5. 303:130-5. 346:905-12. 288:3137-46. 7) Fried LP. N Engl J Med. Mittelmark MB. 2) Cutler DM. Berkman LF. N Engl J Med. Established populations for epidemiologic studies of the elderly: study design and methodology. Smith DM. Weinberger M. 12 . 1980. A controlled trial of inpatient and outpatient geriatric evaluation and ma nagement. 2003. Hsieh F. Taylor JO. et al. Hornick T. Kronmal RA. May C. JAMA. Courtney D. Ormel J. Ostfeld AM. 2002.

J Am Geriatr Soc. Designing a community study of moderately to severely disabled older women: the Women's Health and Aging Study. Ann Epidemiol. 2003. 12) Comijs HC. attrition and mortality. 2003. Bandeen-Roche K. J Am Geriatr Soc. decline. 48:1618-25. Johnson BA. Shapiro S. 15:174-83. The influence of differing social ties on decline in physical functioning among older people with and without chronic diseases: the Longitudinal Aging Study Amsterdam. 2003. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study.15:164-73. 13) Bisschop MI. 15) Penninx BW. Deeg DJ. J Am Geriatr Soc. Penninx BW. Bandinelli S. Anderson GF. Benvenuti E. The protective effect of emotional vitality on adverse health outcomes in disabled older women. Macchi C. recovery. Fried LP. 11) Weiner M. Knipscheer KP. Deeg DJ.54:P240-5. Predictors of health resource use by disabled older female Medicare beneficiaries living in the community. Bandeen-Roche KJ. 2000. Fried LP. 51:371-9. Guralnik JM. Penninx BW. Kasper JD. Aging Clin Exp Res. 1999. 1999. 9:498-507. Simonsick EM. Penninx BW. Guralnik JM. Kasper JD. Fan MY. 13 . 14) Broese vanGroenou MI. van Eijk JT. Guralnik JM. Income differentials in functional disability in old age: relative risks of onset. Psychological distress in victims of elder mistreatment: the effects of social support and coping. Harris TB. Aging Clin Exp Res. 2000. van Tilburg TG. Di Iorio A. van Tilburg W. Ferrucci L. J Gerontol B Psychol Sci Soc Sci. 48:1359-66.9) Kasper JD. Fried LP. Kriegsman DM. 10) Ferrucci L.

Applegate WB. Wojta DM. J Am Coll Cardiol. 2001. 48:M84-90. Steiner JF. Wan JY. Franse LV. Fumagalli S. Somes GW. 21) Kirwan JP. Am J Epidemiol. Improved exercise tolerance and quality of life with cardiac rehabilitation of older patients after myocardial infarction: results of a randomized. Burgisser C. Schlenker RE. Circulation. Outcomes and costs after hip fracture and stroke. J Am Geriatr Soc. 18) Di Bari M. Kroupis C. Shorr RI. Karavolias G. 2002. 17) Kramer AM. Del Lungo F. 1993. Eckhoff DG. Tropea DA. Exercise-induced oxidative stress in older adults as a function of habitual activity level. Morosi L.16) Marchionni N. 153:72-8. 19) Meijer EP. 39:653-63. Holloszy JO. Eilertsen TB. J Gerontol. 277: 396-404. 107:2201-6. controlled trial. 2003. Kremastinos DT. Goris AH. van Dongen JL. Paraskevaidis J. Ahmad 70-year-old men and women. Ferruccci L. A comparison of rehabilitation settings. Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. 50:349-53. 20) Adamopoulos S. 2002. Westerterp KR. Kohrt WM. Koniavitou K. Bourey RE. Massotti G. Georgiadis M. JAMA 1997. Coats AJ. Parissis J. Pahor M. Bast A. Oldridge N. Karatzas D. Endurance exercise training reduces glucose-stimulated insulin levels in 60. Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial. 14 . Hrincevich CA. Fattirolli F.

2000. Callis A. Rantanen T. Seeman T. Tangen CM. 1996 Sep. Kop WJ. A short physical performance ba ttery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. Holly JM. Simonsick EM. Gottschalk M. Wallace RB. Wallace RB. Cwyfan-Hughes S. Berkman LF. elderly persons who live at home. 25) Guralnik JM. Tracy R. Brun JF.22) Manetta J. Maimoun L. Frailty in older adults: evidence for a phenotype. Guralnik JM. Glynn RJ. Gottdiener J. Baker DI. 49:M85-94. Newman AB. Leveille SG. Blazer DG. Ferrucci L. Local disruption of the insulin-like growth factor system in the arthritic joint. J Gerontol 1994. Hirsch C. A program to prevent functional decline in physically frail. 15 . Ferrucci L. 27) Fried LP. Simonsick EM. J Gerontol A Biol Sci Med Sci 2001. Blazer DG. Scherr PA. Billingham ME. Ferrucci L. Byers A. Berkman LF. Glynn RJ. Am J Physiol Endocrinol Metab. N Engl J Med 1995. Arthritis Rheum. Peduzzi PN. 24) Guralnik JM. Burke G. 28) Fernihough JK. J Gerontol A Biol Sci Med Sci. 23) Gill TM. Pahor M. 55:M691-7. Walston J.283:E929-36. Scherr PA. 2002. Effect of training on the GH/IGF-I axis during exercise in middle-aged men: relationship to glucose homeostasis. Mercier J. McBurnie MA. N Engl J Med 2002. 26) Penninx BW. 332:556-61. 56:M146-56. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. Lower extremity performance in nondisabled older persons as a predictor of subsequent hospitalization. 347:1068-74. 39(9):1556-65. Allore H. Prefaut C.

31) Bonnefoy M. Mathian B. 16 . 2001. 27:745-51. 19:193-200. J Neuroimmunol. Cytokine. Gamma(2)-melanocyte-stimulating hormone suppression of systemic inflammatory responses to endotoxin is associated with modulation of central autonomic and neuroendocrine activities. Daun JM. Krukoff TL. 30) Xia Y. tumor necrosis factor and associated receptor secretion in postmenopausal women. 1998. Tupper CE.29) Brooks -Asplund EM. Berthouze SE. Cannon JG. Kenney WL. Kostka T. insulin-like growth factor I and testosterone in healthy active elderly people. Patricot MC. Physical activity and dehydroepiandrosterone sulphate. Wikberg JE. Hormonal modulation of interleukin -6. Lacour JR. 120:67-77. 2002. Age Ageing.