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FRAILTY AND FAILURE TO

THRIVELINDA P. FRIED JEREMY WALSTON

The identification, evaluation, and treatment of frail older adults constitute a cornerstone of thepractice of geriatric medicine. This is the case for several reasons. First, the frail elderly aregenerally the older adults most in need of health care, community and informal support services,and long-term care. Second, given the increasing numbers and proportion of older adults in thepopulation, our obligation to provide care for a commensurately increasing subgroup of frailindividuals is a critical public health concern. It is thought that between 10 and 25 percent ofpersons aged 65 years and older are "frail," with the proportions increasing dramatically withincreasing age. According to the AMA White Paper on Elderly Health (1990), "after the age of 85,46 percent of those living in the community fall into this group of frail elderly." Finally, andcentrally, much of geriatric medicine is directed toward care of the frail older adult. Manygeriatric interventions, such as geriatric assessment, are thought to be most cost-effectivelytargeted to the frail elderly. This is the subset most likely to benefit from such comprehensive

evaluation and preventive interventions and team-based care.Geriatricians often state that the clinically expert can readily distinguish a frail from a nonfrail

older person. Frail individuals are perceived to constitute those older adults at highest risk for anumber of adverse health outcomes, including dependency, institutionalization, falls, injuries,acute illness, hospitalization, slow or blocked recovery from illness, and mortality (Fig. 109-1).Although a clinical "sense" of frailty exists, there is still no explicitly agreed-on, standard clinicaldefinition of frailty or of failure to thrive that would assist identification of this high-risk subset ofthe population prior to the onset of these adverse outcomes. In fact, the development of such adefinition proves to be a highly complex task.

Despite the difficulty of defining who is frail, it is important to translate clinical instinct intoexplicit definitions of frailty and what the underlying etiology is. Such definitions are needed toteach geriatric medicine, to develop useful screening tools to identify the people at high risk forpoor outcomes and those most likely to benefit from geriatric care, to target interven

tions effectively, and to further guide clinical and molecular research in the field of geriatricmedicine.

It is the goal of this chapter to consider the currently used definitions of frailty and failure tothrive, to propose a definition and framework that could organize our understanding of thephysiologic characteristics of these syndromes and their possible etiologies, and to reviewpotential treatments and preventive strategies.

DEFINITION OF FRAILTY AND FAILURE TO THRIVE

Frailty

We suggest that frailty and failure to thrive represent a continuum of a clinical syndrome, with

failure to thrive being the most extreme manifestation that is associated with a low rate of recoveryand presages death. The manifestations of frailty that are most widely agreed on in the literatureare a constellation of symptoms including weight loss, weakness, fatigue, inactivity, and decreasedfood intake (see Fig. 109-1). In addition, signs of frailty frequently are cited as components of thesyndrome; these include sarcopenia (decreased muscle mass), balance and gait abnormalities,deconditioning, and decreased bone mass (osteopenia) (see Fig. 109-1). Each of these clinical char-acteristics has been shown to be highly predictive of a range of adverse outcomes clinicallyassociated with frailty, including decline in function, institutionalization, and mortality. Consistentwith the definition of a syndrome, the phenotype of frailty may vary across this constellation of


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possible manifestations, with multiple components present, but not always the same ones fromindividual to individual.

Disability and Comorbidity: Are They Indicators of Frailty?The current literature also uses the term frailty as synonymous, variously, with one or more of thefollowing

Modal pathway of frailty. The clinical phenotype of frailty that is associated with causing adverse health outcomes and appears

to result from declines in physiologic function and reserve, as well as disease precipitants.

characteristics: extreme old age, disability, and the presence of multiple chronic diseases(comorbidiry) and/or geriatric syndromes. Each of these characteristics has been used as a measure

of frailty itself. We review here the bases for such use and their limitations. First, in terms of

disability, measures that have been used as indicating frailty include chronic limitations or

dependency in mobility and/or activities of daily living (ADLs) or instrumental activities of daily

living (IADLs). Such disability is highly prevalent in the older population, particularly those over

age 75, and it is associated with fair or poor health or declines in health, as reported by the

individual. Disability is also a predictor of future risk; for example, it is associated with increaseduse of physician services, hospitalizations, and mortalitv. Thus older adults with physical disabilityare a group at high risk for other adverse outcomes. A clinician is more likely to consider a patient

with problems ambulating as being frail than another patient who has no such difficulty. Use of dis-

abilitv as an indicator of frailty can assist in the identification of those with special medical and

service needs and in planning for service provision at an organizational level. However, clinical

experience suggests that while many (but not all) frail individuals are disabled, not all disabled

individuals are frail. This was supported in a survey of geriatricians, in which 98 percent of

respondents thought that frailty and disability were not the same. Disability is more likely an

outcome


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of frailty or a contributor to frailty than the essence of frailty itself; this is discussed further below.

Disabilit, does not appear to be synonymous with frailty.

The presence of multiple chronic diseases (comorbidiy) is often used as another marker of frailw. Not

surprisingly, comorbidiry is associated with increased risk of adverse outcomes, as evidenced by higher

shomand long-term mortality rates and significantly increased physical disability compared with thosewithout diseases. However, the presence of two or more diseases may not, in itself, identify the highest-

risk group's or those most frail. For example, analysis of longitudinal follow-up of persons 70 years ofage and older. surveyed in the Health Interview Survey Supplement on Aging, showed rates of new

confinement to bed or chair for those with two or more chronic diseases (considering arthritis, heart

disease, stroke, diabetes, cancer, cataracts, and broken hip) only slightly higher than those for all persons

age 70 and older: 24 verstL 17 percent, respectively, were newly confined after vears. In contrast, 36

percent of those with physical disabili ty as well as two or more chronic diseases were newly confined to

a bed or chair after 2 years, as were 42 percent of those 80 years of age and older who also had the othercharacteristics of disability and comorbidity. Thus comorbidity alone does not appear to capture the

group at highest risk of adverse outcomes. which is theoretically the group that would be frail. This may

be because just identifying the presence of a

chronic disease does not specify those with severe disease. Overall, the presence of comorbidity alonealso may not be synonymous with frailty.

These population-based data are supported by conclusions from a consensus conference of

geriatricians and gerontologists. This group concurred that the presence of chronic disease, in itself, isgenerally not sufficient to define the older adult who is frail. Rather, it was thought that other

physiologic processes may be more central to the development of frailty. It is hypothesized that

diseases, acute or chronic, may worsen the health and functional status of an individual who is highly

vulnerable due to an already-existing physiologic state of frailty. Alternatively, specific end-stage dis-

eases-may initiate a physiologic cycle of frailty (see below).

Proposed Definition of Frailty

The most widely agreed-on definition of frailty is that it represents a state of age-related physiologic

vulnerability resulting from impaired homeostatic reserve and a reduced capacity of the organism to

withstand stress. It has been suggested that this decline in reserve occurs across multiple physiologic

systems. Those central to the syndrome of frailty appear to be neuromuscular changes resulting insarcopenia, neuroendocrine dysregulation, and immunologic dysfunction (Fig. 109-2 and Table 109-1).

Declines in each of these physiologic realms can leave the frail older adult vulnerable to many types of

stressors. The nature of declines in each of these systems is discussed further below.

Age-Related Physiologic Declines

Age-related declines have been described in a number of physiologic characteristics, includingcreatinine clearance, forced expiratory volume, nerve conduction


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Age-related physiologic changes that are proposed as central to the syndrome of frailty.These changes underlie much of the poor response to stressors and the vulnerable state

exhibited by frail individuals. velocity, insulin sensitivity, muscle mass, strength, and Vo2max. Such

age-related declines in Vo2max are exemplified in Fig. 109-3, in which data are summarized that show aprogressive decline beginning in the thir ties and then accelerating around age 70.

It has been suggested that within each system that declines in function with age, frailty may emerge

from a particular severity of these decrements in physiologic reserve. For example, with Vo2max, it

appears that declines to a threshold level may be necessary for the individual to be compromised in termsof functioning or inability to tolerate an acute exercise stress. These changes in different systems may

occur at different rates as people age but provide a substrate of decreased physiologic reserve with which

the organism can respond to stressors.

The aggregate impact of declines in multiple systems may underlie what is frequently considered a

hallmark of frailty: vulnerability to stressors and compromised ability to maintain homeostasis. Frailty

appears

TABLE lO9-1 Clinical Signs and Symptoms of Age-Related Physiologic System Declines Central

to the Syndrome of Frailty

NEUROENDOCRINE

SARCOPENIA IMMUNE DYSFUNCTION DYSREGULATION

,~ Skeletal muscle mass T Memory cells ~, Growth hormone

~Vo2max ~, Naive cells ~, Estrogen

, Strength and exercise tolerance , ~ I L - 2 ,~ Testosterone

~Thermoregulation ,~ IgG, IgA Gortisol dysregulation

, Energy expenditure T I L - 6 , I L - 1 B T Sympathetic tone

TInsulin resistance ~, Mitogen response


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Change in exercise performance and Vo2max over time, as reported in six studies.(Reprintedwith permission from Bortz WM,1996. )

especially to involve age-related compromise in ability to respond appropriately to dynamic situations, that is,

to stressors such as exercise, temperature extremes, or acute illness, more than to declines noted in a resting

state. Underlying this could be a decreased range and complexity of responsiveness that the organism is ca-

pable o Lipsitz and Goldberger have suggested that a progressive loss of complexity in physiologic systems

with aging can be demonstrated, for example, in de

cline in heart rate variability with aging or in the re;= ulation of anterior pituitary hormone secretion in older

adults (Table 109-2). The result of such decline in complexity may be a narrowing of regulaton - control.

Overall, the aggregate loss of reserve across :v -:tems may lead to an overall decline in the abilit


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Theoretical figure showing the aggregate effect of declines in function across multiple organsystems, especially muscular, neuroendocrine, and immunologic. A multiplicity of systemsaffected is likely to increase risk through cumulatively decreasing ability to respond tostressors and maintain homeostasis.

The Cycle-and Spiral-of Frailty

While these declines in reserve in multiple systems may explain the high risk for adverse outcomesthat clinicians associate with frailty, they do not necessarily explain the syndrome of weakness,weight loss, and decreased activity, as well as balance and gait abnormalities, that is alsoassociated with frailty (see Fig. 109-1). Recent research on aging provides a basis for proposing anintegration of these clinical presenting symptoms and signs as manifestations of a downward cycleof energetics that may occur as a second stage of frailty, when aggregate reserve has declined to athreshold level and, particularly, occurring in relation to sarcopenia. We suggest that underlying thisclinical syndrome of frailty may be a cycle of undernutrition relative to activity level, with resultingnegative nitrogen and energy balance, loss of muscle mass (sarcopenia) and bone mass(osteopenia), and further declines in strength, exercise tolerance, and activity level.This vicious cycle-or spiral-of the syndrome of frailty, based on current evidence, is portrayed in

Fig. 109-5. This cycle may begin at any point shown. For example, let us start with nutritional intake.There is reasonable evidence that aging is associated with decreased ability to appropriatelymodulate food intake to match total energy expenditure, with increased likelihood of inadequatedietary intake. This anorexia of aging can be compounded by many factors that can decrease foodintake, including decreased taste and smell, poor dentition, depression, dementia, and illness. Energyintake lower than caloric needs due to energy expenditure can lead to a state of chronic protein-energy undernutrition or malnutrition, loss of body protein, and a negative nitrogen balance. Thischronic state can lead to loss of lean body mass alone

or, with malnutrition, fat loss as well. The major component of lean body mass is skeletal muscle, andloss of muscle mass results in sarcopenia. The latter also can result from senescent changes inmuscle, perhaps genetically controlled (see below). Sarcopenia, or decreased muscle mass, thencontributes to loss of strength and decline in maximal exercise tolerance (Vo zmax). The latter twochanges are known to then contribute to slowed walking speed. Past a certain level of severity, theyare also likely to contribute to disability in tasks requiring strength and/or exercise tolerance. Finally,

sarcopenia also leads to a decrease in resting metabolic rate, which-together with further declines inactivity resulting from decreased strength, exercise tolerance, and disability-causes a further declinein total energy expenditure. Entry at a number of other points shown in Fig. 109-5 also couldprecipitate the cycle.

Thus the core cycle of negative energy balance is consistent with the clinical phenotype offrailty. Much of this cycle of frailty can be explained through intrinsic age-related changes at eachpoint in the core cycle at a number of potential initiation points (see Fig. 109-5). One, for example, issarcopenia itself It is known that fat-free mass declines by about 15 percent between the third andeighth decades and leads, in itself, to declines in basal metabolic rate. One study has reporteddeclines in strength of 24 to 36 percent in men between 50 and 70 years of age, primarily due to


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selective atrophy of type II muscle fibers. Others report declines in muscle strength of 15 percentper decade in the sixth and seventh decades and 30 percent thereafter, again especially related todeclines in the number of type II muscle fibers. There is a related loss of total body potassium withage, in men occurring from 41 to 60 years of age and in women after age 60. Maximal exercisetolerance, or Vo2max, also declines

The cycle of frailty. Key components of frailty that appear to underlie its phenotypic manifestations in a negative cycle are chronic

undernutrition; sarcopenia; declines in strength, power, and exercise tolerance; and declines in activity and total energy expenditure.

Factors that could precipitate or exacerbate this core cycle are indicated with dashed lines. Factors in which a relationship is

hypothesized are indicated in italics.

with age. The amount attributed to age per se is a decline of 0.5 percent per year from ages 25 to 65(see Fig. 109-3). This may accelerate thereafter, although the latter may be due to superimposed

declines in activity. Each of these changes with age, along with basal metabolic rate and the anorexiaof aging, could be an initiating point in the cycle of frailty. The core components of this cycle of frailtyappear related to aging and not due necessarily to disease.

This energetics cycle can explain the phenotype of frailty (see Fig. 109-1), unifying the relationshipof weakness, weight loss, inactivity, and decreased food intake. It provides an explanation as to the co-occurrence of these components of the phenotype that are cited by clinicians. It also supports findingsfrom a recent survey of one group of geriatricians, 100 percent of whom thought that frailty was mostlikely to be

found in individuals with more than one defining characteristic.


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Frailty, Disability, Falls, and Disease

This cycle also provides a framework for understanding the relationship between frailty anddisability. It suggests a cause-effect relationship between the two, with frailty likely causing aparticular aspect of disability, that which results when a threshold severity of weakness anddecreased exercise tolerance is crossed. These effects of frailty on physical function are thuslargely to be found in difficulty ambulating and with other tasks requiring exercise tolerance andstrength (from stair climbing and heavy housework to transferring from a bed, chair, or toilet) andaffected by the de-

clines in balance and slowed walking speed associated with the frailty cycle. Thus, in this conceptualframework, physical disability is an outcome of being frail, and frailty leads to limitations inperforming tasks that depend on strength and energy. This definition of frailty thus refers to aphysiologic state that increases the risk of disability, likely occurring when a certain level of severity

of frailty is reached. There are many other pathways to disability through specific diseases that mayhave an impact on other aspects of physical function and not include the syndrome of frailty in thecausal pathway.

Thus, while some types of disability can be an outcome of frailty, disability does not appear to bean integral, causal part of the cycle. Other characteristics that clinicians often associate with frailtyalso may be an outcome of frailty, but they are not solely due to being frail. Falls are one example. Asshown in Fig. 109-5, falling is known to result from declines in strength and postural stability andcould thus result from the cycle of frailty. Speechley and Tinetti have shown that falls occur, however,in both frail and nonfrail, or vigorous, older individuals. They developed and applied a definition of frailindividuals as having four or more of the following characteristics: age over 80, balance and gaitabnormalities, infrequent walking for exercise, decreased strength in shoulder and/or knees, lowerextremity disability, depression, sedative use, and near vision loss. The "frail" group fell three timesmore frequently than the vigorous group (52 versus 17 percent), but falls were still common amongthe vigorous group. However, the percentage of falls resulting in serious injury was much higher inthe vigorous group than in the "frail" group (22 versus 6 percent). The circumstances of falling also

differed between the two groups: The "frail" group was most likely to fall at home, whereas thevigorous group fell primarily in more active endeavors-away from home or on stairs. Thus, while thefact of falling may not differentiate frail from nonfrail individuals, the situations and injuries associatedwith falling may be important in providing insight into who is and is not frail.

Figure 109-5 suggests that frailty can result exclusively from changes of aging and unrelated todisease. However, diseases can, potentially, have an impact on every point in the cycle. In somecases, they actually may initiate the aging-related cycle. One example of this could be depressionleading to declines in activity and/or energy intake, which then precipitate the cycle of frailty. Somediseases also could, potentially, precipitate frailty as part of their end-stage pathophysiology. In thisscenario, catabolic states, resulting, for example, from chronic inflammation or end-stage congestiveheart failure, could lead to sarcopenia and then precipitate the resulting cycle (see Fig. 109-5).

This cycle of negative energy balance, sarcopenia, and decreasing activity may identify manywho are frail. However, these factors are not always present or clinically evident in persons clinicallythought to be frail or who, post hoc, demonstrate an inability to tolerate

even minor stressors. Clinical observation suggests that some older individuals may not displaythis phenotype, be active and functioning well, and yet, in the face of a stressor such as a hipfracture, display little reserve and manifest unexpected but catastrophic decline. These individualsmay be in an earlier stage of the frailty cycle that is not yet clinically apparent. It is also possiblethat this cycle is not entirely explanatory of frailty.

In fact, while this cycle of negative energy balance matches the clinical phenotype of frailty, itdoes not fully explain the vulnerability to stressors and decreased reserve that is central to thedefinition of frailty. Frailty is likely more complex than this cycle alone. A more completeexplanation would exist if the phenotype of frailty that results from this cycle were superimposedon the less readily apparent processes that contribute to vulnerability and risk via decreases in


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physiologic reserve. It may even be that the declines in reserve (see Fig. 109-4) precede thedevelopment of the clinical syndrome of frailty displayed in Figs. 109-1 and 109-5.

This combined process of decreased reserve and a negative energetics cycle may well, in someindividuals, progress to become a downward spiral of frailty. Outcomes of this spiral could includefalls and disability, which in themselves could exacerbate declines in activity and worsen thedownward spiral. The literature to date also suggests that an end stage of this spiral may bemanifested as "failure to thrive."

Failure to Thrive

Frailty and failure to thrive are sometimes used as interchangeable terms. The term failure tothrive, however, is generally thought to indicate something beyond the vulnerability for futureevents associated with frailty. It is more often used in the context of the end stage of decline,often after these events have occurred and when the decline may be irreversible. In addition, fail-ure to thrive may well be a final, common end-stage process of both frailty and severe chronicdiseases (such as congestive heart failure, malignancy, human immunodeficiency virus infection,and dementia).

The term failure to thrive is drawn from pediatrics. It was initially applied to elderly nursinghome residents who gradually lost weight, declined in physical and cognitive function, withdrew

from social activity, and had a poor appetite. Depression is often seen as a component. While theterm is used as a clinical diagnosis, there is controversy about doing so because of concern that itreinforces pejorative and fatalistic images of aging.

The hallmark of failure to thrive is unexplained weight loss, due to malnutrition and resultingloss of fat as well as muscle mass. Thus failure to thrive can be associated with sarcopenia andmany of the resulting complications associated with frailty. It is hypothesized that failure to thrivemay be a manifestation of

loss of physiologic reserve. It is also reported to be a syndrome presenting with metabolicabnormalities, including hypoalbuminemia, low creatinine, acquired hypocholesterolemia andanemia of chronic disease, and decubitus ulcers, along with the weight loss and sarcopenia.

The individual components associated with failure to thrive are, in themselves, predictive ofmortality. For example, among people 45 to 74 years of age who participated in the FirstNational Health and Nutrition Examination Survey (1971-1975) and survived the next 5 years,mortality through 1987 was twice as likely in subjects who lost 15 percent or more of their max-

imum weight compared with those who lost less than 5 percent. Additionally, hypoalbuminemiais associated with a 2- to 4-fold increased mortality risk compared with those with normalalbumin levels among adults 71 years of age and older. Similarly, hypocholesterolemia isassociated with increased risk of mortality.

Several reports describe series of patients with unexplained weight loss or with diagnoses offailure to thrive. In one series of older outpatients, the incidence of unexplained weight loss was13 percent. However, of 15 people in this sample who subsequently died, 6 died of heartdisease, 6 died of cancer, and 3 died of infection, suggesting that the unexplained weight lossmay have been due to occult disease. In a second series of inpatients admitted with a diagnosisof failure to thrive, the most common etiologies were found to be dementia, depression, delirium,drug reactions, and chronic diseases. A third study on people aged 65 years and older in anintermediate care facility who became bed-bound during a 1-year period showed an incidence of13 per 1000. Forty-two percent had lost at least 5 pounds in the prior 6 months. Medicaldiagnoses were identified in all, and almost half died within 6 months. A fourth study looking atall patients over age 65 admitted with a diagnosis of failure to thrive to one hospital in a 1-year

period described the presenting symptoms and signs as poor appetite (55 percent), pain controlneeds (43 percent), malnutrition (40 percent), falling (36 percent), and memory impairment (40percent). The mean number of diagnoses was 6, and 21 percent had 9 or more. In this sample,55 percent were limited in their ability to undertake rehabilitation and 5'7 percent in their abilityto follow medical recommendations. Discharge diagnoses included cancer (20 percent), nervousand mental disorders (13 percent), respiratory disorders (9 percent), digestive disorders (6percent), circulatory problems (5 percent), and pancreatic disease (5 percent), as well asnutritional disorders (12 percent). Sixteen percent of this group died during hospitalization. Itwas concluded by the authors that the diagnosis of failure to thrive "seems to be used when theelderly patient's ability to live with multi-system disease, cope with the ensuing problems, and


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manage his/her care are remarkably diminished and no longer responsive to medical andnonmedical interventions." Thus, clinically, the term failure to thrive is often used to representend-stage disease(s). It also

Importance of trigger events in frailty and failure to thrive. Conceptual model of how risk factors precipitate frailty and of incomplete,

blocked recovery after event. (Reprinted with permission from Buchner D, 1992.) may represent the more irreversible

end of the natural history of the syndrome of frailty.

The Importance of Trigger Events in Frailty and Failure to

Thrive

Several authors have proposed that frailty and failure to thrive become manifest when a triggerevent occurs. This event or events, such as acute illness, injury, or an adverse life event, canprecipitate decline. In the presence of underlying loss of reserves, declines in activity level andenergy or micronutrient intake due to the trigger event may precipitate the syndrome of frailty, andthe individual may not be able to fully recover. Episodic negative energy balance and incomplete re-

covery from each trigger event may be an important pattern for progression toward frailty (Fig. 109-6) and initiation of the frailty cycle (see Fig. 109-5). There may be profound obstacles to recoveryfrom these events, particularly related to correcting the negative energetics cycle.

A UNIFYING PHYSIOLOGIC FRAMEWORK TO UNDERSTAND THE CLINICALSYNDROME OF FRAILTYWe suggest that the clinical presenting symptoms and signs of frailty aremanifestations of an underlying, cardinal physiologic decline in reserve of multiple physiologic systems,

plus a downward spiral related to energetics, and that both these integrated processes are highlyassociated with aging and not disease-specific. Three physiologic systems appear to be integral com-

ponents of frailty and key to understanding the causes of the vulnerability tostressors associated with the syndrome. They are sarcopenia, or loss of leanbody mass, immune dysfunction, and neuroendocrine dysregulation (see Fig.

109-2). We propose that age-related changes in these three systems are allmajor contributors to the syndrome of frailty. Their impact is, in part, due totheir direct effects and in part because each influences the other twophysiologic systems. In addition, decline across the three systems likely has asummary physiologic effect that explains a frail individual's aggregatevulnerability to stressors. In each of these physiologic realms, there areimportant component declines or dysregulations that leave the frail older adultvulnerable to many types of stressful events, including exertion, temperatureextremes, emotion, infection, medications, and medical illnesses (Table 109-3).We will first review the changes in each individual component system and then


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propose an integrating framework that may be explanatory of the clinicalsyndrome.

Component Systems of Frailty SarcopeniaIt is well established that sarcopenia, or the decline in muscle mass associatedwith aging, advances steadily starting at approximately age 35. This processmay progress to the point where up to 50 percent of lean body mass (mostlyskeletal muscle) is lost and replaced with fibrotic and/or adipose tissue. Thiscumulative loss of muscle mass has a profound impact on functional abilities ofindividuals in the oldest age groups via resulting decreased strength andexercise tolerance, weakness and fatigue, and diminished ability to performmany activities of daily living. Declines in strength are, further, risk factors forpoor balance, slowed gait, and falling. It is well known that a decline in Vozmaxof 0.5 to 1 percent per year starts around age 35 (see Fig. 109-3). Part of thisloss is due to declines in physical activity with age, but much of it correlateswith the loss in lean body mass seen with age. Age-related sarcopeniatherefore is the major com

TA BL E 10 9- 3

Proposed Provocations That May Trigger or Accelerate the Syndrome of Frailty

Chronic or acute psychological stress Disuse, low activity

Injury causing physical disability and low activity Dietary factors includingdecreased micronutrients and protein calorie malnutrition

ponent in the marked decrease in exercise tolerance seen in older frailindividuals.

The loss of skeletal muscle has substantial metabolic consequencesbeyond the loss of strength. Skeletal muscle is a major component in energyexpenditure, and loss of skeletal muscle results in the decline in resting

metabolic rate seen with aging. The direct metabolic consequences of thislower metabolic rate are unclear. However, thermoregulation appears to be acritical component in this axis, and much of the cold and heat intoleranceseen in older individuals is related to this phenomenon. Finally, the gradualreplacement of lean tissue with fat (and fibrous tissue) is, in part, responsiblefor the increasing insulin resistance and glucose intolerance seen in middleand older age groups. Since insulin is one of the major anabolic hormones,decreasing levels of insulin effectiveness at a tissue level may contribute tothe generalized catabolic state that characterizes frail individuals.

The extent of sarcopenia varies among older individuals. Muscle massmaintenance depends on a number of regulatory and environmental factors,including exercise, medications, acute or chronic illnesses, growth hormone,and other neuroendocrine factors. Whatever the contributors to sarcopenia in agiven individual, people with the greatest lean tissue loss are among the most

vulnerable to falls and injuries.

Immune Dysfunction

The immune system is composed of a complex and interactive group of organs,tissues, and cells that act, in sum, to defend the host organism againstpathogens and malignancies. The system must respond and adapt quickly andappropriately in order to protect the individual, while at the same timepreserving normal host tissue. A large body of literature lends supportive, butsometimes conflicting, evidence that age-related changes occur in immune


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function. These changes have been observed at the organ level, the cellularlevel, and the molecular genetic level. It appears that the sum of thesecomplex age-related changes makes the host more vulnerable to infection. Atthe same time, emerging evidence supports the concept that very oldindividuals, in particular, have abnormally elevated levels of cataboliccytokines that contribute to an inflammatory state. This age-related immunesystem dysfunction appears to be most exaggerated in the frailest older

individuals, with vulnerability to infections and a generalized inflammatorystate potentially contributing to physiologic declines of sarcopenia andneuroendocrine dvsregulation and a downward spiral of frailty. A summary ofthe changes that may contribute to the immune dysfunction associated withfrailty follows.

Increased Vulnerability to Infection: Cellular ImmunityT cells are the cornerstone of cellularimmunity and provide critical sensing, processing, and messenger roles inmounting an immune response. Many subsets of T cells, characterized bysurface receptors and func-tional roles, have been identified to date. Several component changes in T-cellfunction contribute to agerelated immune dysfunction. The overall number of Tcells declines in aging organisms, and the ratios of T-cell subsets change. Thelatter is, in part, due to the proportionally greater loss of naive T cells, the

subset of cells that has not been exposed to antigens in the past. Aconcomitant proportional increase in T-memory cells also has been observed,and this may influence the decreased response to newer antigens as well.Although there is a proportional increase in the pool of these memory cells,they appear to be less effective than memory cells of younger individuals. Thislikely results in the shorter duration of effectiveness of immunizations in oldercompared with younger individuals. Animal and human studies show an age-related decrease in ability to mount T-cell proliferation in response to antigenicstimulation. A potential reason for loss of immune system responsiveness isthe decline in ability of T cells to secrete interleukin 2 (IL-2), a cytokine criticalin mounting hypersensitivity responses, generation of cytotoxic cells, andstimulation of B-cell proliferation and, hence, humoral immunity.

Humoral Immunity Humoral immunity is the component of the immune system

responsible for generating specific antibodies that act to isolate and renderpathogens ineffectual. The B cell is the major component of this system. It iswell known that the production of antibodies declines with age. Since theseantibodies act as first-line defense against antigens of all kinds, lower levels ofthese would be expected to make the older, frail individual more vulnerable toattack and to the spread of infection. It is unclear whether these changes aredue to age-related changes in B-cell responsiveness or to decline in total B-cellnumber. Both these changes may be due to the T-cell changes characterizedearlier and hence the lack of appropriate stimulation of Immoral immunity.

The combined result of these age-related changes in humoral and cellularimmunity alters the organism's ability to respond to infectious challenge. Likemost physiologic changes associated with aging, there is a large amount ofinterindividual variability that makes some older individuals more vulnerable toinfection than others. We suggest that individuals with the syndrome of frailty

would include the subset of the oldest individuals with the most immunevulnerability. Support for this comes from a Swedish study that evaluatedimmune function in an ambulatory, healthy cohort ages 86 to 92. Three groupsof individuals were identified based on T-cell proliferation capacity, T-helper to

T-suppressor cell ratio, and total B-cell numbers. After 2 years, the group withthe lowest T-cell proliferation capacity, lowest T-helper to T-suppressor ratio,and lowest total B-cell number had the highest mortality (Fig. 109-7).

Generalized Inflammation A number of authors have reported generalized immunesystem activation related to age. This may contribute to the development ofthe


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Identification of most vulnerable group by immune function status. Twoyear mortality datafrom apparently healthy Swedish individuals aged 86 to 92 years, grouped according toimmune function status. Group 1 had significantly lower T-cell proliferation in response to

antigen exposure, lower total CD4 counts, lower CD4/CD8 ratio, and lower CID 19 (B cells)counts as compared with group 2. Mortality reached 64 percent at 2 years in group 1 and 12percent in group 2 (p = .0008). (Adapted with permission from Ferguson F et al: Immuneparameters in a longitudinal study ofa very old population ofSwedish people. J Gerontol A BiolSci Med Sci SO:B378, 1995.)

syndrome (and cycle) of frailty through pathologic influences on otherphysiologic systems. Specifically, the level of autoantibodies not related toidentifiable autoimmune diseases increases with age. However, generalizedautoimmune tissue damage that would contribute to age-related functionaldecline has never been identified, although studies of specific autoantibodiesand their potential role in immune dysfunction continue.

A number of mediators of inflammation have been noted to be elevated in

older adults and in some cases found to be associated with physical disabilitynot related to specific disease states. Age-related increases in theinflammatory cytokines IL-6, IL-1B, and tumor necrosis factor alpha (TNF-a)have been identified. These increased levels likely stem from declining reg-ulatory mechanisms that allow an activated cell to continue the secretion ofthese potent catabolic agents well after the stimulus is over. Long-termexposure to higher levels of these agents may contribute to the cycle of frailtyvia catabolic influences on skeletal muscle (increased sarcopenia) andworsening neuroendocrine dysregulation via increased stimulation of theadrencr cortical axis (see Fig. 109-2). We suggest that the sum of increasedvulnerability to infection along with the increased inflammatory state leads to asubset of individuals especially vulnerable to stressors, thus potentiallycontributing to the development of frailty.

Neuroendocrine Dysregulation

The neuroendocrine system in its normal state is a highly integrated andcomplex regulatory system that

monitors environmental and other sensory input and maintains homeostatic balance via nerve andendocrine signaling to end-organ systems. This balance is critical in maintaining homeostasis forbasal functioning, as well as in providing much of the dynamic signaling that allows appropriatehormonal and neuronal responses to environmental changes and/or stressors. It is apparent thatmany components of this intricate system change with age. The best known example of this changeis the loss of estrogen in women at the time of menopause. This age-related phenomenon leads to


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alteration in several metabolic functions, including maintenance of bone and lean tissue mass.Declines in the latter lead to declining metabolic rate. Other examples of these changes with ageinclude declines in growth hormone level, increases in sympathetic nervous system tone, andaltered cortisol secretory patterns, among others (see Table 109-1).

Many of the observed neuroendocrine changes are related to a loss of the coordinatingmechanisms and fine regulation of the component systems. Some investigators have related a lossof complexity with aging to the chaos theory and have identified several physiologic systems,

including neuroendocrine systems, that demonstrate this "chaos" or loss of complexity with age(see Table 109-2). There is intriguing evidence that there is an associated loss of physiologiccomplexity in a number of systems with age, which may contribute to a different kind of loss ofreserve, the range and accuracy of responsiveness of the system. In the neuroendocrine systems,normal responses are often pulsatile and quickly turned "on" and "off." However, the complexnetwork of control begins to function less sensitively with advanced age, leaving neuroendocrinesystems with lagging or slowed responses to normal stimuli and slow or sluggish negative feedbackmechanisms. The latter can lead to slowed turning off of responses to stressors, as well as delay ininitiating them in the first place. Since many of the neuroendocrine pathways are complex andinterrelated, the loss of complexity and decline of one system likely has an impact on many others,leading to a cumulative loss of regulation across multiple systems. Given that these changes aremost apparent in oldest individuals and that the systems affected are critical in the response tostressors of all kinds, we hypothesize that this dysregulation is central to the syndrome of frailty.

Stress Response Hormones Part of the definition of frailty involves excess vulnerability to stressors. The

most important neuroendocrine responses to stress in humans are the activation of the sympatheticnervous system, with its concomitant release of epinephrine and norepinephrine, and the elevation ofplasma glucocorticoid levels. These comprise key physiologic responses to stressors of all kinds,including physical danger (e.g., exertion, temperature extremes, infection, inflammation),psychological distress (e.g., anxiety, depression, fear, social isolation), and pain. The events thatfollow the secretion of these stress hormones are many, including the well-known physiologicresponses

of tachycardia, dilation of the airways, hyperalertness, and a short-term increase in muscularstrength, all related to immediate effects of beta-adrenergic receptor stimulation. The immediateeffects of the glucocorticoids are less well studied, but these include short-term elevation of glucoseand lipid levels. This pathway may be a major source of energy liberation during the stress response.In a well-regulated system, these pathways are very finely tuned and function to minimize the im-pacts of dangerous situations and stressful encounters. However, the long-term effects of activatedstress-response systems may well be deleterious, especially if the responses are prolonged.

Many studies have shown that baseline activity of these stress-response systems is elevatedwith age, i.e., higher baseline sympathetic nervous system activity and tone and elevated cortisollevels. There is evidence that these responses, while beneficial in the short term, can, in the longterm, lead to pathologic changes in this and other systems. From rodent studies it is known thatlong-term exposure to cortisol leads to the loss of important regulatory elements on thehippocampus, with the loss of negative feedback and, hence, inhibition of this stress response. This,in turn, leads to higher and more active cortisol systems. The potential long-term clinical outcome ofchronic overproduction of cortisol in response to stress includes suppressed immune function,increased insulin resistance and adipose tissue, and loss of lean and bone mass.

The elevation of sympathetic nervous system output with aging is well known, as demonstratedin most studies in humans and in mammals. The exact mechanism of the decline of tight regulationin this system is unknown. The end-organ response to this system also declines with age, so theresponses to the chronically elevated levels of norepinephrine and epinephrine are not as vigorous.However, there is evidence that the increased activity of the locus ceruleus (brain center forsympathetic nervous system activity) elevates corticotropin-releasing factors (CRF), which in turncauses an increasing level of cortisol secretion, leading to further dysregulation of the stressresponse. Other effects of long-term elevated sympathetic tone are less well studied.

Growth Hormone Growth hormone (GH) and its major messenger molecule, insulin-like growth factor1 (IGF-1), play a critical role in the growth and development of immature organisms and remainimportant components of development and maintenance of lean body mass well into adulthood andolder age. Growth hormone is generally released from the pituitary gland in a pulsatile fashion, anda gradual loss in this pulsatile secretion occurs with aging. Many studies have demonstrated thatthe loss of normal GH secretion has an impact on the maintenance of both lean body mass and


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bone mass, which are both components of the frailty phenotype we have proposed.Supplementation of growth hormone in older men with low IGF-1 levels led to increased lean bodymass (4 percent). However,no increases were seen in strength or endurance over 6 months.

Estrogen and Testosterone The finely regulated female reproductive neuroendocrinepathway changes markedly at the onset of menopause. This sudden, age-re-

lated loss of estrogen from ovarian failure and the h}pothalamic dysregulationof gonadotropins has a profound effect on women, with rapid decline in bonemineral density, loss of lean body mass and increased fat mass, and increasedcardiovascular risk accompanying this change. The male reproductive neuroen-docrine system also undergoes age-related changes that include a gradual lossin testosterone levels and an ~ increasing sensitivity to the negative feedbackeffects of testosterone on the hypothalamus. These decreased levels of sexhormones may have an effect on frailty via a direct contribution to decline inlean tissue (sarcopenia).

DHEA The adrenal cortex secretes dihydroxyepiandrosterone (DHEr1) at lowlevels until age 5, when it increases markedly and peaks at age 20. Secretionthen gradually falls to low levels in old age. There are a number of suggestive,but conflicting, studies that may support a role for this hormone in the

maintenance of lean body mass and appropriate immune function. In fact, anumber of human and rodent trials support a role for this steroid in thesuppression of catabolic or inflammatory cytokines (IL-6, IL-1B) and theinduction of the immune stimulatory cytokine IL-2. Hence a low level of thissteroid, as part of the neuroendocrine dvsregulation of old age, may contributeto the primary physiologic characteristics of frailty.

Other Metabolic Pathways The neuroendocrine system is also the major force in theregulation of several critical homeostatic functions, including maintenance ofbody weight, appetite regulation, thirst centers, and thermoregulation. Therecently elucidated hormones and ligands include leptin and the leptinreceptor, neuropeptide Y, and the neuropeptide Y5 receptor subtype in thehypothalamus. In addition, important connections between the sympatheticnervous system and these pathways have helped to define the importance of

these pathways in appetite control, body composition, and energy expenditure.To date, there has been little study of age-related changes in these pathways.However, given other neuroendocrine dysregulations, this pathway may befound to play a contributory role in the underlying physiologic changes in bodycomposition related to frailty.

Interactions Between the Physiologic Components The aggregate effect of theseage-related changes of sarcopenia, immune dysfunction, and neuroendocrinedysregulation is likely to increase the vulnerability of the organism to stressorsof all kinds, with decreased ability to adapt, compensate, or modulate (see Fig.109-2). Each of these physiologic components of frailty has significant effects onthe others, leading to or accelerating declines in other regulatory mechanisms that in turn may contributeto a clinical outcome of frailty that is independent of any specific disease pro-cess. This underlying physiology can be acutely worsened by many triggeringevents such as disease, medication, injury, or depression, as described above.

This can be the point of entry into the cycle of frailty.A complex and interactive network that is only partially understood connects

each of the three primary physiologic components of frailty. Several exampleswere listed in the preceding discussion of component parts of the physiologicsystem declines. In sum, these interrelated physiologic alterations contributeto and accelerate the other physiologic components, thus accelerating thecycle of frailty.


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Potential Molecular Mechanisms That May Predispose to FrailtyThe presence of a cycle of frailty, a spiral of decline, and underlyingphysiologic vulnerability that appears to be independent of disease and relatedto age suggests that basic underlying mechanisms related to the aging processitself may be responsible for the development of this vulnerability. Despite thetremendous complexity of the study of human aging, great progress has beenmade over the past several years in the understanding of several molecular

processes that lead to a functional decline in cellular pathways. Some of thesemolecular processes, including oxidative genomic and mitochondrial DNAdamage, oxidative and glycation protein changes, and finite cellular repro-ductive capacity and cell senescence, may play a role in increasingvulnerability. Although none of these processes has been linked ~ directly toany of the physiologic states proposed to underlie frailty, it is likely that manyof these mechanisms contribute in meaningful ways to the complex molecularchanges of aging and the accompanying functional decline seen in frailty.Because the underlying molecular etiology of the syndrome of frailty, muchlike the phenotype and physiology, is likely to be highly complex, studies toevaluate these potential mechanisms and their complex interactions will becrucial in the identification of preventive and treatment modalities for thesyndrome of frailty. A summary of molecular factors that may contribute to thesyndrome of frailty follows (also see Table 109-4).

Oxidative DNA Damage and RepairThe generation of free radicals from oxidativephosphorylation and other cellular metabolic processes is well known todamage both genomic and mitochondrial DNA. This is especially true in themost metabolically active tissues, where the highest number of free-radicalproducts are generated. In genomic DNA, a number of cellular mechanismsnormally repair the damage and allow transcriptional and cellular reproductiveprocesses to continue unaltered. However, there is evidence that thefunctionality of these repair mechanisms changes with age, leading to adecline in mutagenesis in DNA

TA BL E 10 9- 4

Age-Related Molecular/Cellular Processes That May Contribute to Frailty

Cumulative oxidative damage to DNA Decline in repair capabilities Transcription

abnormalities Unstable RNA transcripts Mitochondrial DNA deletions/mutations

Decline in bioenergetic molecules Replicative senescence

Telomere shortening Protein alterations Glvcation

Oxidation

and hence the potential for functional decline in a number of systems.

Support for these age-related changes in DNA repair and the cumulative functional decline related

to this comes from recently discovered mechanisms of several progeroid syndromes. Werner's

syndrome is an autosomal recessive disorder that has been linked to the helicase gene located onchromosome 8. Individuals homozygous for a mutation in this gene develop an accelerated aging

phenotype that is characterized by skin and hair changes in the teens and twenties, glucose

intolerance, osteoporosis, cataract development, and hypogonadism in the twenties and thirties, and

premature death in the forties. Helicase is an enzyme critical for unwinding the double-helix structure

of DNA, which, in turn, allows DNA reproduction and transcription. Without this enzyme, cellular

reproductive processes and normal transcription cannot take place, leading to abnormalities in a

wide variety of systems and early functional decline. The phenotype of individuals with Werner's

syndrome is similar to that of frail individuals, suggesting some mechanistic overlap. However,some differences in clinical outcomes, such as the common development of sarcomas and de-


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velopment of osteoporosis in the cortical, rather than trabecular, bones, makes it clear that this is

not the only mechanism that may have an impact on the development of the frailty phenotype.

Additional support for cumulative DNA damage contributing to frailty comes from studies of the

enzyme poly (ADP-ribose)polymerase. This enzyme is activated when DNA strands are broken.

Overproduction of this enzyme leads to consumption of NAD + for replenishment of the enzyme.This, in turn, leads to depletion of ATP, the other major energy-supplying molecule of the cell. The

large-scale activation of this enzyme in acute ischemic events has been shown to lead to anirreversible decline in the steady-state cellular levels of ATP and NAD+ and cell death. However, it

is not yet known if this mechanism can cause cell death or a significant slowdown in metabolic

processes on a more chronic basis. If so, this could prove to be a key pathway in the gradual

breakdown of metabolic integrity and the physiologic disarray and dysregulation seen in frail ty

(Fig. 109-8).

Age-Related Mitochondrial DNA Damage Mitochondrial DNA has been shown to be especially

vulnerable to cumulative oxidative damage generated by free radicals from oxidative

phosphorylation. There are a number of reasons for this. First, the mitochondrial genome does not

have mechanisms for DNA repair. Second, mitochondrial DNA is especially vulnerable to oxidative

damage because mitochondria are the major source of oxidative phosphorylation and hence freeradical production. The mitochondrial genome en

Hypothetical pathway for low-energy state of frailty related to DNA repair defectsand loss of bioenergetic molecules. (Adapted with permission from Grossman L: Therole ofDNA damage and its repair in the aging process. Aging (Milano) 4:252, 1992.)

codes for enzymes critical in the process of transforming glucose into a usable form of energy(ATP), which is then utilized in many cellular processes that maintain homeostasis. Many studieshave shown large areas of mitochondrial DNA deletion and a number of mutations thataccumulate with age. This damage potentially could affect the energy-production pathways thatare critical for the maintenance of most cellular and metabolic integrity. Given the markedfatigue and lack of energy that many frail individuals exhibit and the reduced ability to respondto a variety of stimuli, this molecular pathway critical for the generation of usable energy maywell play a crucial role in the development of frailty.

Replicative Senescence Hayflick and other investigators in the 1960s found that cells in culturehave a finite number of reproductive cycles and that the number of senescent cells risesexponentially with the age of the culture. In addition, it was noted that short-lived species havethe lowest number of cellular reproductive cycles. Although most of these findings have beendemonstrated in cell culture, one could hypothesize that, in vivo, cells critical to metabolic orhomeostatic processes eventually would arrive at the senescent state. This mechanism would beconsistent with the phenotype of frailty and, especially, failure to thrive, given that frail, olderindividuals have lost much responsive capacity and that this could result from such cellularsenescence.

One potential mechanism for this finite number of cell divisions and the development ofcellular senescence is the loss of the telomere region of chromosomes. Telomeres are repeating


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DNA base pairs that are located at the ends of chromosomes that act as protective caps for thecritical coding sequences further inside the chromosome. With each cellular division,chromosomal unwinding must take place and new DNA strands must be synthesized. With eachunwinding, some of the telomeric DNA is lost from the most distal ends of the chromosome.Normally, the enzyme telomerase replaces these bases, effectively capping and protecting thegene coding regions located further inside the chromosomes. Telomerase is gradually lost withage, and therefore, the protective segments of DNA are gradually lost over time, exposing the

coding regions of the chromosome to base-pair loss. This, in turn, may lead to the loss over timeof the expression of a variety of genes that may be critical in the maintenance of homeostaticprocesses.

Protein Modifications Proteins are vulnerable to both pre- and posttranslational modification thatmay affect long-term function. Free oxygen radicals and derivative molecules are known to alteramino acids in a variety of ways, many of which have functional consequences. Intracellularrepair mechanisms normally correct many of these changes. However, over time, the accu-mulation of modified proteins may be expected to have functional consequences. For example,metalcatalyzed oxidation by-products have been demon

strated to cause cumulative damage in critical enzyme pathways such as cytochrome P450 andNADH and NADPH oxidases. Age-related accumulations of these altered and hence less effectiveproteins may well contribute to the phenotype of frailty. Another well-studied pathway of proteinalteration is glycation leading to advanced glycation end products (AGEs). These products

accumulate with age, potentially changing structure and function of critical proteins in regulatorypathways.

In summary, a number of age-related molecular processes, including cumulative oxidativegenomic and mitochondrial DNA damage, oxidative and glycation protein changes, finite cellularreproductive capacity, and cell senescence, may all play a role in increasing vulnerability tophysiologic stressors. Most of these mechanisms have not been linked directly to changes seen invivo, but changes in bioavailable energy, altered cellular reproduction, and altered protein con-stitution may all contribute to the underlying alterations in normal physiology seen in frailty.

DIAGNOSIS AND TREATMENT

Diagnosis and therapeutic approaches can be based on our growing understanding of frailty. Thefirst premise of evaluation is to seek to identify vulnerable, frail individuals before the occurrence ofthe adverse outcomes for which they are at risk. Such a clinical approach should include carefulattention to identification of secondary frailty due to latent or undertreated disease that could becausing weight loss or decreased nutritional intake. A number of diseases that are responsive totherapy can cause wasting, including congestive heart failure, diabetes, thyroid diseases, tuber-culosis and other chronic infections, undiagnosed cancer, and inflammatory conditions such astemporal arteritis. Psychological conditions such as depression, psychosis, and grief-as well asdementia-also can present in this manner. Whether or not frailty is due to underlying disease, focusalso should be placed on prevention of related adverse outcomes, including falls and disability.Evaluation also should include screening for factors that may exacerbate vulnerability for theseoutcomes, such as medications, with intervention as indicated.

If other diseases are ruled out as the cause of frailty or failure to thrive, i.e., if it appears to beprimary, a goal should be to institute supportive interventions early. These include targeting theenvironmental provocations that can trigger or accelerate the manifestations of frailty, especially

low activity, inadequate nutrition, and catabolic medications. The goal of this intervention wouldbe prevention of loss of muscle mass and improvement in strength and energy.

Attention to maintaining strength and nutritional intake may include prescription of regularexercise, as well as nutritional supplementation if indicated. In addition, screening of frailindividuals should evaluatefactors such as depression that may contribute to decreased activity or foodintake. There is now good evidence indicating that resistance exercise to increasestrength of a frail older adult has potential from both a preventive andtherapeutic point of view. In very frail nursing home patients, aged 72 to 98years, progressive resistance exercise training over a 10-week period was shown


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to improve strength, gait velocity, stair-climbing power, and spontaneous physicalactivity. Greatest benefit from this weight-lifting exercise was seen in those whowere initially weakest but did not have severe muscle atrophy. This suggests agroup with more recent onset of weakness. These findings thus indicate benefitfrom exercise for even the most frail while suggesting that improvement isgreatest if declines in strength are caught earlier rather than later. At the otherend of the spectrum, primary prevention of frailty through regular strength

training also has good potential. In one study of 40 postmenopausal women aged50 to 70 years, high-intensity strength-training exercises 2 days per week led toincreased bone mineral density in the femoral neck and lumbar spine, plussignificantly improved muscle mass, muscle strength, and dynamic balance inthose receiving training, compared with controls. In addition, the exercise groupincreased their energy expenditure 2'7 percent in activities outside theintervention itself compared with the controls, who decreased their energyexpenditure by 25 percent. Thus resistance training appeared to improve anumber of risk factors for frailty, as well as for osteoporotic fractures. Evans alsohas reported that high-intensity strength training appears to have highly anaboliceffects in the elderly. He reported a 10 to 15 percent decrease in nitrogenexcretion at the initiation of such training, which persisted for 12 weeks. That is,progressive resistance training improved nitrogen balance. As a result, olderpatients performing resistance training had a lower mean protein intake

requirement than did sedentary subjects. In contrast, aerobic exercise causes anincrease in protein requirements. Overall, it is notable that increases in strengthfrom high-intensity strength training are substantially greater than those seenwith growth hormone.

Preservation of fat-free mass and prevention of sarcopenia should help preventthe decrease in metabolic rate described in association with frailty. Maintenanceof strength should facilitate maintenance of exercise tolerance, both directly andbecause those with improved strength appear to engage more spontaneously inother activities. In prevention of frailty, this appears to be a critical stage, both toprevent the downward cycle toward failure to thrive and to prevent disability.Otherwise, with declining exercise tolerance, activities of daily living start to takeup larger proportions of Vo2max, with highly sedentary older adults requiring asmuch as 90 percent of their Vozmax to carry out basic self-care tasks.

The role of nutritional supplementation in treating frailty is less well defined. In

Fiatarone's trial of resistance exercise and nutritional supplementation in frailnursing home patients, total energy intake did not in

crease in those exercising (without nutritional supplementation) or in thosereceiving nutritional supplementation but no exercise compared with controls.

This was the case even though this population had a marginal nutritionalintake at baseline. Only with both exercise and nutritional supplement didenergy intake increase; these people gained weight but not fat-free mass.Additionally, Poehlman's research indicates that older men and women have toincrease energy expenditure by 1000 kcal per week to get compensatory in-creases in energy intake (food) and increases in resting metabolic rate.

Hormonal TherapyA number of endocrine system changes have been noted with age. Theseinclude falling levels of estrogen, testosterone, growth hormone, and DHEA,among others. While several of these changes are measurable, there is noclear evidence that these changes in and of themselves are diagnostic of thesyndrome of frailty. However, in combination with other physiologic changes,the endocrine changes may well contribute to the syndrome of frailty. Thesehormones are important in the maintenance of lean body mass and bonemineral density. Several studies have looked at replacement therapies for the


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prevention or treatment of hormonal declines and in some cases of lean bodymass decline.

The best known and accepted hormonal therapy is estrogen replacement.There is little evidence to show that it prolongs survival or increases lean bodymass, but it does help maintain bone mineral density and plays a role in theprevention of cardiovascular disease and possibly dementia. Testosteronelevels do not decline as precipitously, and there appears to be a large amount

of variability in levels between elderly men. While it is clear that testosteronereplacement therapy in by pogonadal younger men leads to increased musclemass, it is not clear that muscle mass increases in older men who arehypogonadal and are treated with physiologic replacement doses. In addition,supplementation is associated with increased risk for benign prostatichypertrophy and potential stimulatory effects of the hormone on preexistingprostate cancer.

Growth hormone levels decline in older age groups. Replacement protocolshave shown some efficacy in increasing lean body mass, in decreasing fatmass, and in slowing the catabolic effects of acute and chronic diseases orinjuries such as hip fracture and infections. However, it is not clear that suchchanges due to growth hormone replacement can be sustained, and there is noevidence that supplementation improves functional status in growth hormone-deficient men. In addition, the long-term risks of growth hormone replacement

on tumor development remain unclear. Therefore, there is currently no clearindication for growth hormone use in relation to lean body mass loss with age.

In recent years, attention has focused on the adrenal hormone DHEA and its effects on immune function,lean body mass, fat mass, and cardiovascular disease. It is clear that DHEA falls to very low levels in oldage, and those with the lowest levels appear to have the lowest level of functionality, as measured by

activities of daily living. Replacement trials have shown some improvement in lean body mass anddecreasing fat mass but little or no improvement in strength in younger individuals. Given the conflictingdata and limited safety information on long-term use of hormone replacement, it does not appear that

DHEA has a place in the treatment of frailty at the present time. SUMMARY

Frailty and failure to thrive appear to comprise a continuum of decline in reserve and ability torespond effectively to stressors. Clinical signs and symptoms include weight loss, loss of musclemass, and declines in energy and activity level. Secondary frailty could be initiated by chronic

disease, but there may well be a primary form of frailty that is related to age, not to disease. Anumber of events can serve as triggers or contribute to the cycle of frailty-including acute illness,psychological stressors, depression, malnutrition, or injury causing disability. There is potential for thissyndrome to become a self-perpetuating cycle or downward spiral.

The physiologic systems involved in the development of this vulnerability include sarcopenia,neuroendocrine dysregulation, and immune dysfunction. A number of alterations within each systeminfluence the development and downward progression of frailty. Molecular changes likely underlie thechanged physiology, including cumulative oxidative damage to genomic and mitochondrial DNA,replicative senescence, and protein alterations.

Clues to the diagnosis of frailty are mostly related to weight loss, weakness, and vulnerability.Exerciseespecially resistance exercise-appears to be a particularly important mode of prevention andtreatment of

frailty. More research into the underlying physiologic basis of frailty may reveal more specificdiagnostic and treatment protocols. The construct of frailty presented here represents a framework

from which new research into this important area can evolve.

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Bortz WM IV, Bortz WM II: How fast do we age? Exercise performance over time as a biomarker. J Gerontol Med Sci 51A:M223,

1996. Bortz WM II: The physics of frailty. JAm Gerzatr Soc 41:1004, 1993. Buchner DM, Wagner EH: Preventing frail health. Clin

Geriatr Med 8:1, 1992.


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Clark LP et al: Taking to bed: Rapid functional decline in an independently mobile older population living in an intermediate-

care facility.J Am Geriatr Soc 38:967, 1990.Evans WJ: What is sarcopenia?J Geronlol 50A:5, 1995.

Evans WJ: Exercise, nutrition and aging. Clin Geriatr Med 11:725, 1995.

Fiatarone MA, Evans WJ: The etiology and reversibility of muscle dysfunction in the aged.J Gerontol 48:77, 1993.

Fiatarone MA et al: Exercise training and nutritional supplementation for physical frailty in very elderly people. NEnglJMed

330:1769, 1994.

Fried LP et al: Conference on the physiologic basis of frailty.Aging Clin Exp Res 4:251, 1992.Lipsitz LA, Goldberger AL: Loss of "complexity" and aging: Potential applications of fractals and chaos theory to senescence.

JAMA 267:1806, 1992.

Nelson ME et al: Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures. JAMA 272:1909,

1994. Palmer RM: "Failure to thrive" in the elderly: Diagnosis and management. Geriatrics 45:47, 1990.

Poehlman ET et al: Sarcopenia in aging humans: The impact of menopause and disease. J Grrontol 50A:73, 1995.

Roberts SB: Effects of aging on energy requirements and the control of food intake in men. J Gerontol 50A:101, 1995.

Roubenoff R, Rall LC: Humoral mediation of changing body composition during aging and chronic inflammation. NutrReu51:1,

1993. Speechley M, Tinetti M: Falls and injuries in frail and vigorous community elderly persons. J Am Geriatr Soc 39:46, 1991.

Verdery RB: Failure to thrive in older people.JAm Geriatr Soc 44:465, 1996.

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