Relative – Frailty and Exercise Training

Jason Cholewa

Introduction

As medicine is improved and life expectancies are extended, the elderly population in the United States continues to expand. With this increase in population comes the challenge of providing care for the elderly. In fact, the American Medical Association stated in 1990 that “…one of the most important tasks that the medical community faces today is to prepare for the problems in caring for the elderly in the 1990’s and 21^st century” (Council on Scientific Affairs, 1990). A major topic in the report presented by the AMA emphasized the growing population of frail and vulnerable elderly, and the special care they would need.

To better understand the concept of frailty, the paper will be divided into the following sections: Clinical descriptions of frailty, epidemiology, pathophysiology, and clinical significance.

Describing Frailty

Frailty is a term that has been used to identify a syndrome containing a compilation of different symptoms such as loss of reserves that leads to vulnerability, injury, and death (Rockwood et al., 2005).

While frailty, disability, and comorbidity are often interrelated, they are not the same disease and the terms should not be used interchangeably. The following sections will delineate the differences between disability, comorbidity and frailty, and discuss the quantitative challenges in defining frailty.

Disability

Disability has been defined as a difficulty or dependency on others to carry out activities essential to independent living. These activities include tasks essential to self-care, living independently in a home, and desired activities important to quality of life (PopePope & Taylor, 1991). The prevalence in disability in community-dwelling adults over 70 years of age is estimated at 20-30% (Adams et al., 1999).

Comorbidity

According to Fried et al. (2004) comorbidity is the concurrent presence of two or more medically diagnoses diseases in the same individual. It has been estimated that 35.3% of the population over the age of 65 is comorbid, and that an excess of 80% of individuals over 80 years old possess two or more diseases (Adams et al., 1999). Currently, researchers are investigating the physiological impacts of comorbidity in the development of frailty. This research includes the interactions between strength and balance, vision and hearing, and biomediators such as interleukin-6 and IGF-1 (Cappola et al., 2003; Rantanen et al., 2001).

Frailty

Fried et al. (1998) surveyed 62 geriatricians using a self administered questionnaire. 98% stated that frailty and disability are separate entities; and 97% agreed that frailty involves more than one characteristic (A: Fried et al., 1998). The following characteristics, in order of frequency, were observed in association with frailty: under nutrition, functional dependence, prolonged bed rest, pressure sores, gait disorders, general muscle weakness, greater than 90 years of age, weight loss, anorexia, fear of falling, dementia, hip fractures, delirium, confusion, infrequently going outdoors, and polypharmacy.

Frailty is the dynamic process of increasing vulnerability, leading to functional decline and ultimately death (Cohen, 2000; Liptz, 2008). These vulnerabilities are typically seen in a broad range of domains, including physical, nutritive, cognitive and sensory (Strawbridge et al., 1998). In frailty the ability to maintain homeostasis compromised such that the individual is unable to withstand illness or injury without loss of function (Wells et al., 2003). Frailty is clinically viewed as a transitional state in the functional process from robustness to functional decline (Lang et al., 2009). Fried et al. (2004) has constitutively described frailty as:

“A state of increased vulnerability to stressors that results from decreased physiological reserves and multi-system dysregulation, limited capacity to maintain homeostasis and to respond to internal and external stresses. Frailty is an aggregate expression of risk resulting from age or disease-associated physiologic accumulation of sub threshold decrements affecting multiple physiologic systems resulting in adverse health outcomes” (Fried et al., 2004).

An operative description of the frailty phenotype proposed by Fried et al. (2001) has been adopted by the American Geriatric Association. The phenotype is defined by the presence of 3 or more of the following symptoms: 1. unintentional weight loss greater than 4 kg per year; 2. weakness measured by grip strength in the lowest 20% in the dominant hand; 3. self-reported exhaustion that indicates reduced VO_2MAX and graded exercise performance; 4. time to walk 15 ft in the slowest 20%; and, 5. low physical activity in the lowest 20% for caloric expenditure. Other similar models of identifying the frail have also been proposed (Bortz, 2002; Rockwood et al, 2005; Strawbridge et al., 1998)

Epidemiology

Balducci & Santa (2000) estimate that in the year 2000 there were 6 million frail persons living in the United States. Because there is a multiplicity of approaches in defining and diagnosing frailty, Bortz (2002) states this number may be an underestimate.  Winograd et al., (1991) reported that 27% of patients over the age of 65 admitted to the Palo Alto Veterans Hospital were frail, and of those the 1 year mortality rate was 45%. In 2000 it was estimated that 15% of the population over 65 years old in Rochester Minnesota had significantly diminished muscle mass (Melton et al., 2000).

Frailty Process

Three stages have been identified in the developmental process of frailty: a pre-frail process, the frailty state and frailty complications (Ahmed et al., 2007). The pre-frail process is described as a steady decline in physiological reserves. During the pre-frail stage, however these reserves are sufficient enough to allow the individual to respond adequately to an injury or stressor, and thus the symptoms are clinically silent. During the frail stage, physiological reserves have declined beneath the functional threshold. This state is characterized by inadequate response to a stress or injury (Ahmed et al., 2007). Thus, recovery is slow and/or incomplete because the available functional reserves are insufficient to allow for a full recovery (Lang et al., 2009). The frailty stage eventually progresses into the stage where complications due to frailty present. The complications of frailty lead to an increased incidence of falls, functional decline leading to disability, polymedication, increased hospitalization and institutionalization, infection, and death (Cohen, 2000; Fried et al., 2001; Wells et al., 2003).

The epidemiology of frailty is includes many distinct, yet related characteristics. To better understand the risk factors associated with frailty, this section will be divided into the following risk factors: inactivity, malnutrition, chronic disease, cognitive decline, social aspects, and gender differences

Inactivity

Bortz (2002) has described loss of muscular function as the “gateway” to frailty, and implicates inactivity as a major contributor. The correlation between inactivity and frailty has been intensely investigated. Rockwood et al. (2005) reported that a decline in fitness associated with inactivity is a major contributor to the loss of muscle mass and the initiation of frailty. Chin et al. (2003) examined a cohort of 450 elderly people using inactivity and weight loss as criterion to assess frailty. Physical inactivity in conjunction with weight loss was shown to have an odds ratio of 5.2 for disability and 4.1 for mortality. The Beaver Dam Eye Study (Klein et al., 2003) reported that the slowest quartile gait time was an early sign of frailty, and that inability to stand from a sitting position and low grip strength characterized severe frailty.

Malnutrition

In the frailty phenotype presented by Fried et al. (2001), the unintentional loss of weight was indicated as one indicator of frailty. Nutritional deficiencies, either due to loss of hunger cues or inability to perform ADL’s such as cooking, lead to the loss of weight and muscle mass (Bortz, 2002). Chin et al. (2003) identified low energy intake associated with weight loss as a predictor of functional decline over a 3 year period. Similarly, Vellas et al. (2006) identified elderly individuals at risk of malnutrition, and reported this risk to be a significant marker of frailty and correlated with weight-loss, poor appetite, and functional and cognitive decline. Weight loss, low BMI, and loss of muscle mass are correlated with frailty; however, overweight and obesity have been received less attention. Blaum et al. (2002) investigated the correlation between overweight and obesity in elderly women with a baseline BMI above 18.5. Overweight individuals were found to be associated with pre-frailty and obese individuals were found to be associated with pre-frailty and frailty. Thus, malnutrition and excessive energy intake alike can contribute to the development of frailty.

Chronic Disease

Bortz (2002) suggested that diseases and injuries contribute to the development of frailty via inhibition of physical activity. Toxins, infections, and injuries all reduce the ability of the individual to participate in physical activity. Furthermore, as repeated microinjuries result in osteoarthritis, the pain of movement will often discourage activity. The hypothesis proposed by Bortz (2002) is supported in reports by Toth and Poehlman (2000) that common chronic diseases in the elderly significantly limit physical activity and accelerate the catabolic cascade.

Cognitive Decline

Cognitive dysfunction has also been suggested as a contributing factor to functional decline (Chin et al., 2003). Binder et al. (1999) examined the role of cognitive function in the loss of independence and ability to perform activities of daily life (ADL). The authors reported that participants with a decreased cognitive function displayed twice the risk of developing a loss independence and ability to perform ADL than those who maintained cognitive function.

Sensory declines have also been implicated as indicators of frailty (Bortz, 2002; Fried et al., 2004) The Beaver Dam Eye Study (Klein et al., 2003) reported that visual acuity and contrast sensitivity was lowest in the frailest group.

Social Aspects of Frailty

In a questionnaire administered to 62 geriatricians, fear of going outdoors and lack of ambition to take part in social activity were indicated as qualities associated with frailty (Fried et al., 1998). Strawbridge et al. (1998) investigated the differences in the quality of life between the frail and non-frail elderly. An increased risk of frailty was found for individuals who were socially isolated (made minimal contact with friends and relatives) for more than 10 years. Strawbridge et al. (1998) also reported that frail subjects were less likely than non-frail subjects to go out for entertainment or visit family and friends. Furthermore, a lower life satisfaction was found amongst the frail. Thus, frailty appears to affect the quality of life by negatively impacting activity seeking, social relationships, and mental health. These results are in agreement with previous studies which show that social participation predicts reduced morbidity, better physiological function, and successful gaining (C: Kaplan et al., 1993; Strawbridge et al., 1996).

Mood disturbances have also been suggested as a risk factor in the development and progression of frailty (Lang et al., 2009). Lenze et al. (2005) analyzed depression as a means of predicting functional decline using the Cardiovascular Health Study. Chronically depressed and moderately depressed individuals displayed a 5-fold and 2-fold increased risk of functional decline, respectively, compared to a non-depressed control.

Gender differences

Frailty between genders appears to be more prevalent in the female population. Fried et al. (2001) found an increased likelihood of frailty amongst women, possibly due to women starting with less lean mass and strength then men and crossing the threshold of lean mass loss sooner than men. It has also been stated that women have a greater extrinsic vulnerability to sarcopenia then men. Because women live longer than their male counterparts, they generally live alone more often (Evans, 1995). As such, women are more prone to nutritional deficiencies and social seclusion.

Pathophysiology

     Frailty is disease that is manifest in the decline of several physiological systems. Because of the complexity of the disease, the pathophysiology of frailty will be broken down into the following sections: physiological reserves, sarcopenia, hormonal changes, and osteopenia.

Physiological Reserves

The pathological development of frailty has been identified as a “tendency to fail”, which describes the capacity of the body systems with regard to reserve capacity during the pre-frail stage (Bortz, 2002). The organ systems of a healthy individual have a capacity such that when environmental perturbations occur, the organism may respond and adapt. Organ systems will continue to exhibit normal function until the marginal loss of capacity exceeds 70% (Bortz, 2002). The following functions all exhibit a 30% threshold capacity: VO_2MAX, myocardial VO₂ consumption, arterial cross-sectional area, maximal breathing capacity, forced expiratory volume, hematologic values, renal and hepatic function, blood sugar, sensory capacity, cognitive skills, and CNS dopamine content (Colenbrander, 1994; Diamond, 1998; Sanchez-Ramos, 1999). It has been shown that the average young human possess 5 W/kg of strength in the leg and 1.2 W/kg is required to walk. This value displays a reserve capacity of approximately 24%; however, when leg strength declines below 10% of maximum capacity movement becomes impossible (Bassey et al., 1992). The loss of leg strength has been shown to be the strongest predictor for institutionalization (Judge et al., 1996).

Hence, the downward spiral of frailty and inactivity is again seen: Loss of movement reduces the capacity of other systems, which in turn negatively impact the ability to generate movement. In this model receptor sites and hormonal production down regulates, hunger cues are lost, circulatory function is compromised, sleep is altered, and depression may ensue (Bortz, 2002). Thus, the loss of function and continuation of the catabolic cascade reduces and individuals capacity to respond to environmental perturbations and recover from injury or illness.

Once reserve capacity has decreased below the 30% threshold, failure will begin to present. This failure places the individual in the frailty stage and awareness of symptoms occurs. Furthermore, the greatest health care costs are generated in this range of diminished function (Fried & Walston, 1998).

Sarcopenia

Bortz (2002) specified that a reduced function of the musculoskeletal system initiates of frailty. Frailty is extremely prevalent among the elderly, and is often typified by a person of small stature with severe impairments in mobility, strength, balance and endurance (Fried, 1992). Sarcopenia, the loss of muscle mass, begins at age 40 and by 80 years of age is generally between 30-50% in both men and women. This loss of muscle mass is associated with even greater decreases in strength, power, and endurance (Fried, 1992; Young et al., 1985). The loss of muscle mass associated with aging places the elderly at increased risk of falls and injury and at greater risk of disability because the capacity of skeletal muscle to recover from injury is reduced in old age (Faulkner et al., 2007).

To understand how muscles are affected with age, it is first important to describe the different types of muscular injuries and how these injuries occur. The performance of an unfamiliar stimuli results in a contraction-induced injury to the muscle fibers recruited. This injury is a disruption of sarcomeres, and may be followed 24-48 hr later by the infiltration of inflammatory cells and the generation of free radicals (Faulkner et al., 1995). Injury is often due to a single severe lengthening of maximally activated muscle fibers, such as during a fall, or due to multiple smaller stretches of activated muscle fibers, as encountered during running. It has been shown that for a given activity the muscles of older animals experience greater injury and slower to incomplete recovery. Furthermore, following a severe injury, such as one that may occur during a fall, recovery may be incomplete (Faulkner et al., 1995). Thus, incomplete recovery from micro-injuries to muscle fibers may result in the permanent loss of muscle mass in the older individual (Raider & Faulkner, 2006).

The direct causes of sarcopenia are still not clear; however, muscle fiber denervation has been implicated as a contributing factor to the loss of muscle fibers, motor units, and motor unit remodeling (Faulkner et al., 2007). The number of motor neurons innervating skeletal muscles has been shown to decrease in the aging human (Tomlinson & Irving, 1977), and the loss becomes most apparent starting at around 50 years of age (Campbell et al., 1972).

Sarcopenia is exacerbated by inactivity, such that the cross sectional area (CSA) of fibers decreases concomitantly with a loss in individual fibers, compounding in a greater loss of muscle mass. Type II fibers suffer the greatest loss in CSA, while type I tend to retain size even in the elderly, and may explain why strength decreases disproportionately to muscle mass (Lexell et al., 1988). Thus, although the loss of muscle fibers appears inevitable, the magnitude of loss may be attenuated via hypertrophy due to regular physical activity.

Lang et al. (2009) has described the manifestation of sarcopenia as the process where the loss of reserve capacity results in an increased sense of effort for a given activity. Cardiovascular and skeletal muscle reserves decline with age, as evidenced by a reduction in maximal oxygen consumption and strength, leading to an increased perceived exertion for a given task (Flegg & Lakatta, 1998). As a result, the trend to avoid the physical task is increased, and as a result of more and more physical exertions avoided sarcopenia is exacerbated and physiological function declines further (A: Janssen et al., 2002; Morley, 2008).

Thus, the relationship between inactivity, loss of reserves, and frailty is a downward cycling process, whereby as physical activity decreases with age, physical stress-stimulation is reduced, physiological systems down regulate, standard tasks become increasing difficult and physical activity is further avoided (Lang et al., 2009).

Hormonal and Inflammatory Implications

The hormonal abnormalities and inflammatory markers present in the frail individual may shed some light on the pathological development of the disease (Cappola et al., 2003). Insulin resistance (IR) associated with aging and inactivity has been implicated as one factor contributing the initiation of frailty. IR decreases nitric oxide production, reducing the absorption of available amino acids, thus reducing protein synthesis and exacerbating sarcopenia (Leng et al., 2007). Furthermore, the IR associated with aging and inactivity increases the concentration of clotting factors and production of inflammatory cytokines, and thus places additional strain on the cardiovascular system (Abbatecola & Paolisso, 2008).

The anabolic-catabolic balance is essential in maintaining muscle mass and defending against sarcopenia (Bortz, 2002). Decreases in GH, IGF-1, and testosterone, and increases in cortisol are prevalent in the frail population (Abbatecola & Paolisso, 2008). This disruption of hormones leads to an increase in catabolic metabolism, a decrease in anabolic metabolism, and ultimately a decrease in muscle mass.

Using information from the Cardiovascular Health Study, Walston et al (2002) demonstrated that the inflammation markers and clotting factors CRP, fibrinogen, factor VIII, and D-dimers were significantly elevated in the frail. Similarly, Cohen et al. (2003) demonstrated the risk of death over 5 years was 2-fold greater in the highest quartile for IL-6 and D-dimer blood values. Additionally, inactivity increases oxidative stress and inflammation, via increases in interleukin-6, C-reactive protein, and increased leukocyte counts (Leng et al., 2007).

Osteopenia

The endocrine dysfunction associated with frailty is a due to the decline and dysfunction in the hypothalamic-pituitary-gonadal/adrenal and growth hormone-IGF axis (Topinkova, 2008). Endocrine-immune dysregulation results in a decline in estrogen and androgen levels which in turn increase local bone cytoclastic cytokines. As a consequence, there is an increase in osteoclastogenesis and bone loss ensues. Additionally, low gonadal hormones and IGF-1 in conjunction with systemic inflammation, low vitamin-D, and pro-coagulation increase the risk of osteopenia and frailty (Joseph et al., 2005). Furthermore, decreased physical activity associated with frailty leads to the abolishment of minimal essential strains on the skeletal system and a further decrease in anabolic hormone production. Consequently, due to the absence of loading and decreased osteogenic factors, the stimuli to maintain bone mass are withdrawn and bone fragility ensues (Bortz, 2002).

Clinical Findings

     According to the AMA, the increased incidence of frailty and the complications that arise will pose a great challenge moving forward in caring for the elderly (Council on Scientific Affairs, 1990). There are two issues to address with regards to the clinical significance of frailty: Predictors of strain on the health care system; methods of prevention and treatment.

Frailty as a Predictor of Continuing Health

The complications that arise from frailty include disease, institutionalization and death. Frailty is associated with a number of chronic diseases, including pulmonary dysfunction, cardiovascular disease, diabetes, and atherosclerosis (Fried et al., 2001).

Frailty is also associated with increased risk of institutionalization and hospitalization. Fried et al. (2003) using the Cardiovascular Health Study reported that 60% of frailty people were admitted to a hospital in 3 years. In a 5 year prospective study Guilley et al. (2005) reported an increase relative risk in the frail group for falls, disease, dependence, and death.

Ultimately, if left untreated, frailty will result in death. Fried et al. (2001) reported that elderly individuals identified as frail have a 6-fold mortality increase over a three year period, and an increase of 3-fold over 7 years compared to non-frail individuals. In 84 months, 43% of the frail subjects had died, compared to 23% who were pre-frail and only 12% who were considered robust at baseline.

Treatment and Prevention

Vanitallie (2003) has stated “One characteristic of the frailty syndrome, that distinguishes it from the effects of aging per se is the potential reversibility of many of its features.” Frailty is a unique disease, in that with proper diagnosis and treatment it may be prevented and even reversed. It has been suggested for some time that frailty is not an inevitable process and with physical activity-based intervention programs may be prevented or reversed (Fiatarone et al., 1990). The following subsections will discuss the different interventions investigated including: exercise programs, combination programs, pharmacological treatment, and improved care.

Exercise programs

Inactivity has been implicated as a major risk in the development of sarcopenia, insulin resistance, and loss of mobility. Furthermore, inactivity has been implicated as one of the identifiers in the frailty phenotype (Fried et al., 2001). Thus, it stands to reason that physical activity should improve the frail condition.

Binder et al., (2002) assessed the effects of resistance exercise plus balance training versus balance training only on the progression of functional decline in frail elderly men and women. The exercise plus balance group displayed significant improvements in function while the balance only group made no improvements. Similarly, Gill et al. (2002) compared the effects of an exercise program focused on muscle strength, balance and transfer ability versus an educational program on functional ADL. The results displayed significant improvements in the exercise treatment group for the moderately frail, but not the severely frail. The educational group made no improvements.

According to Faulkner et al. (2007), significant improvements in muscle mass, strength and function will occur when the following 4 components are included in an elderly strength and conditioning program: participation 3 times a week on non-consecutive days; muscle contractions involving isometric, concentric and eccentric action; continuous increments in loading based on strength improvements; and, a duration of at least 12 weeks.

     Combination Programs

Lebel et al. (1999) suggested a 6 mode approach to treating and slowing the progression of frailty. The program consisted of: A. adequate diet with sufficient vitamin, mineral and protein intake; B. regular physical exercise including resistance training; C. regular monitoring of physical abilities; D. prevention of infections via vaccines; E. anticipation of stressful events such as elective surgery; and, D. immediate reconditioning after stressful events via individually tailored physical therapy. Based on intervention studies using the Lebel et al. (1999) model however, only physical activity, particularly that containing resistance, balance, and endurance training displayed potential for improving physical function (Liang et al., 2009).

Pharmacology

Drug interventions have been limitedly investigated, and include the administration of anabolic hormones such as megestrol, growth hormone, and testosterone. Clinical trials suggest that in the absence of exercise muscle mass increases, however there were no positive effects on muscular strength or function (A: Walston et al., 2006). The side effects associated with administration anabolic/androgenic hormones and the unproven efficacy limits androgen replacement therapy (Liang et al., 2009). Erythropoietin, beta-adrenergic agonists, ACE inhibitors, and statins have also been investigated in the treatment of frailty, but have not been shown to demonstrate clear benefits (Walston et al., 2006).

Improvements in Care

Arora et al. (2007) examined the care of vulnerable elders in a clinical setting. The results showed that there was a significant variation in the quality-of-care process for several criteria of care in hospitalized vulnerable elderly patients. Specifically, poorer care conditions were found in geriatric patients than those hospitalized for general medicine. Given the lack of care for geriatrics, it has been suggested that more in-depth training is needed for caregivers in the prevention and care of frailty (Laing et al., 2009).

Conclusion

     As the elderly population in the United States continues to grow, the incidence of frailty will increase. Frailty is a disease marked by a reduction in the functional capacity of several biological systems, including musculoskeletal, cardiovascular, immune, sensory, and cognition (Fried et al., 2004). The disease manifests in the inability to respond to perturbations in the environment and recovery from stress or injury. Frailty is associated with several risk factors, including inactivity, malnutrition, cognitive and social decline, and chronic disease (Bortz, 2002). Frail individuals are at an increased risk for falls, cardiovascular and pulmonary disease, and mortality (Lang et al., 2009). Frailty, however, is not an inevitable disease of aging, and may be prevented or reversed with exercise and nutritional intervention (Vanitallie, 2003).

Further research should be conducted to improve understanding of the complex biological factors leading to age-related muscle loss outside of the contributions of inactivity and malnutrition (Lang et al., 2009).

Also, research is needed to determine how best to quantitatively measure loss of physiologic reserves, and the association between markers of physiological reserve loss and the progression of frailty (Rockwood et al., 2005).

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