6.2 Frailty and sarcopenia 521

6.2 Frailty and sarcopenia 521

6.2 Frailty and sarcopenia Andrew Clegg and Harnish Patel ESSENTIALS Sarcopenia and frailty are inter-​related expressions of ageing which identify people at risk of important adverse health events such as falls, disability, and mortality, and the consequent health and social care needs such as hospitalization or care home admission. Sarcopenia is the progressive and generalized loss of skeletal muscle mass and function with age. It has a complex aetiology involving neurohormonal, immunological and nutritional mechan- isms, and is a core component of frailty, which is characterized by reduced biological reserves across a range of physiological systems that increase vulnerability to adverse outcomes following minor stressor events. Detection of frailty should be an essential part of assessment of older people, and the Clinical Frailty Scale is a simple tool based on comprehensive geriatric assessment that enables assignment of a frailty category based on clinical judgement. Adverse trajectories of sarcopenia and frailty can potentially be modified through targeted treatment and multifactorial interven- tions. There is robust evidence to support the use of exercise inter- ventions for older people with sarcopenia and frailty. Introduction The populations of all the world’s countries are ageing. This world- wide increase in life expectancy is remarkable, and should be cele- brated, but living into old age has profound implications for health and well-​being. Sarcopenia and frailty are inter-​related conditions that are common and problematic expressions of ageing. They identify people at risk of a range of important adverse health events such as falls, disability, and mortality, and the consequent health and social care needs such as hospitalization or care home admis- sion. The impact of sarcopenia and frailty extends beyond geriatric medicine across primary care, secondary care, and social services. There is accumulating evidence that the adverse trajectories of sarcopenia and frailty can potentially be modified through tar- geted treatment and multifactorial interventions. Sarcopenia is a muscle disease characterized by poorer muscle strength, loss of skeletal muscle quantity and quality and poorer physical function. Sarcopenia is a core component of frailty, a con- dition characterized by reduced biological reserves across a range of physiological systems, which increase vulnerability to adverse outcomes following minor stressor events. A  unifying feature of sarcopenia and frailty is loss of physical function, which adversely im- pacts the ability to sustain independence in daily living. This in turn leads to reduced social interactions and psychological well-​being. In this chapter we will review the epidemiology, consequences, pathogenesis, diagnosis, and management of sarcopenia and frailty, and consider the how the relationship between them may help better targeting of interventions and holistic care. Sarcopenia Sarcopenia is associated with adverse individual physical and metabolic changes contributing to morbidity, disability, impaired quality of life, and mortality. The health and socioeconomic impli- cations of sarcopenia are considerable: the annual healthcare cost of sarcopenia in the United States has been estimated at $18.5bil- lion. Sarcopenia is now recognized as a disease specific to muscle and has been assigned an official ICD-10-CM diagnosis code. Skeletal muscle comprises approximately 40% of total body mass. It therefore constitutes one of the largest organ systems of the body, playing an essential role in both physical and metabolic func- tioning, including locomotion, thermoregulation, and metabolism of glucose and amino acids. Muscle is a reservoir for proteins and energy that can be utilized in periods of stress or undernutrition; for example, use of amino acids for the synthesis of antibodies and for gluconeogenesis. Reduced muscle mass may therefore help ex- plain the lower metabolic adaptation and immunological response to disease in hospitalized or institutionalized older people. Aetiology—​a life-​course approach Although traditionally associated with the ageing process, the devel- opment of sarcopenia is recognized to begin earlier in life and that the sarcopenic phenotype we recognize in later life is a consequence of adverse muscle changes that accumulate throughout the life-course. In humans, muscle development occurs in stages, beginning at 6

522 Section 6  Old age medicine weeks of gestation until the total number of fibres is set at approxi- mately 24 weeks. Any subsequent increase in muscle bulk occurs by hypertrophy as evidenced by an increase in fibre cross-​sectional area, and not by hyperplasia, so the number of muscle fibres formed prenatally influences the potential for postnatal hypertrophy. Muscle fibre development is determined by muscle use, nutrient availability, and the action of hormones and growth factors that affect regulatory and structurally important myogenesis-​related genes. Muscle mass increases during childhood until adult muscle cross-​sectional areas are reached shortly after puberty, then remain relatively constant in early adulthood until the decline from the late 40s. On average, men have greater muscle mass and strength than women at any given point in the life course. Between the ages of 20 and 80 years, total lean body mass declines by approximately 18% in males and by 27% in females. The resulting health of muscle is a func- tion of the peak attained in early life and the extrinsic and intrinsic changes operating through middle years into old age (Fig. 6.2.1). Pathogenesis At a cellular level, skeletal muscle (Fig. 6.2.2) is continuously remod- elled in response to workload, tension, growth factors, nutrition, and hormones. These factors affect the dynamic balance between muscle fibre protein synthesis and breakdown. Multiple cell signalling pathways mediate the environmental and cellular cues that impact myofibre size through synthesis or degradation. Skeletal muscle is composed of multiple bundles of fascicles sur- rounded by the epimysium Fig. 6.2.2a and 6.2.2b. Each fascicle is bound by the perimysium and is composed of bundles of muscle fibres bound by the endomysium. Each muscle fibre is surrounded by the sarcolemma Fig. 6.2.2c and 6.2.2d. Multiple nuclei reside on the periphery of the fibre under the sarcolemma, while mitochon- dria reside within interfibrilar spaces. Each myofibril is composed of thick myosin and thin actin filaments that form the contractile elements of the muscle and are responsible for the light and dark striations characteristic of skeletal muscle. Proposed mechanisms for the age-​related decline in muscle mass and strength (Table 6.2.1) include a decrease in physical activity/​ sedentary lifestyle, undernutrition, hormonal changes, inflamma- tion, oxidative stress, and denervation. For example, the IGF-​I/​ AKT/​mTOR pathways promote protein synthesis and the mainten- ance of skeletal muscle mass, while catabolic pathways can involve activation of NFkB (nuclear factor kB) by inflammatory mediators including TNF (tumour necrosis factor) and IL-​6 (interleukin 6). Downstream effects of NFkB activation include up regulation of the E3 ubiquitin ligases MAFbx (atrogin-​1) and MURF-​1 that are in- volved in muscle atrophic processes. In sarcopenic muscle the rate of muscle injury (from normal con- traction) exceeds that of repair and regeneration. These effects are a consequence of decreased satellite cell (muscle stem cell) prolif- erative capability and renewal, with added effects of altered inter and intracellular environments favouring catabolism mediated by decrease in growth factors such as circulating insulin, growth hormone, and testosterone and muscle-​specific IGF-​1 levels. Furthermore, production of reactive oxygen species and oxidative stress can lead to mitochondrial DNA damage and a progressive de- cline in mitochondrial function and therefore to energy depletion. Ageing muscles are also characterized by a continuous neuro- pathic cycle of denervation and reinnervation, giving rise to larger, inefficient motor units. The main causes include loss of alpha-​ motoneurones within the central nervous system, withdrawal of nerve terminals from the neuromuscular junctions, and axonal sprouting from remaining neurons. Ultimately, remodelling of skeletal muscle tissue through neuro- pathic and neurohormonal and inflammatory pathways leads to a reduction in muscle cross-​sectional area, volume, and reduced rate of force generation. There are fewer type I  oxidative, slow twitch, and type II glycolytic, fast twitch myofibres, and predom- inantly type II fibre atrophy. The loss of type II fibres, which have relatively more satellite cells, is associated with decreased strength and ability to generate power. The concomitant increase in non-​ contractile material within the fascicles affect muscle quality and lead further to impaired muscle function. In combination, these processes lead to the reduced muscle functional performance. The force generated per unit muscle area is affected by the fibre myosin content, innervation, and increase in connective tissue fat content. Clinical impact of reduced skeletal muscle mass and strength Skeletal muscle strength is determined, in part, by muscle mass, which is a function of myofibre size and number (Fig. 6.2.2). Reduced skeletal muscle mass has been associated with increased functional impairment and disability in both men and women. However, muscle strength and function are more predictive of morbidity and mor- tality than muscle mass alone and this is reflected in recent diagnostic algorithms for sarcopenia. Grip strength is a simple, reliable, and valid proxy measure of body strength, and has good correlation with lower limb physical performance. Low grip strength of community-​ dwelling older people is associated with morbidity including falls, in- creased rate of transition into disability, and premature mortality. In male patients on admission to hospital, lower grip strength was asso- ciated with slower recovery and lower likelihood of discharge to usual residence following a period of inpatient rehabilitation. Slower gait speed has been associated with risk of future dis- ability, falls, institutionalization and death, and is therefore suitable for inclusion in diagnostic algorithms for sarcopenia. Other phys- ical performance measures include chair rise time, time taken to complete five sit to stand actions, and standing balance (the time for sustaining balance on one leg). These objectively measurable variables have been associated with higher risk of all-​cause mor- tality in older people. Gait speed requires intact coordination, Age Range of muscle mass and strength between individuals Growth and development to maximize peak Maintaining peak Minimizing loss Muscle mass and strenght Adult life Early life Older life Fig. 6.2.1  A life-​course approach to sarcopenia.

6.2  Frailty and sarcopenia 523 neural control and joint control, and thus may not be practical in all contexts, when grip strength may be more feasible and have better predictive value. Measures of sarcopenia in practice Measuring muscle strength Grip strength, measured using hand-​held dynamometry, has gained wide acceptance as a reliable and valid measure of muscle strength across healthcare settings. Other modalities include knee extensor power and isometric knee strength and quadriceps torque measurement, but these require static and bulky equipment which may not be appropriate in large-​scale epidemiological studies or routine clinical practice. Measuring muscle mass The commonest approach to measuring muscle mass is through dual-​energy X-​ray absorptiometry (DXA) and bioimpedance scan- ning (BIA), although gold standard modalities include computed tomography (CT) and magnetic resonance imaging (MRI). As muscle mass is correlated with body size, this value can be adjusted for body size using weight or body mass index (BMI). Commonly, the index usually calculated is the appendicular lean mass (ALM)— the muscle mass of the four limbs—expressed as a function of the patient’s height squared, ALM/ht2. Skeletal muscle (a) (b) (c) (d) Epimysium Muscle fascicles Perimysium Endomysium Muscle fibres Mitochondrion Sarcolemma Myofibril Thick (myosin) filament Z disc Z disc I band I band M line A band sarcomere H zone Dark A band Thin (actin) filament Light I band Nucleus Muscle fibre Muscle fascicle Fig. 6.2.2  Anatomical organization of skeletal muscle. (a) Skeletal muscle is contiguous with tendons that connect muscle to bone. Skeletal muscle consists of several hundred to thousands of muscle fibres arranged within fascicles, connective tissue, blood vessels, nerve fibres and is covered externally by the epimysium. (b) Fascicles consist of bundles of fibres separate from the rest of the muscle by connective tissue and are surrounded by the perimysium. (c) An individual muscle fibre is an elongated, multinucleated cell that has a characteristic striated appearance and is covered by the endomysium. An individual fibre is composed of several bundles of myofibrils. Mitochondria reside within the sarcolemma in between the myofibrils and provide energy for muscle contraction through the generation of ATP. (d) Myofibrils constitute the contractile units termed sarcomeres that are arranged end to end. A myofibril is composed of the contractile proteins actin and myosin that overlap to form the dark A bands. Approximation of the sarcomeres in series leads to myofibrillar contraction; the A bands stay the same width but the Z discs move closer together and the I bands shorten. Adapted from OpenStax Anatomy and Physiology. © 18 May 2016 OpenStax, licensed under a Creative Commons Attribution License 4.0 license.

524 Section 6  Old age medicine Measuring physical performance Physical performance measures can be obtained by measuring gait speed alone, or through a well-​characterized battery of measurements encompassing gait speed, standing balance, and chair rise time (collect- ively known as the Short Physical Performance Battery (SPPB)). Use of questionnaires to measure physical function Based on physical performance parameters, the SARC-​F question- naire was developed to predict poor muscle function (Table 6.2.2). It is based on five questions based on: • ability to rise from a chair • ability to walk assisted or unassisted • ability to climb stairs • ability to carry heavy loads (strength) • number of falls A score of ≥4 (scale 0–​10) suggests that the subject is symptom- atic of sarcopenia. The questionnaire has excellent specificity but poor sensitivity for sarcopenia based on consensus criteria (see next), is useful in its predictive power for four-​year physical limi- tation, and may be useful for case finding in clinical practice. Definition and case finding Sarcopenia, can occur primarily due to the ageing process (pri- mary sarcopenia) but can also occur secondary to systemic illness or other interactive factors such as inactivity or malnutrition. For example, in clinical practice, falls, slower gait speed, difficulty rising from a chair, weight loss or muscle wasting should highlight the need for further diagnostic evaluation. The SARC-F question- naire can help elicit self-report from patients who may be symp- tomatic of sarcopenia. Recent definitions of sarcopenia emphasize the ascertainment of muscle strength, followed by measures of muscle quantity and/or quality followed by measures of physical performance. Notable diagnostic criteria with algorithms include those proposed by the European Working Group on Sarcopenia in Older People 2018 (EWGSOP2) (Fig. 6.2.3), the older International Working Group (IWG) on Sarcopenia, the Foundation for the National Health Institutes of Health (FNIH) Sarcopenia Project, and the Asian Working Group for Sarcopenia (AWGS). The EWGSOP2 definition use normative reference values for young healthy adults where possible with cut-off points usually set at –2 or –2.5 standard deviations compared to a mean refer- ence values. Sarcopenia is probable when low muscle strength is present (grip <27 kg for men, <16 kg for women) or time taken to compete five chair rises is greater than 15 seconds. A diagnosis of sarcopenia is confirmed by the presence of low muscle quantity de- fined for example as ALM/ht2 <7.0 kg/m2 for men and <6.0 kg/m2
for women) (Fig. 6.2.3). If these parameters are accompanied by poorer objective physical performance measures e.g. gait speed ≤0.8 m/s, then sarcopenia is considered severe. The International Working Group on Sarcopenia also advocate the measurement to impaired physical performance in addition to slow walk speed as a prelude to measuring muscle mass. The Foundation for the National Health Institutes of Health sarcopenia project was designed to iden- tify clinically relevant cut points of low muscle mass and strength based on their association with impaired mobility. These were grip strength less than 26 kg for men and less than 16 kg for women, and ALM adjusted for BMI under 0.789 kg/m2 for men and under 0.512 kg/m2 for women. The Asian Working Group for Sarcopenia diag- nostic algorithm, relevant criteria include gait speed under 0.8 m/s, ALM/ht2 under 7.0 kg/m2 in men, and under 5.4 kg/m2 in women, and grip strength less than 26 kg for men or 18 kg for women. There has been excellent progress in defining and implementing diagnostic criteria for sarcopenia case finding over the past decade. However it would be helpful for both observational and intervention studies to have agreement on global diagnostic criteria for sarcopenia based on cut off values from skeletal muscle mass indices, grip strength, and walking speed, accounting for gender and culture differences. Table 6.2.1  Anatomical and biochemical changes in ageing muscle Anatomical changes Reduced structural integrity of the myofilaments Reduction in total myofibre number Reduced number and size of type II fibres Decreased muscle mass and cross-​sectional area Infiltration of fat and connective tissue Decrease in number of motor neurons, increase in size of motor units Accumulation of non​contractile proteins Decreased blood flow Biochemical changes Decreased myosin heavy chain synthesis Reduced global muscle protein synthesis Increased oxidative stress Decline in mitochondrial activity Table 6.2.2  The SARC-​F questionnaire for sarcopenia Score Strength How much difficulty do you have in lifting and carrying 10 pounds? None 0 Some 1 A lot or unable 2 Assistance in walking How much difficulty do you have walking across a room? None 0 Some 1 A lot, use aids, or unable 2 Rise from a chair How much difficulty do you have transferring from a chair or bed None 0 Some 1 A lot or unable without help 2 Climb stairs How much difficulty do you have climbing a flight of ten stairs None 0 Some 1 A lot or unable 2 Falls How many times have you fallen in the last year none 0 1–​3 falls 1 4 or more 2 0 = best, 10 = worst, 0–​3 healthy, ≥4 is symptomatic for sarcopenia

6.2  Frailty and sarcopenia 525 Frailty As we age, the cells and tissues of our bodies accumulate damage, which causes gradual loss of physiological reserve. Sarcopenia is a core component of frailty, indicating loss of physiological reserve in the skeletal muscle system, and has been proposed as a key mechanism in the development of frailty (Fig. 6.2.4). However, in frailty, the gradual decline in reserve is accelerated and accumulates alongside skeletal muscle across multiple systems, including the brain, immune, endo- crine, cardiorespiratory, renal, and haematological systems. This accelerated decline across multiple systems can lead to failure of homeostatic mechanisms, which leads to vulnerability to adverse outcomes following minor stressor events. Evidence suggests that it is the total loss of physiological reserve across multiple systems that is important, rather than loss of reserve in any particular system, and sarcopenia is a core component of this multiple system idea. Epidemiology Frailty is common in older age, with prevalence estimates of 10% in the over 65 population, rising to between a quarter and a half of people aged over 85. Higher prevalence rates of frailty in older people has been reported in people living in Southern Europe, older African Americans, and Hispanic populations. There is ac- cumulating evidence of an association between frailty and health inequalities. The prevalence of frailty, and associated outcomes, are strongly linked to national economic indicators—​in higher income countries, the prevalence of frailty is lower, and those with frailty live longer. Furthermore, there is evidence for an association be- tween frailty and measures of social vulnerability, including level of social deprivation. Aetiology—​a life-​course approach Ageing is considered to result from the lifelong accumulation of unrepaired molecular and cellular damage. This damage is inher- ently random and is caused by multiple mechanisms that are regu- lated by a complex maintenance and repair network. Oxidative DNA damage and shortening of telomeres (specialized structures situated at the ends of human chromosomes that help protect the chromosome from enzymatic damage during replication) are thought to be important mechanisms. Interestingly, an association SARC-F or clinical suspicion FIND CASES ASSESS CONFIRM SEVERITY No sarcopenia; rescreen later No sarcopenia; rescreen later Sarcopenia probable* In clinical practice, this is enough to trigger assessment of causes and start intervention Muscle quantity or quality DXA; BIA, CT, MRI Sarcopenia confirmed Sarcopenia severe Physical Performance Gait speed, SPPB, TUG, 400m walk Muscle strength Grip strength, Chair stand test NEGATIVE NORMAL NORMAL LOW LOW POSITIVE OR PRESENT LOW Fig. 6.2.3  Sarcopenia: European Working Group on Sarcopenia in Older People (EWGSOP) algorithm for case-finding, making a diagnosis and quantifying severity in practice. The steps of the pathway area described in stages Find-Assess-Confirm-Severity or F-A-C-S.

• Consider other reasons for low muscle strength, e.g. depression, stroke, balance disorders, peripheral vascular disorders. From Cruz-​Jentoft AJ, et al. (2018). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing, doi: 10.1093/ageing/afy169. [Epub ahead of print], by permission of Oxford University Press.

526 Section 6  Old age medicine has been reported between oxidative DNA damage and frailty, al- though no association between telomere shortening and frailty has been demonstrated. A life-​course approach to frailty is worth considering because if the situation in old age is the consequence of accelerated loss of biological reserves across multiple systems over a lifetime, then there may be potential benefit from identifying markers and mech- anisms with a view to modifying the relevant processes. For ex- ample, there is evidence for a partially hierarchical development of frailty. One large longitudinal study has identified that weakness tends to be the first sign of frailty, and that weakness, slow walking speed, and low physical activity typically precede weight loss and exhaustion. The presence of weight loss and exhaustion may iden- tify people at especially high risk of rapid decline. The presence of weakness as an early sign of impending frailty is consistent with life-​course evidence in sarcopenia which indicates that the decline in muscle mass and strength is observed in midlife. Identification of sarcopenia may therefore be an especially useful method of identifying people at increased risk of later life frailty. Pathogenesis Frailty is best understood as a multisystem disorder, with per- haps both independent and linked mechanisms operating across organ or physiological systems. Furthermore, accumulating dysregulation across multiple systems can subsequently adversely affect systems previously functioning at a normal level, accelerating Ageing Chronic low-grade inflammation, depletion of endogenous antioxidant defence systems, decrease in motor unit number vs FRAILTY Neuropathic and hormonal changes, anorexia of ageing, protein intake, co-morbid illness, sedentary lifestyle IL-6, TNF, ROS IGF-1 and steroid hormones, dennervation Myofibre protein catabolism Myofibre regeneration Type I and II myofibre number, Type II fibre atrophy, decrease in muscle quality SARCOPENIA Strength, power and endurance Difficulty with weight bearing tasks, falls and fractures, increased fatigue and inability to exercise Satellite cell activation/proliferative capacity Myofibre protein synthesis and anabolism Fig. 6.2.4  Sarcopenia as a component of frailty.

6.2  Frailty and sarcopenia 527 the development and progression of frailty. This is relevant not only for improved understanding of the condition, but also because a key implication of loss of reserve across multiple systems is that thera- peutic replacement of any single system is unlikely to ameliorate the abnormal health state of frailty. A schematic representation of this concept of the pathogenesis of frailty is shown in Fig. 6.2.5. Endocrine system During ageing, a decline is observed in production of growth hor- mone, insulin-​like growth factors, oestradiol, testosterone, and dehydroepiandrosterone sulphate, a major sex steroid precursor. Alongside this decline, there is a rise in production of cortisol. These changes may promote a shift to a state of increased catab- olism, leading to loss of muscle mass, anorexia, weight loss, and reduced energy expenditure—​cardinal clinical features of frailty. Insulin-​like growth factors (IGFs) are a family of small pep- tides that increase anabolic activity in many cells. Promotion of neuronal plasticity and increased skeletal muscle strength are con- sidered to be particularly important effects. The principal IGFs are IGF-​1, IGF-​2, and insulin. IGF-​1 is synthesized in the liver in response to circulating growth hormone, secretion of which is regulated by the hypothalamic-​pituitary axis. A range of growth factors and hormones also stimulate local synthesis of IGF-​1 by neurons, muscle cells, and white blood cells. The local autocrine and paracrine actions of IGF-​1 are considered to be important for the promotion of neuronal plasticity and increased skeletal muscle strength. Insulin-​like growth factors promote neuronal survival by inhibiting apoptosis and can increase learning and memory in hu- mans. Primary neuronal changes in the hippocampus and hypo- thalamus may affect the IGF pathway, resulting in a predisposition for accelerated neuronal death and a consequent deterioration in physiological function. There is evidence that IGFs may play an important role in frailty. A 2004 cross-​sectional study including 51 older partici- pants reported significantly lower levels of IGF-​1 in those who were identified as frail, compared to age-​matched controls. An inverse correlation between IGF-​1 and IL-​6 levels was observed, identifying a potential relationship between IGF-​1 and the frail immune system. A 2009 cross-​sectional study involving 696 older women from the US Women’s Health and Aging Study identi- fied a significant correlation between white blood cell counts and IGF-​1. Brain The ageing brain is characterized by changes to the structure and function of neurons and supporting cells. Changes to hippocampal neurons may be particularly important in frailty, as these cells are involved in homeostatic control of the inflammatory response and implicated in cognitive problems commonly associated with frailty, including dementia. Microglial cells are the resident im- mune cells of the brain and may also be important: they have been implicated in the pathogenesis of delirium, which is independently associated with frailty. The hypothalamus receives and integrates multiple afferent in- puts from diverse regions of the brain to coordinate the organ- ismal response to stress and inflammation, partly through the control of glucocorticoid secretion. Basal glucocorticoid secretion is necessary for the normal function of many cells and levels are increased in response to virtually any stress, including physical and psychological stress, or the presence of inflammation, to pro- vide the altered physiological requirements that promote survival. Peripheral cytokines such as IL-​1 and IL-​6 that are released in re- sponse to stress and inflammation have both direct and indirect effects on the hypothalamus to promote glucocorticoid secretion. Circulating glucocorticoids are subsequently sensed by the hippo- campus, which suppresses hypothalamic stimulation of gluco- corticoid production in a negative feedback loop. Uncontrolled inflammation has the potential to cause cellular damage, and a functional glucocorticoid system is an important component of the homeostatic regulation of local and systemic inflammation. The loss of hippocampal neurons that is observed in both normal ageing and Alzheimer’s dementia may impair the homeostatic control of the glucocorticoid system, with the consequence of uncontrolled inflammation and increased cel- lular damage, promoting organismal ageing. Loss of homeostatic control of the glucocorticoid system may itself promote further neurodegeneration, as chronically elevated levels of glucocortic- oids have been hypothesized to increase hippocampal neuronal damage. The loss of hippocampal neurons that is observed in both normal ageing and Alzheimer’s dementia may therefore pro- mote a spiral of accelerated neuronal damage through impair- ment of the glucocorticoid negative feedback loop, uncontrolled inflammation, and neurotoxic effects of chronically elevated glucocorticoid levels. Genetic factors Epigenetic mechanisms Environmental factors Cumulative molecular & cellular damage Physical activity Nutritional factors STRESS Falls Delirium Fluctuating disability Increased care needs Admission to hospital Admission to long-term care FRAILTY Reduced physiological reserve Brain Endocrine Immune Skeletal muscle Cardiovascular Respiratory Renal Fig. 6.2.5  Schematic representation of frailty.

528 Section 6  Old age medicine A recent cross-​sectional study involving 214 female participants reported that frailty, measured using the phenotype model, was inde- pendently associated with chronically elevated diurnal cortisol levels. Evidence indicates that glucocorticoids may play an important role in the pathophysiolgy of delirium, alongside alterations to microglial cell structure and function. This is likely to be partly related to the role of glucorticoids in homeostatic control of the in- flammatory response, but also potentially via a direct role on cere- bral glucocorticoid receptors. This is supported by the observation that high doses of glucocorticoids can precipitate acute deficits in attention and memory—​core clinical features of delirium. Immune system Ageing is associated with changes to immune stem cells, T-​lymphocyte production, B-​lymphocyte response, and reduced phagocytic activity of neutrophils and macrophages. These changes can precipitate an abnormal inflammatory response to stressor events such as infection or surgical procedures, which may help explain the accelerated catab- olism of skeletal muscle and adipose tissue that is observed when an older person with frailty is challenged by an acute illness. Nutrition The synthesis of muscle fibres requires adequate protein substrates. Physiological changes in the gastrointestinal system with age dic- tate that older people eat less, have early satiety, lose their sense of taste, and have a blunted anabolic response to ingested proteins. Collectively, anorexia of ageing leads to impaired muscle mass and performance. In addition, older people require more protein to counteract the inflammatory and catabolic effects of coexistent co​morbidities and their exacerbations. Diagnosis Detection of frailty should be an essential part of assessment of older people because dimensions of frailty may be amenable to interven- tions. Failure to detect frailty potentially exposes patients to conven- tional interventions that may not be beneficial, and indeed could be harmful. Conversely, excluding fit older people from interventions from which they may benefit on the basis of age alone is unacceptable. Gold standard models The two established international models of frailty are the pheno- type model and the cumulative deficit model. The phenotype model developed by the Fried group identifies frailty by the pres- ence of at least three of five physical characteristics: weight loss; exhaustion; low energy expenditure; slow walking speed; and low handgrip strength. The cumulative deficit model developed by Rockwood and colleagues identifies frailty on the basis of the accu- mulation of a range of ‘deficits’, which can be symptoms, sensory deficits, clinical signs, diseases, disabilities, and abnormal labora- tory test results. Despite the distinct conceptual bases of these ap- proaches, convergence in performance has been demonstrated, which provides support for the notion of frailty as a unified con- struct. Although well-​validated in large international epidemio- logical studies, the two gold standard models are more suited to a research setting, as the time required to complete the assessments limits use in day-​to-​day clinical practice. Clinical assessment Identification of frailty in clinical practice is frequently based on comprehensive geriatric assessment (CGA). This is a process to identify an older person’s medical, functional, social and psy- chological capacity, and limitations to enable a plan for ongoing care. The Clinical Frailty Scale (CFS) is a simple tool based on CGA that enables assignment of a frailty category based on clin- ical judgement. There are seven Clinical Frailty Scale categories ranging from one (fit) to seven (severe frailty), and increasing CFS frailty has been demonstrated to have excellent predictive validity for adverse outcomes of care home admission and mortality. Simple tools to identify frailty There are a range of simple assessments and questionnaires avail- able to identify frailty in routine clinical practice. Gait speed A gait speed of less than 0.8 m/​s (taking more than five seconds to walk 4 m) is a reliable method of identifying frailty. At this cutpoint, both sensitivity (0.99) and specificity (0.64) are high, compared to the phenotype model as research standard. Timed-​up-​and-​go test This assesses how long it takes a person to stand up from a chair, walk 3 m, turn around, and walk back again. A time exceeding 10 seconds can be used to identify the likely presence of frailty. This demonstrates excellent discrimination for identifying frailty (AUC = 0.87), but is less able to discriminate fit people from either prefrail or frail people (AUC = 0.73). PRISMA 7 questionnaire The PRISMA 7 questionnaire screens for frailty using seven ques- tions and is suitable for postal completion/self report. A score of 3 or greater can be used to identify frailty (Box 6.2.1). Other validated tests that are suitable for use in day to day clin- ical practice include the FRAIL tool and the Edmonton Frail Scale. This multidimensional assessment instrument is less comprehen- sive than a full CGA but includes the timed-​up-​and-​go test, and a test for cognitive impairment. It is quick to administer (less than five minutes) and is valid, reliable, and feasible for routine use by trained non​geriatricians. Box 6.2.1  PRISMA 7 questionnaire 1 Are you more than 85 years? Yes = 1 point 2 Male? Yes = 1 point 3 In general, do you have any health problems that require you to limit your activities? Yes = 1 point 4 Do you need someone to help you on a regular basis? Yes = 1 point 5 In general, do you have any health problems that require you to stay at home? Yes = 1 point 6 In case of need, can you count on someone close to you? Yes = 1 point 7 Do you regularly use a stick, walker, or wheelchair to get about? Yes = 1 point

6.2  Frailty and sarcopenia 529 Use of routine data to identify frailty The cumulative deficit frailty index identifies frailty on the basis of the accumulation of a range of deficits, which are multiple patient characteristics including clinical signs, symptoms, and disease states. Electronic health records use clinical codes to categorize and log multiple patient characteristics, including symptoms, signs, la- boratory test results, diseases, disabilities, and information about social circumstances. They therefore provide a potentially simple yet powerful mechanism for identifying cumulative deficits to recog- nize and characterize frailty as part of routine care. As the data are collected routinely, there would be minimal resource implications involved in generating a frailty index using electronic health records. An electronic frailty index (eFI) has been developed and val- idated using routine data from over 900 000 UK primary care patients, and is now available in primary care settings. The eFI identifies older people with mild, moderate, and severe frailty, with robust predictive validity for outcomes of mortality, hospitaliza- tion and care home admission, and good discrimination for these outcomes. More widespread use of the eFI may promote a shift from the currently prevalent reactive approach to frailty to a more proactive primary care model that could enable deployment of a range of interventions, described later on in this chapter. Treatment of sarcopenia and frailty A  multidimensional approach to frailty may include promoting regular physical activity, exercise, medication reviews, social network supports, home adaptations, carer support, and nutritional optimiza- tion. The ultimate treatment goal for an older person with sarcopenia and consequent frailty is to improve physical function, maintain in- dependence, and well-​being. Published diagnostic algorithms for sarcopenia are useful for case finding and established outcome meas- ures can be used when designing intervention trials. For example, the ability to walk a defined distance, gait speed, and grip strength are valid outcome measures given their predictive ability of future dis- ability, hospitalization, mortality, and healthcare expenditure. Exercise programmes Evidence supports the use of progressive resistance exercise (exercise against an increasing external load) as well as endurance based exercise for treatment of sarcopenia. Both modalities have positive effects on muscle strength and physical function with reduction in disability and systemic inflammation. There is evidence that targeted home-​based or group-​based exercise interventions may also improve mobility and functional outcomes for older people with frailty, although those with severe frailty may gain less benefit. Identification of sarcopenia alongside frailty may therefore be an attractive method of improving targeting of exercise programmes to those most likely to gain benefit. Nutrition Current recommendations for protein intake in older people to maintain homeostatsis is 1–​1.2  g protein/​body weight (kg) per day. Observational evidence suggests protein, specifically essential amino acids (e.g. leucine), stimulate muscle protein synthesis more than non​essential amino acids. Protein supplements vary in their composition and evidence from trials is at present inconsistent to develop evidence based recommendations for protein supplemen- tation in sarcopenia. Vitamin D Polymorphisms in vitamin D receptors have been associated with muscle function. Vitamin D supplementation has been shown to have a positive impact on global muscle strength but not mass in older people, and may be beneficial in deficiency states. UK NICE guidance recommends increasing availability of vitamin D sup- plements for older people, particularly those with frailty as an especially high risk group for deficiency. Expert consensus recom- mendations support intake of at least 800 IU/​d of vitamin D and calcium intake of 1000 mg/​day for postmenopausal women for the prevention of age-​related deterioration in musculoskeletal health. Primary care interventions Personalized care planning Measurement of quality of primary care has historically focused on preventive and disease-​specific care processes. Similarly, out- come measurement has focused on disease-​specific indicators. Disease-​specific processes and outcomes are less relevant for older people with frailty, who frequently have multiple co​existing con- ditions and different personal priorities. An alternative approach to providing better care for older people with frailty is to identify a patient’s individual health goals across a range of dimensions. This is the purpose of personalized care planning, which is at the core of international models of long-​term condition manage- ment, for example, the Chronic Care Model and the World Health Organization (WHO) model. A medication review should be undertaken as part of person- alized care planning. Certain medications are associated with in- creased risk of falls and delirium in older people with frailty (e.g. benzodiazepines, opiate analgesia) and should be avoided, or doses reduced, where possible. Palliative care Frailty has been identified as the most common condition leading to death in older age, yet advance care planning discussions are not routinely initiated in people with severe frailty. Routine rec- ognition and severity grading of frailty would enable appropriate advance care planning discussions for people with severe frailty, including involvement of palliative care teams for those with ad- vanced frailty who may be entering the terminal phase of life. Possible targets for pharmacological treatment Observational studies have indicated potential beneficial effects of testosterone on muscle mass and function related to its ana- bolic functions and satellite cell stimulatory activity. However,

530 Section 6  Old age medicine randomized controlled trials have not demonstrated benefit be- cause effects on skeletal muscle appear to be offset by adverse cardiovascular outcomes. Trials of testosterone are presently underway, which should provide some guidance on target popula- tions, effective dosing regimens, duration of treatment to improve muscle mass and strength, but also to reduce the risk of harmful side effects. Growth hormone supplementation was also thought to have promising therapeutic effects, but a multitude of studies have shown more harm than benefit in older people. While it may in- crease muscle mass, it does not increase muscle strength or func- tional performance. Side effects include arthralgia, paraesthesiae, fatigue, and carpal tunnel syndrome. More importantly, growth hormone supplementation has been associated with mortality in some observational human studies. Interest in selective androgen receptor modulators, which are androgen receptor ligands that display selective activation of androgen signalling in target tissues, stems from the observed anabolic effect of testosterone. Early phase II trials are underway, but in the longer term trials will be needed on their safety and efficacy in improving physical function in older people with sarcopenia. Myostatin is a member of the TGF​β superfamily. It acts as a nega- tive regulator of skeletal muscle and is upregulated in many muscle wasting disorders, hence myostatin and its receptor, activin type IIb, are attractive targets for therapy, and myostatin receptor anti- bodies are currently under development with the focus on older people with lower lean mass. The anticipated outcomes would need to include sustained positive effect on muscle function. Bimagrumab, an activin type II receptor antagonist that blocks the effect of myostatin, GDF-​11, and activin, has been shown to im- prove six-​minute walk distance by 52 metres compared with pla- cebo, as well as to increase thigh muscle volume, in a small scale trial of 11 patients with spontaneous inclusion body myositis. Clinical trials of potential therapeutic effects in older people with sarcopenia and frailty are awaited. Other drugs that may have beneficial effects on muscle func- tion include the angiotensin converting enzyme inhibitors (ACEi). Improvement in six-​metre walk test has been seen with the use of perindopril in older persons with functional impairment, but did not show synergistic effects with exercise training. However, a re- cent meta-​analysis of four trials concluded that ACEi did not im- prove walk distance or age-​related strength decline in older people. Clinical trials are ongoing. The role of pharmacological agents in frailty is likely to be mainly focused on long-​term treatment, due to the length of time required for beneficial effects to be observed at a biological level, and for these benefits to translate into clinically meaningful outcomes. However, the role of rapid acting agents to augment the blunted recovery responses in older people with frailty may also represent an attractive option for pharmacological treatment. Other aspects Frailty in hospital and specialist settings Frailty is an independent predictor of adverse outcomes across set- tings, and decision-​making and treatments for older people with frailty in these areas should be structured around a personalized, holistic, goal-​orientated approach to care. There is robust evidence that the provision of inpatient comprehensive geriatric assessment on specialist elderly care wards for older people with frailty im- proves rates of discharge home, improves cognitive and functional outcomes, and reduces mortality compared to provision of usual care on general medical wards. The recognition of frailty as a risk factor for adverse outcomes has led to the establishment of specialist orthogeriatric care based on the principles of comprehensive geriatric assessment for older people admitted to hospital with hip fracture, which has led to im- proved outcomes for this group. Evidence indicates that outcomes may also be improved for patients undergoing elective surgical procedures. Frailty is prevalent in many other specialist settings, including oncology, cardiology, and respiratory medicine. For example, over 50% of older people with cancer have frailty or prefrailty and are at increased risk of chemotherapy intolerance, surgical complica- tions, and mortality. However, it is not yet usual practice to iden- tify the presence of frailty as part of routine cancer care to inform decision-​making based around an individualized balance of risk and benefit (see Chapter 6.6). Impact of sarcopenia and frailty on health and
social care systems Frailty is independently associated with increased risk of falls, de- lirium, disability, dementia, hospitalization, and care home admis- sion, all of which are outcomes that have considerable implications for health and social care services. It is therefore unsurprising that older people with frailty are majority users for many health and social care services. However, systems of care have historically been organized around single illnesses more typically found in younger people. Internationally, health and social care systems need to better meet the needs of older people with frailty and their carers. Integrated care is an approach that seeks to improve quality of care by ensuring that services are well coordinated around individ- uals’ needs. A key principle of integrated care is to identify services and user groups where the potential benefits from an integrated approach are greatest. Older people with frailty frequently need to move between services and organizations. They are therefore particularly susceptible to the effects of multiple assessments, de- lays, or the simple abandonment that are characteristics of poorly integrated services. Successful models of integrated care that de- liver improved quality of care for older people with frailty and demonstrate better outcomes at lower cost have been identified internationally. FURTHER READING Cesari M, et al. (2015). Pharmacological interventions in frailty and sarcopenia: report by the International Conference on Frailty and Sarcopenia Research Task Force. J Frailty Aging, 4, 114–​20. Chen LK, et al. (2014). Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc, 15, 95–​101. Clegg A, et al. (2012). Do home-​based exercise interventions improve outcomes for frail older people? Findings from a systematic review. Rev Clin Gerontol, 22, 68–​78.

6.2  Frailty and sarcopenia 531 Clegg A, et al. (2013). Frailty in elderly people. Lancet, 381, 752–​62. Collard RM, et  al. (2012). Prevalence of frailty in community-​ dwelling older persons: a systematic review. J Am Geriatr Soc,
60, 1487–​92. Cooper R, Kuh D, Hardy R (2010). Objectively measured phys- ical capability levels and mortality: systematic review and meta-​ analysis. BMJ, 341, c4467. Cruz-​Jentoft AJ, et al. (2018). Sarcopenia: revised European con- sensus on definition and diagnosis. Age and Ageing, doi: 10.1093/ ageing/afy169. Ellis G, et al. (2011). Comprehensive geriatric assessment for older adults admitted to hospital:  meta-​analysis of randomised con- trolled trials. BMJ, 343, d6553. Fielding RA, et al. (2011). Sarcopenia: an undiagnosed condition in older adults:  current consensus definition:  prevalence, etiology, and consequences. International working group on sarcopenia.
J Am Med Dir Assoc, 12, 249–​56. Rockwood K, et al. (2005). A global clinical measure of fitness and frailty in elderly people. CMAJ, 173, 489–​95. Rockwood K, Andrew M, Mitnitski A (2007). A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci, 62, 738–​43. Shaw SC, Dennison EM, Cooper C (2017). Epidemiology of Sarcopenia: determinants throughout the lifecourse. Calcif Tissue Int, 101(3), 229–47. Studenski SA, et al. (2014). The FNIH sarcopenia project: rationale, study description, conference recommendations, and final esti- mates. J Gerontol A Biol Sci Med Sci, 69, 547–​58. Valenzuela T (2012). Efficacy of progressive resistance training inter- ventions in older adults in nursing homes: a systematic review.
J Am Med Dir Assoc, 13, 418–​28. Woo J, Leung J, Morley JE (2014). Validating the SARC-​F: a suitable community screening tool for sarcopenia? J Am Med Dir Assoc, 15, 630–​4.