Sarcopenia: Potential interventions for a newly recognized disease

This article discusses sarcopenia, a newly recognized skeletal muscle disease. The authors review the disease, its diagnosis, the role of malnutrition in muscle deterioration, nutritional interventions, and EU regulatory considerations. They conclude that good nutritional health, physical activity, and pharmacologic options are the most effective early interventions. The most promising nutritional interventions are high-quality, protein-enriched supplements and multivitamin/multimineral supplements, with special attention to vitamin D intake.
 
Introduction
Sarcopenia and the revision of a newly recognized disease
Sarcopenia is a disease term derived from the Greek words, sarx, meaning “flesh,” and penia, meaning “poverty,” and refers to a “poverty of flesh.” The disease was first described in the 1980s as an age-related decline in lean body mass affecting mobility, nutritional status, and independence.^1,2 Since then, the definition has been refined by the introduction of muscle function into the concept.^3,4 Muscle function includes physical performance, muscle strength, or muscle power, and is a more powerful predictor of clinically relevant outcomes than muscle mass alone.⁵ Low muscle strength has overtaken low muscle mass as a principal characteristic of sarcopenia because it is often reduced to a greater extent during aging⁶ and muscle strength is superior to muscle mass in predicting adverse outcomes.⁷ Malnutrition is an important factor in sarcopenia and is prevalent in institutionalized or hospitalized older individuals.⁸

Recognizing sarcopenia
The recognition in 2016 of sarcopenia as an independent condition with an International Classification of Diseases-10 code (M62.84) was a major landmark.⁹ Sarcopenia is now considered a muscle disease, characterized by muscle failure or insufficiency. With the inclusion of sarcopenia in the World Health Organization medical classification list, there has been a significant growth in interest among physicians and pharmaceutical and nutrition companies about its diagnosis and the development of drugs or treatment interventions.
 
The most cited definition sarcopenia is one proposed by the European Working Group on Sarcopenia in Older People: “A progressive and generalized skeletal muscle disorder involving the accelerated loss of muscle mass and function that is associated with increased adverse outcomes including falls, fractures, disability, and mortality.”¹⁰ There is also a close relationship between sarcopenia, bone loss, or hip fractures, called osteo-sarcopenia.¹¹ The prevalence of sarcopenia increases with age and is higher among people older than 60 years, with prevalence ranging from 6%-19%, depending on the chosen definition.¹²
 
Muscle mass and strength
Muscle mass and strength vary throughout life, with both generally increasing with growth in youth, remaining the same in middle-aged people, but decreasing with aging. From the age of 50, there is a progressive loss of muscle mass (1%-2% a year) and of muscle strength (1.5%-5% a year).¹³ As a result, many older people experience difficulties in carrying out activities of daily living and face a significant increase in the risk for falls and fractures, both of which can lead to a reduction in quality of life.¹⁴
 
The loss of muscle strength and mass in older people is caused by muscle atrophy and changes in muscle composition because of an increase in fat and connective tissue and a decrease in the percentage of contractile tissue.¹⁵ Thus, sarcopenia is associated with low muscle quantity and quality. Today, muscle quality is used mainly in research, rather than in clinical practice, because of the technical difficulties in accurately measuring it.
 
Sarcopenia categories
Two categories of sarcopenia ‒ primary and secondary ‒ have been recognized in the literature.¹⁶ Sarcopenia is considered to be either age-related, or primary, when no other specific cause is evident. It is secondary when causal factors other than aging are evident. Factors possibly contributing to secondary sarcopenia include physical inactivity owing to limited mobility, disease-related bedrest, or a sedentary lifestyle; poor nutrition owing to undernutrition, inadequate intake of energy or proteins, limited ability to eat, malabsorption or anorexia; and a systemic disease, such as an inflammatory condition (e.g., osteoarthritis, organ failure) or a neurological disorder.
 
There are two subcategories of sarcopenia, acute or chronic. It is termed acute when it lasts for less than 6 months and is generally associated with an injury or illness. It is chronic when it lasts longer than 6 months and usually is related to a progressive condition.
 
Sarcopenia diagnosis
The initial lack of consensus in the definition of sarcopenia explains why so little attention was paid to the syndrome in the past. As a result, most cases of sarcopenia tended to go undiagnosed. The recognition of sarcopenia as a disease and the efforts to propose a consensus definition represent a turning point in the recognition of the disease and the development of proper tools for diagnosing and evaluating it.
 
As shown in Figure 1, sarcopenia diagnosis in clinical practice involves measurement of a combination of muscle strength, muscle mass, and physical performance (in that order) during patient screening.

 
Sarcopenia can be identified early through use of two fast-screening tools, the SARC-F questionnaire and the Ishii's score.¹⁷ These tools can be used to measure:
 

• Muscle strength. There are three recognized methods to measure muscle strength to assess sarcopenia. The most widespread and recommended test evaluates quantitatively grip strength by using hand dynamometers.¹⁸ Gender is considered to establish the cut-off points for grip strength in sarcopenia (Figure 1).¹⁹
• Muscle quality or quantity. If a low muscle strength has been identified in a patient the confirmation of the diagnosis of sarcopenia includes the evaluation of muscle quantity or quality by using the following techniques: dual-energy x-ray absorptiometry, bioelectrical impedance analysis (BIA), magnetic resonance imaging or computed tomography. Among them, BIA is an affordable and portable tool whose usefulness to estimate muscle mass based on whole-body electrical conductivity, has been shown in the clinical practice.²⁰
• Physical performance. To assess sarcopenia severity, measurements of physical performance must be performed. In terms of its suitability and ability to predict adverse outcomes, the Gait Speed²¹ and the Short Physical Performance Battery²² are considered the two most feasible and recommended tests in the context of sarcopenia.

 
Malnutrition and sarcopenia, a vicious circle
Malnutrition is highly prevalent in hospitalized patients. It accelerates skeletal muscle loss and functional decline and is an important consideration in sarcopenia, especially in institutionalized or hospitalized, older individuals. Malnutrition can contribute to the loss of muscle mass and function to the extent that low muscle mass has recently been proposed as part of the definition of malnutrition.^23,24
 
The link between nutrition and muscle health underpins the importance of maintaining an optimal nutritional status in the prevention of sarcopenia.²⁵ Early nutritional interventions are essential to prevent, or treat the loss of, muscle mass and function as a result of a disease, bedrest, or aging.²⁶
 
The deterioration in the anabolic response and the subsequent decrease in the rate of protein synthesis is a critical factor in the loss of muscle mass associated with primary sarcopenia.²⁷ Although not all muscle proteins show altered synthesis rates, the myosin heavy chain displays a reduction with age that correlates with the loss of muscle mass and strength.²⁸
 
An insufficient intake of dietary protein could contribute to the loss of muscle mass with age. As we age, insufficient protein intake is correlated with decreased muscle mass, decreased immunity, poor wound healing, and a longer recovery period after illness.²⁹ Moreover, there are age-related differences in the muscle anabolic response to submaximal doses of essential amino acids. After ingesting a bolus of amino acids, older adults synthesize a significantly lower amount of muscle protein compared with younger adults. This may be owing to impaired insulin sensitivity that results in a decreased uptake of amino acids for protein synthesis. However, healthy older people, with normal glucose tolerance, also show an altered anabolic response.³⁰ This points toward the deterioration of the IGF-1/PI3K/Akt1/mTORC1 pathway in the suppression of protein synthesis in older individuals.³¹ The mTORC1 complex, also known as mammalian target of rapamycin complex 1, is the main protein complex that acts as a nutrient/energy sensor and regulates protein synthesis in the cell.³² In this pathway, the availability of amino acids is crucial in activating TORC1.³³
 
Although older adults are less sensitive to the stimulatory effect of amino acids on protein synthesis, recent evidence shows that an increase in protein/amino acid intake can preserve such stimulation and result in increases in lean mass, strength, and function. Landi and colleagues reported that “a daily protein intake of 1.0-1.2 g/kg body weight has been recommended for the preservation of healthy aging muscles, whereas a daily intake of 1.2-1.5 g/kg may be necessary in older patients with acute or chronic diseases. Older individuals with severe illness or malnutrition may need as much as 2.0 g/kg of protein daily.”³⁴
 
Currently, the most promising nutritional intervention for preventing skeletal muscle loss in clinical populations is high-quality, protein-enriched, oral nutritional supplements whose benefits have been extensively demonstrated.^35,36 These supplements do not modify the spontaneous food intake and contribute to the increase of total energy and protein consumption leading to weight gain in both hospital and community-dwelling older individuals.³⁷ It is known that essential amino acids, including branched chain amino acids, are necessary for the maintenance of muscle health in older individuals. Among the essential amino acids, leucine plays a major role in improving sarcopenia in this population.³⁸
 
Other aspects, such as the distribution of proteins in meals, or the joint intake of proteins and carbohydrates, have been studied in older individuals and seem also to promote protein synthesis.³⁹
 
The value of individual nutrients has also been studied in the context of sarcopenia. Supplementation with fish oil‒derived, long-chain omega-3 polyunsaturated fatty acids increases muscle function and mass in healthy older adults and is considered a useful therapeutic agent for the treatment and prevention of sarcopenia.⁴⁰ Omega-3 fatty acids have anti-inflammatory properties, which may help alleviate muscle anabolic resistance in older adults.⁴¹
 
Regarding micronutrients, Ames has shown that “most of the world’s population are moderately deficient in one or more of the roughly 30 essential vitamins/minerals. Moreover, since the damage from moderate deficiency is insidious, its importance for health is not being appreciated.”⁴² This is especially important in older populations and supports the idea that multivitamin/multimineral supplements may be required. It is highly unlikely that persons, especially when they live alone, will take five portions of fruits or vegetables daily, and not doing so can aggravate sarcopenia.
 
Vitamin D intake has been identified as an important nutritional factor in the management of sarcopenia.⁴³ A low level of vitamin D ‒ concentration in serum less than 30 nmol/L ‒ is correlated with a low muscle mass, muscle strength, and physical performance.⁴⁴ A variety of mechanisms of action have been proposed to explain how vitamin D interferes with skeletal muscle function. The explanations became possible after the discovery the vitamin D receptor. The number of vitamin D receptors decrease with age, which can contribute to a reduction in muscle strength with aging.⁴⁵ Thus, the provision of a protein-enriched, oral nutritional supplement with a supplement of vitamin D is important in sarcopenic older adults.⁴⁶
 
The prevalence of malnutrition in older individuals (those over 65) in the US and Western Europe is 23% (range, 6%-51%).⁴⁷ That broad range is explained by the considerable differences between the settings that were analyzed for the reported study: rehabilitation, 50.5%; hospital, 38.7%; nursing home, 13.8%; community, 5.8% (see Figure 2).
 

These high rates of malnutrition and the role of malnutrition in the development of sarcopenia reinforces the need for nutritional interventions in older adults to delay or avoid its onset.
 
Sarcopenia’s economic burden
Sarcopenia may cause a significant personal, social, and economic burden if it remains untreated. As mentioned in previous sections, sarcopenia has an impact on the quality of life of individuals because it increases the risk for falls and fractures,⁴⁸ decreases the ability to perform activities of daily living,⁴⁹ and is associated with poor outcomes, such as diseases, hospitalization, and even death.⁵⁰
 
In addition, sarcopenic patients also present a 2.4-times higher probability of increases in their hospital costs compared with cost for an “average” patient.⁵¹ It has been estimated that a reduction of 10% in the prevalence of sarcopenia would result in savings of $1.1 billion annually in US healthcare costs.⁵²
 
By the 2050, the number of people older than 60 years is projected to be five times that in 1950.⁵³ Although lifespan has increased significantly, life expectancy in good health, formerly called “years of life with no disability,” has not improved. In fact, 42% of people older than 65 report having limitations in performing daily tasks essential for their independence and autonomy, such as transferring from the chair or walking. What is of more concern, is that 20% of older people report being dependent on caregivers to successfully perform those tasks.⁵⁴
 
Sarcopenia is associated with disability. Older adults with low levels of muscle strength have 2.6-fold greater risk of severe mobility limitation.⁵⁵
 
The social, health, and economic burden of a severely disabled person is €14,000 a year, compared with €900, for a vigorous older person, that is, monthly expenses go from €1,200 a month to €75, respectively (see Figure 3).⁵⁶
 

Thus, a universal screening for sarcopenia in older individuals, and the promotion of its optimal care, is mandatory for the reduction of social and health care costs and the maintenance of well-being in older persons.
 
Potential interventions in sarcopenia
There are three interventions for delaying or treating age-associated loss of mass and/or muscle strength: good nutritional health, physical activity (resistance training), and pharmacologic options. In addition to protein supplementation, exercise and pharmacologic interventions are crucial for treating or preventing sarcopenia.
 
Physical activity
A recent consensus statement for the management of sarcopenia from the International Conference on Sarcopenia and Frailty Research concluded that the principal intervention for treating sarcopenia is a “prescription” for resistance exercise.⁵⁷ Even in active older adults, there is evidence that aerobic activity may not mitigate the loss of muscle strength with aging.⁵⁸ Middle-aged, endurance-trained men and women report rapid annual losses of isometric knee extensor strength (about 5.0% ) and flexor (about 3.6%) strength, indicating that even active individuals lose muscle strength that could lead to functional limitations.⁵⁹
 
Resistance-training programs (lasting 8-24 weeks, 2-3 sessions a week, and ranging from moderate- to vigorous-intensity, 65%-80% of maximal strength) improve lean body mass, muscle fiber size (type I and type II), muscle strength, and physical function (sit-to-stand test) in older adults.^60,61 A variety of resistance training modalities have shown their efficacy in older populations, and they include free weights, machines, body weights, or elastic bands.⁵⁸ The reported improvements in muscle strength with resistance training are notable, for both upper body (about 24% increase) and lower body (about 33%), in men and women older than 50 years.⁶² It is important to note resistance training in older adults is also effective in improving muscle power, which is a strong predictor of physical function.⁶³
 
Regular physical exercise can provide “pharmacologic” benefits, particularly for treating age-associated frailty.^64,65 Exercise during youth and middle age reduces the risk of sarcopenia and positively predicts muscle strength and physical performance in older age. In a report by the Academy of Medical Sciences, Bailey and colleagues referred to exercise as the “miracle cure.”⁶⁶
 
Sarcopenia is usually associated with frailty. Abizanda and colleagues showed that controlled exercise, especially when associated with protein supplementation, is useful for treating frailty in institutionalized, older persons.⁶⁷ Moreover, Gomez-Cabrera and colleagues have demonstrated that a controlled exercise program is effective in reverting frailty in a community-dwelling population.⁶⁸ The synergistic effect of protein supplementation with exercise in community-dwelling individuals still has to be shown.
 
Pharmacologic interventions
Sarcopenia therapeutics can either activate anabolism or reduce catabolism in muscle. Despite the potential adverse effects, testosterone supplementation is still deemed the safest and most efficacious anabolic drug therapy for sarcopenia.⁶⁹ Anabolic agents are recommended for use in combination with adequate protein intake and exercise.⁷⁰
 
Appetite stimulants,⁷¹ ACE1 inhibitors,⁷² troponin activators, and oral antidiabetic drugs⁷³ have all shown promising results in the improvement of muscle function or mass in different models. However, there is scant clear evidence on their effects in sarcopenia.
 
Finally, three other interventions aiming at inhibiting catabolism have been studied in the context of sarcopenia. They include the myostatin antibodies,⁷⁴ the activin receptor therapies,⁷⁵ and the reduction of inflammation with anti TNF-α76 or anti IL-677 treatments. However, these drugs are in the preliminary phases of development, and their efficacy has not been clearly established.
 
It is important to note that widely prescribed oral drugs in older patients can have a negative impact on sarcopenia. Among those drugs are statins and the potassium channels blockers (sulfonylureas and glinides), which have been consistently linked with muscle weakness.⁷⁸
 
Regulatory considerations for malnourished patients with sarcopenia
In 2016, sarcopenia was recognized as an independent condition with an International Classification of Diseases-10 code (M62.84). It is closely related to the nutritious status of patients, and it is thus reasonable to expect that certain nutritional products can be designed to meet the specific nutritional requirements associated with sarcopenic patients. In Europe, these products are intended for the “dietary management of malnourished patients with sarcopenia” and are classified as Food for Special Medical Purposes (FSMPs), as defined in Regulation EU Nr. 609/2013 and further in Regulation 2016/128.⁷⁹
 
FSMPs are defined in article 2(2)(g) of framework Regulation (EU) 609/2013 as “foods specially processed or formulated and intended for the dietary management of patients, including infants, to be used under medical supervision; it is intended for the exclusive or partial feeding of patients with a limited, impaired or disturbed capacity to take, digest, absorb, metabolize or excrete ordinary food or certain nutrients contained therein, or metabolites, or with other medically-determined nutrient requirements, whose dietary management cannot be achieved by modification of the normal diet alone.”
 
The nutritious status of patients is intrinsically related to quality of life and improved outcomes of patients with sarcopenia. FSMPs meeting these distinctive nutritional requirements are of utmost importance because it is impractical and unrealistic to expect sarcopenic patients to achieve their nutritional needs with a regular diet.
 
Conclusions
Sarcopenia is considered a muscle disease highly prevalent in older individuals and is associated with increased adverse outcomes, including falls, fractures, disability, and mortality. It imposes a significant economic burden on the national healthcare services. There are three types of interventions to delay or even treat primary sarcopenia (i.e., age-associated loss of mass and/or muscle strength): good nutritional health, physical activity, and pharmacologic options. Malnutrition, especially protein malnutrition, is one of the most important factors in sarcopenia. Early nutritional interventions are essential to prevent or treat this disease.

The most promising nutritional interventions to prevent skeletal muscle loss in clinical populations include high-quality, protein-enriched, oral nutritional supplements that contain essential amino acids; fish oil‒derived, long-chain omega-3 polyunsaturated fatty acids; and multivitamin/multimineral supplements, with special attention to vitamin D intake. FSMPs for use in patients with sarcopenia should include these nutritional supplements.

Abbreviations
BIA, bioelectrical impedance analysis;  EWGSOP, European Working Group on Sarcopenia in Older People; FSMP, Food for Special Medical Purposes; WHO, World Health Organization.
 
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About the authors
Mari Gomez Cabrera, PhD, is a professor at the department of physiology at the University of Valencia, Spain. She teaches exercise physiology at the faculty of medicine as is a member of FreshAge Research Group. Gomez Cabrera’s research focuses on the study of cell signalling in skeletal muscle during contraction, the mechanisms involved in skeletal muscle atrophy in primary and secondary sarcopenia, and the benefits of physical exercise to ensure healthy aging. She obtained her doctorate degree from the University of Valencia. Gomez Cabrera can be contacted at carmen.gomez@uv.es.
 
Jose Viña, MD, PhD, is a professor of physiology at the University of Valencia, Spain. His research focuses on aging and exercise. He leads the FreshAge Research Group, which works on different aspects of oxidative stress, and has received numerous prizes for research. Viña has published widely on glutathione, mitochondria, exercise, aging, and nutrition. He obtained his medical degree at the University of Valencia and his doctorate in 1978 from Oxford University, UK. Viña can be contacted at jose.vina@uv.es.
 
Citation Gomez Cabrera M, Viña J. Sarcopenia: Potential interventions for a newly recognized disease. June 2020. Regulatory Focus. Regulatory Affairs Professionals Society.