Exercise Interventions for the Management of Sarcopenia: Possibilities and Challenges

Abstract

Skeletal muscles undergo macroscopic changes, including atrophy and myosteatosis, alongside microscopic changes in their phenotype due to aging. Sarcopenia is a muscle disease that affects older people and is characterized by the progressive loss of skeletal muscle, resulting in reduced muscle function and a decrease in quality of life. Following the onset of sarcopenia, current treatment relies upon a progressive resistance training (RT) programme to promote muscle hypertrophy and improve physical performance by the upregulation of protein synthesis and the increase in type II muscle fiber size. However, RT is not appropriate for all patients, and is infrequently integrated into medicine or social care for older people. Alternative interventions to RT include multi-modal training, low-intensity blood-flow restriction training, and whole-body vibration training. Understanding the macroscopic and microscopic changes in the skeletal muscle in response to different interventions is essential to recognizing their validity and further utility as a preventative intervention.

Keywords:

• Sarcopenia
• aging population
• exercise intervention
• barriers to exercise intervention

Introduction

Sarcopenia is a muscle disease observed in older people that is characterized by the progressive loss of skeletal muscle mass, leading to impaired muscle function and physical performance.¹ The loss of muscle mass typically occurs at a rate of 3–8% per decade after the age of thirty,² with multiple age-related processes contributing to the development of the disease, including loss of muscle fibers (primarily type II), anabolic resistance, reduced satellite cell function, chronic low-grade inflammation, and age-related hormonal changes.³ The number of older people is increasing from 727 million people older than 65 years in 2020 to an estimated 1.5 billion people worldwide by 2050, suggesting that there will be a significant increase in those affected by muscle loss during aging. Sarcopenia gained disease status in 2016, highlighting the serious implications to quality of life (QoL) that sarcopenia can present.⁴ Modern changes in lifestyle choices, including the expansion of obesity rates, reduced physical activity, increased alcohol consumption and cigarette smoking, have put a wider age range at increased risk of muscle atrophy, increasing the likelihood of a sarcopenia diagnosis in later life.⁵ Several genetic factors have also been associated with muscle atrophy and sarcopenia, including insulin-like growth factor-1 (IGF-1), vitamin D receptor genes, and variability in birth weight.^6,7 It is becoming evident that chronological aging is not the only cause of sarcopenia. As unhealthy lifestyle choices thrive, and genetic variation prevails, muscle atrophy can be seen across generational boundaries. Secondary sarcopenia can also develop if chronic disease or organ failure occurs.⁸ It is important that healthcare professionals are familiar with the terms cachexia and secondary sarcopenia because the interchangeability of these terms is contentious. Sarcopenia is defined as a loss of muscle mass and function due to aging, whereas cachexia is defined as muscle loss due to an underlying illness.⁹ Despite this, the term sarcopenia is increasingly being used to describe the loss of muscle mass and decrease in physical function in response to both aging and disease, such as cancer. Therefore, there needs to be consideration for interventions for cachexia, primary sarcopenia, and secondary sarcopenia.⁸ Unfortunately, as it is likely that patients will require different interventions based on their healthcare conditions, it is beyond the scope of this review to consider individual conditions which can result in cachexia or secondary sarcopenia.

The current recommended treatment for sarcopenia includes an adequate nutritional intake and a sustained physical activity level throughout aging. However, both nutritional and exercise interventions lack conclusive literature regarding the most effective therapeutic strategy, highlighting the need for the optimal exercise prescription to be established within the literature and implemented clinically.

Methods

Articles were obtained from PubMed, Google Scholar, and ScienceDirect. Search terms included: ‘sarcopenia’, ‘exercise’, ‘older people’, ‘sarcopenic’, ‘resistance training’, ‘whole-body vibration training’, multi-model training’, and ‘low-intensity blood flow restriction training’. The literature search included human and rodent studies. The articles selected were between the years 1983–2022.

Current diagnosis criterion

The earliest stage of sarcopenia development is known as pre-sarcopenia, which is the term used when an individual begins to demonstrate evidence of a decline in skeletal muscle mass.¹⁰ With no intervention, pre-sarcopenia may progress to sarcopenia, which is highly correlated with frailty and a risk of falls in the older population.¹¹ The correlation observed between frailty and sarcopenia is alarming. Frailty proceeds disability and a loss of independence and premature mortality, all of which may be preventable if the sarcopenic phenotype was reversed before the onset of chronic physical decline.¹¹ Unfortunately, sarcopenia is rarely diagnosed in its early stages and does not become apparent until a critical event occurs, such as a fall or a significant physical decline.¹² The European Working Group on Sarcopenia in Older People (EWGSOP) developed a consensus diagnostic criterion for age-related sarcopenia categorizing ˈpre-sarcopeniaˈ, ˈsarcopeniaˈ, and ˈsevere sarcopeniaˈ.¹³ Using the EWGSOP diagnostic guidelines, cases should first be identified using a SARC-F questionnaire (Table 1).¹⁴ The SARC-F questionnaire is a five-item screening test to assess strength, walking ability, ability to rise from a chair, climb stairs, and fall frequency.¹⁵ If sarcopenia is suspected following the SARC-F questionnaire, muscle strength should be assessed. Following the SARC-F and muscle strength assessment, sarcopenia can be confirmed by assessing muscle mass and quality, and severity can be established by evaluating physical performance (Figure 1). The EWGSOP also provide measurement protocols to assess muscle mass, strength, and physical function alongside appropriate cutoff points to aid diagnosis.¹³ Early diagnosis of sarcopenia in the pre-sarcopenic stage would aid the prevention of the disease. However, this would require early screening of the older population, followed by an effective intervention to reverse the pre-sarcopenic phenotype. Neither of which are currently implemented in routine clinical practice.

Figure 1. EWGSOP algorithm for case-finding, making a diagnosis and quantifying severity in clinical practice. Image adapted from Cruz-Jentoft et al.¹³

Table 1. SARC-F Questionnaire used to begin the EWGSOP diagnostic protocol for patients with suspected sarcopenia.

Component	Question	Scoring
Strength	How much difficulty do you have in lifting and carrying 10 pounds?	None = 0 Some = 1 A lot of unstable = 2
Assistance in walking	How much difficulty do you have walking across a room?	None = 0 Some = 1 A lot of unstable = 2
Rise from a chair	How much difficulty do you have transferring from a chair or a bed	None = 0 Some = 1 A lot of unstable = 2
Climb stairs	How much difficulty do you have climbing a flight of 10 stairs?	None = 0 Some = 1 A lot of unstable = 2
Falls	How many times have you fallen in the past year?	None = 0 Some = 1 A lot of unstable = 2

A score equal to or greater than four is predictive of sarcopenia and poor outcomes. Table adapted from Malmstrom et al.¹⁴

Macroscopic and microscopic changes

The loss of muscle mass and strength associated with aging is attributed to a combination of factors. These include a loss of motor neurons, myosteatosis, changes to muscle architecture, muscle inflammation, anabolic resistance, mitochondrial damage, endocrine alterations, and a decline in muscle regenerative capacity (Table 2). These factors all contribute to sarcopenia and a reduction in physical capability as we age.

Table 2. Summary table of the anatomical, cellular, and molecular changes observed in aging and sarcopenia.

Anatomical changes	Cellular and molecular changes
Neurodegeneration	Anabolic resistance
Muscle atrophy	Altered proteostatis
Myosteatosis	Low-grade inflammation
Reduction in type II muscle fibers	Mitochondrial dysfunction (oxidative stress)
	Hormonal changes
	Altered satellite cell number/fucntion

Anatomical changes

Neurodegeneration occurs due to a loss of spinal motor neurons and a reduction in axonal myelination in the peripheral axons.^16,17 However, it is yet to be elucidated which region of the spinal cord is primarily affected or if all regions are equally affected.

Neurodegeneration is the consequence of apoptosis, reduced serum IGF-1 signaling, and increased cytokine and oxidative stress levels which is observed in chronological aging. The loss of spinal motor neurons and their reduced excitability experienced during aging and/or neuro-disability results in a lack of muscle innervation, causing denervated muscle fibers and a reduction in muscle fiber number, size, and strength.¹⁸ With time, a lack of muscle innervation leads to chronic atrophy accompanied by a loss of neuromuscular function, including changes in maximal motor neuron firing frequency, agonist muscle activation, antagonist muscle coactivation, force steadiness and spinal inhibitory circuitry.¹⁷ Furthermore, individuals with neuro-disabilities are also at a greater risk of developing sarcopenic obesity,¹⁹ which is defined as a low skeletal muscle mass coupled with high levels of adiposity and myosteatosis.²⁰

These neurodegenerative changes result in a reduction in physical function. However, exercise has been shown to induce several neuroprotection effects, which in turn sustains physical function as we age.²¹ The most relevant finding concerning the reversal of the sarcopenic phenotype is the protective effect of exercise on motor unit maintenance which can mitigate the natural loss of motors units as we age, delaying the neurodegenerative effects associated with sarcopenia.²²

Myosteatosis describes the process of increased uptake of lipids into the muscle adipocytes and is frequently observed in aging muscle. Myosteatosis can result in decreased physical function and has been found to significantly correlate with frailty.^23,24 Possible explanations for the development of myosteatosis include, the impaired function of subcutaneous depots, increased fatty acid mobilization and storage, reduced fatty acid oxidation, inhibited adipocyte differentiation, muscle disuse, altered leptin signaling, sex steroid deficiency, and age-related alterations to satellite cell differentiation.^25–28 Myosteatosis affects muscle quality and muscle architecture, including changes to muscle fiber orientation which leads to decreased muscle strength and function – which are key elements in the EWGSOP diagnostic criterion. Furthermore, intramuscular fat is metabolically active and has the ability to secrete inflammatory cytokines causing systemic inflammation, alongside a decline in muscle cell proliferation, differentiation, and catabolism.²⁹ Furthermore, Perkisas et al. and Farrow et al. identified that intramuscular fat is negatively correlated with muscle mass, strength, and function.^24,30 However, exercise intervention can reduce the amount of lipid infiltration into the muscle and increase muscle attenuation in adults, indicating that exercise can improve muscle quality in groups at risk of sarcopenia.³¹

Cellular and molecular changes

Anabolic resistance describes the reduced stimulation of muscle protein synthesis (MPS) to a given dose of anabolic stimuli, which results in muscle atrophy. Anabolic stimuli for MPS include insulin, serum IGF-1, and branched-chain amino acids (BCAAs). These anabolic signals affect MPS via the activation of the mTOR pathway and its downstream mediators, increasing ribosomal biogenesis and protein translation (Figure 2).³² MPS is primarily stimulated by BCAAs. However, the presence of all nine essential amino acids (EAAs) are required for significant stimulation of MPS, and the process will be severely limited by a lack of EAA availability.³³ In addition, insulin plays an important role in priming the muscle for protein synthesis.^34,35 Aging and commencement of sarcopenia are often associated with physical inactivity and systemic inflammation, and these factors can induce anabolic resistance and altered proteostasis.^36,37 However, exercise, especially in the form of resistance training, can act as an anabolic stimulus and has been shown to reset the dynamics of the MPS equilibrium, allowing MPS to exceed muscle protein breakdown.^38,39

Figure 2. Simplified mTOR1 pathway for muscle protein synthesis. Anabolic stimuli including insulin/IGF-1, exercise (mechanical stimulation), and BCAAs can induce the mTOR1 pathway for protein synthesis. Insulin/IGF-1 and exercise allow the phosphorylation of PKB/Akt. PKB/Akt phosphorylation stimulates mTORC1 activity via the phosphorylation of TSC2 and PRAS40, both negative regulators of mTOR activity. Exercise also induces mTOR1 activation via the binding of phosphatidic acid (PA) to mTOR1. Sensing of BCAA presence in the muscle cell leads to mTOR1 lysosomal translocation leading to its subsequent activation. Activated mTOR1 phosphorylates translation repressor 4E-BP1. mTOR1 also phosphorylates S6K1, which stimulates a second phosphorylation event by PDPK1 activating S6K1. Active S6K1 can, in turn, stimulate the initiation of protein synthesis.

A second metabolic change observed in the older population is a decline in mitochondrial capacity. Observed declines exist amongst the mitochondrial number, density, and size.⁴⁰ Functional declines have also been demonstrated, including a decrease in ATP production, altered respiration and enzymatic actions, and an increase in reactive oxygen species (ROS) production [38].^40–42 Interestingly, several studies have elucidated that mitochondrial decline is not related to aging but rather by a reduction in physical activity as a symptom of aging, and can be compared to anabolic resistance.^43,44 The ability of exercise to increase mitochondrial content and function is well documented, demonstrating that exercise stimulates mitochondrial biogenesis through increases in the peroxisome proliferator-activated receptor γ coactivator, alongside remodeling of the mitochondrial network.^45,46

Endocrine alterations have also been implicated in aging and sarcopenia, and andropause has been strongly associated with sarcopenia in men. Testosterone replacement therapy with hypogonadism or testosterone levels below the normal range resulted in a significant increase in muscle mass, muscle strength, and MPS.^47,48 More recently, it has been demonstrated that aerobic exercise and interval training can significantly influence basal testosterone levels in older men.⁴⁹ However, the magnitude of effect size was small and inconsistent with other short-term exercise programmes including resistance training (RT).

Serum IGF-1, which stimulates MPS via activation of the mTOR pathway, also exhibits a gradual decline with age.⁵⁰ A combination of diminished mTOR signaling and a decline in the availability of anabolic stimuli suggests that endocrine alterations may play a vital role in the development of sarcopenia.^32,51 Testosterone has also been shown to signal via mTOR and the androgen receptor to induce hypertrophic effects.⁵² The combination of anabolic stimuli loss and aberrant mTOR signaling with age highlights the multifactorial nature in the development of sarcopenia.

Aged muscle has also been shown to possess diminished or delayed regeneration capacity and an increased likelihood for fibrosis formation following injury.^53–55 The proliferative potential of satellite cells (mSCs) diminishes with age.⁵⁶ However, this is not thought to be related to a decrease in their number, but due to the microenvironment of the aging muscle changing from the niche specific for satellite cell function.⁵⁷ Furthermore, growth hormone (GH) levels decrease with age, causing an increase in myostatin expression.^56,58 These changes cause inhibition of mSCs division, Wnt signaling alterations, mSCs differentiation into fibroblasts or adipocytes, insufficient upregulation of the Notch ligand Delta and increased oxidative stress levels.^59–61

Recent research has also implicated cellular senescence-associated alterations in mSCs as a causative mechanism of age-related sarcopenia, resulting in the loss of muscle regenerative potential. Knockout mice and the use of cultured myoblasts investigated factors endothelin-1, TRIM32, and GSK3α and their relation to cellular senescence. These factors are all implicated during aging and have been shown to induce mSC senescence resulting in muscle degeneration.^62–64 Satellite cell senescence has also been associated with chronic low-grade sterile inflammation. This is also known as inflammaging in sarcopenia, where the senescence-associated secretory phenotype (SASP) changes the surrounding muscle microenvironment. The secretion of SASP is hypothesized to disrupt tissue structure and function alongside the promotion of the inflammatory state, as observed in sarcopenia and a number of other age-related pathologies.^65,66

Exercise has been shown to positively affect the regenerative capacity of aged muscles. Resistance and endurance training ranging from a few days to months has been shown to increase the number of mSCs in the older population. Improved muscle regeneration has been observed in trained mice with a concomitant improvement in vascularization and inflammatory response.⁵³ However, exercise-induced mSCs activation will reduce with age due to the intrinsic and extrinsic changes that occur within the mSCs.

Regardless, the literature has demonstrated that lifelong exercise should be pursued as the effects of sarcopenia are dramatically diminished via the promotion of muscle mass, structure, function, metabolism, and regeneration.

Exercise training and the future of exercise interventions for sarcopenia At present, the primary treatment for sarcopenia is exercise in the form of resistance training (RT).⁶⁷ RT is a type of exercise that requires the muscle to work against a force leading to increased muscle mass and strength.⁶⁸ The force could be present in the form of a physical weight or an individual’s body weight using repetition of the same exercises on a regular basis. The literature has demonstrated a positive correlation between RT and increased physical function, muscle strength, and improved body composition.^68–70 Demonstrating this, a 2021 study identified that females with sarcopenia exhibited increased hand grip strength (HGS), gait speed, and isometric muscle strength following a sixteen-week RT programme.⁷¹ However, conflicting evidence exists regarding an increase in muscle mass post-RT in sarcopenic individuals.^72,73

High-intensity interval resistance training (HIIRT) has been shown to increase muscle mass and function.⁷⁴ HIIRT is similar to high-intensity-interval training (HIIT), involving short periods of high-intensity exercise at maximum heart rate. HIIT focuses on cardiovascular fitness; however, HIIRT focusses on strength and RT. Moro et al. compared traditional RT to HIIRT in older adults between 60 and 80 years of age. An increase in muscle strength was observed using both training methods. The study shows that HIIRT is at least as beneficial as traditional RT for muscle strength improvement. However, HIIRT presented a greater increase in testosterone in the female participants and a lesser decrease in GH which are important factors in the regulation of skeletal muscle mass in response to exercise.⁷⁵

RT increases muscle hypertrophy by the upregulation of MPS, alongside increasing the size of the fast-twitch muscle fibers.⁷⁶ These increases allow maximum production of muscle power and improvements to physical performance, thereby reducing clinical features of the sarcopenic phenotype. A 12-week exercise trial implemented in a nursing home demonstrated that exercising for as little as forty-five minutes a week can improve physical performance and the likelihood of falls in the older population.⁷⁷ A recent systematic review also confirmed that low-intensity RT (≤50% 1RM) is sufficient to elicit strength gains in sarcopenic individuals, however high intensity RT (80% 1RM) provides maximal results.⁷⁸ However, high intensity RT is unlikely to be suitable for the majority of the sarcopenic population and may only be advisable for pre-sarcopenic individuals with the physical capability for this type of training.

Despite its positive outcomes, RT struggles to retain participation rates due to its repetitive nature and non-acceptability for all patients, especially those with chronic immobility or health issues, alongside the lack of integration into medicine and social care. A personalized approach to training should be considered for sarcopenic individuals, incorporating RT while encompassing a variety of exercise and rehabilitation methods. Multiple alternative interventions have been included in the literature including multi-model training (MMT), whole-body vibration training (WBVT), and low-intensity blood flow restriction training (LIBFRT).

Multi-model training

MMT is based on a combination of physical exercises typically incorporating traditional RT, aerobic exercises, flexibility, and plyometric training. MMT programmes train a large dimension of physical skills applicable to daily life and contribute to fall prevention in the elderly. To date, a combination of RT and plyometric training has been demonstrated to be the most effective intervention for increased muscle mass and power in the older population.⁷⁹ In 2013, 117 older people (aged 71–90) participated in a separate multifaceted training programme. The training included a combination of aerobic and strength training twice a week for six months and identified positive effects on mobility, motor balance, muscle strength and endurance.⁸⁰ Furthermore, the incorporation of aerobic training with RT demonstrated the ability to ameliorate mitochondrial dysfunction via Sestrin2 in an AMPKα2 dependent manner and boasts a number of other health benefits, including reducing the risk of heart disease, high blood pressure, obesity, type 2 diabetes, metabolic syndromes, and mental health problems.^81,82 Aerobic training alone provides a partial solution for sarcopenia reversal due to the amelioration of mitochondrial-derived ROS but it does not effectuate maximum MPS or muscle strength development thus the requirement of RT in a MTT programme aimed at ameliorating sarcopenia.^83,84

At present MMT presents itself as the most appropriate intervention for those with secondary sarcopenia, especially for individuals who have experienced significant muscle loss alongside cardiovascular health depletion during a period of chronic illness. The implementation of RT should develop muscle strength and aerobic exercise can provide an improvement in cardiovascular function.⁸⁵ Currently, the combination of exercises provided by a professional would be personalized on an individual basis dependent on a patient’s current ability and current goals. However, a recent comprehensive review of the literature has concluded that the limited number of studies involving patients with secondary sarcopenia cannot confirm that exercise reverses the sarcopenic phenotype in individuals with other comorbidities.⁸

Using a MMT as a sarcopenia intervention provides a more comprehensive approach to muscle aging therapy, alongside, improving key skills such as balance and coordination to help older individuals maintain independence and contribute to the prevention of frailty and disability. The variety of activities may also encourage participation/long-term adherence to an exercise programme whilst making exercise more accessible to less-able patients.

Whole-body vibration training

WBVT involves the participant standing or sitting on a vibrating platform whilst partaking in strength and balance exercises.⁸⁶ WBVT has been infrequently trialed in patients diagnosed with sarcopenia.^87–89 The most recent study demonstrated improvements in physical capability following twelve weeks of WBVT. Improvements in one- foot balance, shoulder and arm flexibility, gait speed, HGS, sit-to-stand repetitions, and an increase in muscle mass index were all observed.⁸⁹ Twelve weeks of WBVT has also demonstrated its ability to facilitate voluntary activation (the level of neural drive to the muscle during exercise) of the quadriceps muscle.⁸⁸

Changes to the spinal motor neuron population, denervated muscle fibers and alterations to the neuromuscular junctions have all been reported in aged muscle, resulting in a reduction of force production per unit of muscle fiber size.^90–93 The success of WBVT has been mainly ascribed to a complex spinal and supraspinal neurophysiological mechanism. It has been shown to elicit a reflex loop known as the tonic vibration reflex leading to motor unit activation via the 1-a afferent-α-motor neuron pathway.⁹⁴ Vibration can alter the efficacy of the pathway leading to positive and negative effects on muscle spindle activity and motor neuron output.⁹⁵ In 2017 Wei et al. investigated whether the frequency/exposure time during voluntary contraction influenced WBVT effectiveness in older people with sarcopenia. The chosen mid-range exposure of 360 s at a vibration frequency of 40 Hz over twelve-weeks had the best outcome on physical performance amongst the participants, demonstrating improvements in all outcome variables including the sit-to-stand test, 10- metre-walking test, and the timed-up-and-go (TUG) test.⁹⁶

The low-intensity nature of WBVT makes it an ideal intervention for those with mobility issues. However, skilled staff may be required to ensure WBVT is delivered correctly. Finally, contradictory literature has proven a need for further research into WBVT to establish its effects on motor neuron activation at several frequencies and vibration exposure times, and during voluntary and involuntary muscle contraction to finalize appropriate rehabilitation protocols.

Low-intensity blood flow restriction training

LIBFRT combines RT exercises with blood flow occlusion. A tourniquet is applied around the training limb, disrupting the blow flow, creating an ischemic environment. Under ischemic conditions, fast-twitch muscle fibers are recruited during low-intensity exercise, leading to the promotion of muscle hypertrophy.^97,98 LIBFRT has been suggested as a potential intervention for sarcopenia due to its low-intensity nature. Multiple studies have shown that low-intensity exercise combined with moderate blood flow occlusion can promote muscle hypertrophy at a training intensity of only 20% 1RM.^99,100 A 2019 case study of a 91-year- old sarcopenic male demonstrated improvements in muscle mass, HGS, isokinetic peak torque and the upregulation of important regulars for muscle metabolism (IL-6 and serum IGF-1), following three months of LIBFRT training compared to low- intensity RT alone.¹⁰¹

It has been hypothesized that the success of LIBFR is reliant on several elusive mechanisms; however, metabolic by-product accumulation currently presents itself as the primary process. Whole blood lactate, plasma lactate and muscle cell lactate accumulation have been observed, resulting in an acidic intramuscular environment.^102–104 The change in pH in the ischemic environment leads to the increased expression of GH, causing an upregulation in MPS.¹⁰⁵

Heat shock protein 72 (HSP 72), nitric oxide synthase 1 (NOS-1), myostatin and REDD1 regulation have also been suggested to contribute to the muscle hypertrophy observed during LIBFRT. HSP72 is induced in response to stress including ischemia and has been shown to reduce muscle atrophy.¹⁰⁶ NOS-1 is upregulated, facilitating an increase in satellite cell activation.¹⁰⁷ Myostatin and REDD1 are downregulated, suggesting a possible upregulation of the mTOR pathway leading to stimulation of the MPS pathway.^99,104,108 Whilst much of this literature concerns young, healthy individuals, favorable outcomes have also been shown in a few studies undertaken within an older population.^101,109 LIBFRT may be a highly appropriate intervention for those with sarcopenia. The novel intervention makes muscle hypertrophy, strength, and endurance more accessible to those less physically able due to its low-load and low-intensity approach, similar to WBVT.

The current barriers to exercise intervention for sarcopenia

There is much positive research to suggest that exercise interventions can provide an effective treatment for sarcopenia. However, there are several anatomical, molecular, cellular, and societal barriers to the implementation of exercise interventions for the treatment of sarcopenia (Table 3). The epicenter of the exercise intervention dilemma is not a lack of intervention possibilities, but rather that sarcopenia often remains undiagnosed until a critical stage.¹² The first step for improving sarcopenia management could include screening all older people regardless of their current physical presentation. Early diagnosis would be made possible using EWGSOPˈs consensus diagnostic criterion and measurement protocols or via a biomarker or medical imaging alternative, which is currently unavailable.¹³ Screening the older population may permit early diagnosis of the disease in its pre-sarcopenic phase, ensuring that intervention can be implemented before a further loss of muscle mass or function occurs. If mass screening remains infeasible, screening could begin within an established age range or at-risk populations. Muscle mass decreases at a rate of approximately 3–8% a decade after age thirty and can accelerate to rates as fast as 15% per decade from age sixty with noticeable physical decline.² Therefore, routine screening should ideally begin before this acceleration period of muscle loss. Preventative screening could improve QoL for countless older people, alongside the potential to save the NHS an estimated £2.5 billion spent annually treating muscle weakness and sarcopenia.¹¹⁰

Table 3. Summary table of the current barriers and future possibilities for exercise intervention to reverse muscle aging.

Current barriers to exercise intervention	Future possibilities for intervention
Delayed sarcopenia diagnosis leading to delayed intervention.	Implementation of early screening using EWGSOPˈs diagnostic criterion and the future development of sarcopenic biomarkers.
Staffing and infrastructure changes to provide exercise training to all diagnosed with or at risk of developing sarcopenia.	Introduction of patient organizations, community groups or third-sector exercise professionals to conduct exercise sessions.
Poor adherence to exercise programs.	Remove the barriers to exercise and exploit the ˈexercise motivatorsˈ by conducting free, face-to-face, social, and engaging exercise sessions. Alternatively, home- based exercise support can be provided by regular patient contact with clinicians or via a telehealth approach.

Following diagnosis, those identified as sarcopenic need to be provided with an effective intervention to reverse the phenotype, which is not yet implemented in routine clinical practice or care facilities. Skilled staff are often required to assist in safe exercise intervention, which presents a large-scale staffing and infrastructure requirement.

Furthermore, poor adherence to exercise programmes is well-documented due to a number of barriers that may hinder participation.¹¹¹ These include affordability, motivation, and concerns about other negative health outcomes.¹¹² To retain adherence rates, exercise ˈmotivatorsˈ need to be considered and incorporated into exercise programmes. The MIlk Intervention Muscle Aging (MIlkMAN) study identified five motivators for intervention engagement: self-perceived improved health, knowledge acquisition, social wellbeing, professional support in a fun environment and positive reported outcomes. The study also identified that peer encouragement and social bonds are the motivators that encourage prolonged engagement in exercise following intervention completion.¹¹² To address the identified patient barriers and exploit the ˈmotivatorsˈ, health care providers should incorporate advice about the importance of exercise for sarcopenia prevention in routine clinical visits to empower patients and help develop their knowledge about safety, effectiveness, and limitations. Social innovation is also required to implement the infrastructure required to provide exercise initiatives for those diagnosed or at risk of sarcopenia.

Health care professionals also face barriers to implementing exercise intervention in the clinical setting as there is limited guidance on physical activity advice from official bodies. There is also a lack of high-quality studies to determine patient opinion regarding exercise intervention for sarcopenia. Current advice suggests an RT programme with plyometric training as the most effective intervention for sarcopenia; however, this is not acceptable for all patients due to its high- intensity nature. The recent literature regarding MMT, WBVT and LIBFRT provides promising alternatives to RT alone, but there are still elusive elements to their application. These factors make it hard to advise physicians on the best exercise protocol to follow.

For physicians to provide a holistic approach to sarcopenia management the association between sarcopenia and polypharmacy must be considered. It has been recently reported that sarcopenia is associated with an increased prevalence of polypharmacy.¹¹³ Alongside the acknowledgement that some prescription medication may affect muscle mass and function. For example, corticosteroids have been associated with muscle weakness and low appendicular lean mass.^114,115 Malnutrition has also been associated with polypharmacy due to negative implications for the gastrointestinal microenvironment.¹¹⁶ Malnutrition is often observed in older individuals and is thought to be a key contributor to the development of sarcopenia.¹¹⁷ Therefore, the impact of specific medications and polypharmacy in populations at risk of sarcopenia requires further insight alongside the development of targeted interventions to reduce polypharmacy. This knowledge would help to advise physicians when prescribing medications to older individuals.

Overcoming the barriers to exercise intervention for sarcopenia

The initial barrier to sarcopenia management and the opportunity for prevention is delayed diagnosis. The EWGSOP diagnostic criterion provides a detailed diagnostic process; however, it is multistep, time-consuming, and costly. Currently, there are no established biomarkers for sarcopenia used in clinical practice, highlighting the unmet need to understand the molecular mechanisms underpinning the disease. Identification of a singular biomarker of disease has been deemed unreliable due to the multifactorial nature of the sarcopenic phenotype and the involvement of multiple signaling pathways. Therefore, it is believed that the combined use of multiple biomarkers would allow increased diagnostic accuracy.¹¹⁸ Current research highlights the utility of a several biomarkers including inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor- α (TNF-α), alongside procollagen type III N-terminal peptide (P3NP) as an indicator of muscle loss.¹¹⁹ Existing biomarkers should be further investigated to demonstrate adequate sensitivity and specificity to predict sarcopenia, alongside investigation into additional biomarker candidates. Recent studies have implicated reactive oxygen species (ROS) in the pathophysiology of skeletal muscle aging, providing an example of a novel candidate. If a panel of accurate biomarkers are established, screening those at risk of sarcopenia could be made easily accessible via routine blood testing in the clinic. Extensive biomarker identification would not only allow the diagnosis of sarcopenia in its early stages, but also enhance our understanding of the pathophysiology of the disease to develop the most effective interventions to reverse the sarcopenic phenotype.

There is also minimal understanding of the macroscopic and microscopic changes induced by the variety of available exercise interventions. The challenges include the lack of an established biomarker as discussed, and the inconsistent assessment of myosteatosis and muscle atrophy pre- and post-intervention in the literature. For the most effective exercise prescription to be established, each exercise intervention must be compared by matching the programmes frequency, duration, and intensity. The success of each intervention could be assessed using QoL questionnaires, medical imaging, muscle biopsies, blood analysis and a multitude of physical function assessments. This approach would allow a global assessment of muscle health and any improvements to the sarcopenic phenotype post- intervention, including improvements to physical function, biomolecular changes, and gross anatomical changes that each intervention has effectuated. However, it must be considered that one prescriptive intervention may not be appropriate for all patients, as demonstrated by RT. To avoid this barrier, a prescriptive and personalized rehabilitation management protocol is required to aid and advise physicians on the effective treatment and prevention of sarcopenia for all. Ultimately the research is likely to conclude the need for a MMT approach to ensure inclusivity and optimum health benefits that expand beyond muscle health alone.

Once the most effective exercise interventions are established, the best way to implement it into healthcare needs to be considered. Successful implementation would be defined as ensuring that prescriptive or personalized exercise programmes are accessible to all at-risk or diagnosed with sarcopenia. Exercise referral is currently limited to health-care professionals once sarcopenia is identified.¹²⁰ This presents an infrastructure barrier that must be removed. To allow access to all at risk, social innovation to overcome infrastructure and staffing shortages need to be addressed. Sarcopenia management training is required for all allied health professionals and physicians to help bridge the gap in service provision.

Additional possibilities include ensuring that sport and exercise professionals have the skills to develop individualized and safe exercise interventions for older patients with sarcopenia. Once an improvement in staffing infrastructure and training occurs, patient organizations, community groups, or third-sector exercise professionals could be introduced to conduct free, face-to-face, social, and engaging exercise sessions.

Recent research has also assessed the use of home-based exercise programmes for sarcopenia.¹²¹ Home-based exercise has many advantages, including minimal cost and time expenditure for patients and healthcare providers. It is also accessible to all, and it can fit into the patient’s routine. Tsekoura et al. demonstrated that group-based exercise is more effective than home-based exercise for improving muscle mass and functional performance.¹²² However, their home-based group still saw significant improvements in gait speed, TUG, skeletal muscle mass index (SMMI), HGS, knee strength, and QoL compared to a control group. In the only published study exploring home-based exercise for sarcopenic community-dwelling individualsˈ, the results are comparable, demonstrating increases in muscle strength and function following a six-month home exercise programme.¹²³ Therefore, both home- and group-based approaches can be considered effective for sarcopenia management. Unsurprisingly, adherence rates for home-based exercise programmes are often problematic. However, the Tsekoura study maintained a high adherence rate and no intervention drop-outs by providing regular visits by a member of the study team and telephone counseling providing ongoing support and motivation. Telephone counseling is considered effective for promoting increased physical activity and exercise participation in older people and could provide a low-cost alternative to face-to-face exercise sessions.¹²⁴ In addition, the future looks to the use of telehealth which involves the use of internet-based platforms such as Zoom or Microsoft Teams for live online home-based exercise to encourage motivation and adherence (Table.3). However, the above solutions only protect and accommodate those at risk or diagnosed with age- related sarcopenia in later life. Therefore, they do not resolve or reverse the likelihood of sarcopenia development in future generations. Nutrition, health, and exercise education for young people requires global improvement. Education systems require stricter legislation to ensure that young people are educated on how to live a healthy lifestyle to promote healthy aging. Comprehensive exercise education in schools detailing exercise programmes and their associated physiological effects may be a good place to start.

Allowing young people an understanding of how to exercise and the physiological adaptions it provides could encourage participation but may also promote a commitment to life-long exercise. Several studies have highlighted the success of life-long exercise for healthy aging, especially concerning sarcopenia. Effects include a sustained muscle fiber size, force, and improved physical function due to the prevention of excessive apoptosis, defective autophagy, and mitochondrial dysfunction.^125,126 Data from the British National Survey of Health and Development has also demonstrated the cumulative benefits of increased leisure time physical activity for maintaining HGS at ages 60–64. Individuals in the upper third of lifelong exercise participation had a mean grip strength of 2.11 kg greater than the lowest third.¹²⁷ If life-long exercise was adhered to amongst the global population, it could reverse a multitude of modern health concerns related to poor lifestyle choices, alongside the prevention of muscle atrophy in all age groups. Education surrounding the importance of health and exercise is paramount to ensure healthy aging in future generations and improving QoL for patients.

Conclusions

Research and society are not doing enough for the population at-risk of sarcopenia. A more coherent and integrated approach to sarcopenia is required, with earlier identification and diagnosis of disease in the pre-sarcopenic phase. Screening of all aging and at-risk patientsˈ needs to become routine practice to allow preventative interventions to be implemented. These actions will help contribute to the achievement of a healthy aging society. There are several key barriers to this, including a lack of knowledge regarding exercise prescription, patient adherence and identification of suitable exercise programmes. Scientific research also needs to provide a more coherent assessment of the efficacy of the variety of possible exercise interventions on skeletal muscle mass and function throughout aging, to help identify the most appropriate interventions for sarcopenia management. The advancement of this knowledge could lead to optimal prescriptive and personalized exercise protocols in clinical practice. Consequently, sustaining physical function, productivity and improved QoL as our global society continues to grow older.

Authors’ contributions

All authors participated in the conception of the review article. HE conducted the literature review. HE and MF prepared figures and drafted the manuscript. All authors edited and revised the manuscript and approved the final version.

Disclosure statement

No funding was received to assist the preparation of this manuscript. The authors have no conflicts of interest or competing interests to disclose.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.