Biological basis and treatment of frailty and sarcopenia

Abstract

In an ageing society, the importance of maintaining healthy life expectancy has been emphasized. As a result of age-related decline in functional reserve, frailty is a state of increased vulnerability and susceptibility to adverse health outcomes with a serious impact on healthy life expectancy. The decline in skeletal muscle mass and function, also known as sarcopenia, is key in the development of physical frailty. Both frailty and sarcopenia are highly prevalent in patients not only with advanced age but also in patients with illnesses that exacerbate their progression like heart failure (HF), cancer, or dementia, with the prevalence of frailty and sarcopenia in HF patients reaching up to 50–75% and 19.5–47.3%, respectively, resulting in 1.5–3 times higher 1-year mortality. The biological mechanisms of frailty and sarcopenia are multifactorial, complex, and not yet fully elucidated, ranging from DNA damage, proteostasis impairment, and epigenetic changes to mitochondrial dysfunction, cellular senescence, and environmental factors, many of which are further linked to cardiac disease. Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, growing evidence supports that a combination of exercise training and nutritional supplement improves skeletal muscle function and frailty, with a variety of other therapies being devised based on the underlying pathophysiology. In this review, we address the involvement of frailty and sarcopenia in cardiac disease and describe the latest insights into their biological mechanisms as well as the potential for intervention through exercise, diet, and specific therapies.

Graphical Abstract

Schematic diagram of the biological mechanisms of the development of frailty and sarcopenia, their comorbidities, and potential reversibility by therapeutic intervention. CAD, coronary artery disease; HF, heart failure.

Frailty, Sarcopenia, Heart failure, Biological mechanism, Treatment

1. Introduction

The rapid ageing of societies worldwide leads to attention increasingly focusing on frailty, a state of increased vulnerability to health problems due to age-related functional decline and loss of reserve capacity.¹ By 2050, the percentage of the population aged 65 and over is expected to double as compared to 2015 levels,² and the prevalence of frailty is consequently expected to continue to increase for the foreseeable future.³ Whilst frailty embraces many aspects including physical, social, and psychological factors, one phenotype associated with the occurrence of physical frailty is sarcopenia, a geriatric syndrome defined as age-related (primary sarcopenia) or chronic disease-related (secondary sarcopenia) loss of skeletal muscle mass and muscle strength.^4,5 Recently, frailty and sarcopenia have been reported to exacerbate the clinical outcomes of numerous illnesses, and the same has been shown for major cardiac diseases, such as heart failure (HF), and coronary artery disease (CAD).^6,7 On the other hand, since sarcopenia and frailty are potentially reversible with early intervention,⁸ a better understanding of their biological basis and appropriate therapeutic interventions are crucial to improve prognosis. This review outlines the current findings on the biological basis of frailty and sarcopenia, their association with cardiac disease, and some promising therapeutic approaches (Table 1).

Table 1

Confirmed and unresolved issues in sarcopenia and frailty

Issues	Whether the issues are confirmed or unresolved	References
Definition of sarcopenia and frailty	With numerous definitions of sarcopenia and frailty, the precise and appropriate methods and cut-off values for their diagnosis remain an unmet challenge.	1,9–12
Involvement in frailty and sarcopenia in cardiac disease	Frailty and sarcopenia are independently associated with the risk of developing CAD and HF.	13–16
	Genomic instability: There is some evidence that genomic instability is associated with sarcopenia and frailty, although the causality is not elucidated.	17,18
	Telomere attrition: Telomere length is short in patients with HF and has been associated with disease severity. However, there is no consistent evidence of a relationship between telomere shortening and sarcopenia or frailty.	19–22
	Epigenetic alterations: Several studies have shown that changes in DNA methylation levels, methylation patterns, and miRNAs during the lifespan may play a role in frailty and age-related skeletal muscle dysfunction, although the causal relationship remains unclear.	23,24
	Loss of proteostasis Molecular chaperones: Several HSP maintains muscle function and regulates muscle atrophy.	25,26
	Proteasomal degradation: E3 ubiquitin ligase activity is elevated and is associated with decreased cardiac contractility in chronic HF. However, conflicting evidence exists for the role of UPS in sarcopenia.	27–31
	Autophagy: Autophagy declines with age. Autophagy inhibition induces cardiac hypertrophy, left ventricular dilatation, and cardiac dysfunction. Autophagy dysfunction, i.e. both under- and over-activation can contribute to the development of sarcopenia.	32–36
Biological mechanisms of frailty and sarcopenia	Deregulated nutrient sensing: Low GH, IGF-1, and testosterone levels are associated with impaired cardiac performance and exercise capacity in HF patients. GH and IGF-1 play a pivotal role in protein synthesis and muscle growth, and the association of declines in anabolic hormones with sarcopenia and frailty has been widely examined.	37–40
	Mitochondrial dysfunction: Mitochondrial dysfunction is a common feature of many aspects of ageing, and is associated with the development of various age-related metabolic diseases, including HF and sarcopenia. Oxidative stress is enhanced in patients with HF, contributing to disease severity and exercise intolerance by causing intracellular Ca2+ overload in cardiac myocytes, hypertrophy, apoptosis, and endothelial dysfunction. The role of ROS in mitochondrial dysfunction, however, remains a significant challenge in ageing research.	41–49
	Cellular senescence and stem cell exhaustion: p16INK4a and p19ARF are both encoded by the INK4a/ARF locus, which has been identified as the locus most genetically related to age-related diseases such as CAD and frailty. Excessive senescent cell accumulation plays a crucial role in driving tissue senescence, which contributes to the development of several age-related pathologies such as frailty and sarcopenia. The role of satellite cells in sarcopenia and frailty remains controversial.	50–54
	Altered intercellular communication: Chronic low-level inflammation associated with ageing is related to factors closely associated with physical frailty, such as loss of muscle mass, muscle strength, and bone mineral density. HF patients have chronic low-level systemic inflammation, which promotes cardiac dysfunction and remodelling, further exacerbating HF itself. Enhanced RAS can contribute to muscle wasting by increasing ROS production and inducing the expression of TGF-β1 and connective tissue growth factor.	55–59
	Environmental factors: Smoking, poor dietary patterns, lack of exercise, and a sedentary lifestyle have been implicated in the development and exacerbation of CAD and frailty.	60–65
Treatment strategies	Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, exercise training, nutritional therapies, and disease-specific therapies are certainly the primary treatments for frailty and sarcopenia.
	Exercise: Resistance training has beneficial and significant effects on functional capacity, muscle mass, and strength for the prevention and treatment of sarcopenia. The multicomponent intervention is associated with a reduction in the incidence of mobility disability in frail sarcopenic elderly subjects. Data from several exercise intervention trials have shown that supervised exercise training is safe and useful for improving exercise capacity and quality of life in patients with HF.	66–68
	Nutrition: Energy expenditure is reduced as a protective mechanism in malnutrition whereas it remains inappropriately high in sarcopenia and muscle wasting. Also, increased resting energy expenditure has been shown in HF. High protein intake is generally recommended in elderly patients with sarcopenia and HF, but special attention needs to consider chronic kidney disease, which frequently coexists with these conditions.	69–72
	Drug therapy: There are no pharmacologic agents approved worldwide for the treatment of frailty and sarcopenia. Hormonal treatment is still controversial in its practical application due to uncertainties in efficacy, the need for continuous administration, and side effects. The therapeutic effectiveness of myostatin inhibitors on sarcopenia has only been limited. Ghrelin administration could improve functional capacity, muscle strength, and mass as well as left ventricular ejection fraction in sarcopenic HF patients. GDF-15 neutralization is a transformative therapeutic approach that may restore muscle function and physical performance.	73–79

CAD, coronary artery disease; GDF-15, Growth differentiation factor-15; GH, growth hormone; HF, heart failure; HSP, heat-shock family of proteins; IGF-1, insulin-like growth factor-1; miRNAs, microRNAs; RAS, renin-angiotensin system; ROS, reactive oxygen species; TGF, transforming growth factor; TNF, tumour necrosis factor; UPS, ubiquitin-proteasome system.

2. Definition of frailty and sarcopenia

Frailty is defined as a geriatric syndrome characterized by reduced reserve and ability to cope with endogenous and exogenous stressors that lead to a cumulative impairment in response from multiple physiological systems, resulting in susceptibility and vulnerability to adverse outcomes.^1,9 Although a plethora of different methods has been applied to identify frailty in a cardiovascular disease setting,^9,10 the definition of frailty that has been widely used is based on the physical frailty phenotype, which includes parameters of unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low level of physical activity.¹ The diagnosis of frailty is confirmed when patients meet ≥ 3 criteria, while pre-frailty is identified as the presence of only one or two of the aforementioned criteria. Other models based on a multidimensional approach including functional, psychological, cognitive, and social components have been developed to overcome a simplified physical approach to frailty.^10–12 To encompass all the physiological systems that frailty can affect, the Heart Failure Association of the European Society of Cardiology recently proposed an integral conceptual model of frailty in patients with HF based on four domains: clinical, physical-functional, psycho-cognitive, and social (right circle in Figure 1).⁹ On the other hand, the validity and reliability of frailty assessment tools are highly dependent on the setting and population in which they are developed and validated,⁸⁰ and frailty assessment in critically ill patients, in particular, poses special challenges. During critical illness, there is often a reliance on proxy responders, and proxy assessments do not necessarily correspond to the patient's own evaluation of his or her functioning and quality of life.⁸¹ Frailty itself is also an independent risk factor for delirium, which can coexist with cognitive impairment and is associated with disability.^82,83 Furthermore, there is an inherent risk of mistakenly attributing features of acute illness to underlying frailty. Challenges such as these inherent in the assessment of frailty in critically ill patients raise the need for further research on the feasibility and reliability of frailty assessment tools.

Figure 1

Comprehensive conceptual framework of frailty and sarcopenia. ADL, activities of daily living; ASM, appendicular skeletal muscle mass; SARC-F, strength, assistance walking, rise from a chair, climb stairs, and falls; SPPB, short physical performance battery; TUG, Timed-Up and Go test.

Sarcopenia is characterized by a global and progressive decline in muscle strength, skeletal muscle mass, and physical performance (left circle in Figure 1), often associated with increased risk of falls, physical disability, hospitalization, comorbidities, and premature death.^84–86 In patients with HF, sarcopenia is prevalent in 19.5–47.3% of patients^87–89 and associated with reduced bone mineral density, exercise capacity,^87,90–92 endothelial dysfunction,⁹³ and independently with poor survival.⁹⁴ Prevalence values appear to be similar in patients with HF with preserved and reduced ejection fraction. Since 2016, sarcopenia has also been recognized as a disease and received an ICD-10 code (M62.84).⁹⁵ This recognition has led to an increased awareness of sarcopenia with better screening and diagnostic tools as well as more interest from pharmaceutical companies in the development of new compounds to prevent and treat sarcopenia. Nonetheless, it is worth mentioning that a consensus about the definition of sarcopenia (e.g. methods, cut-off values, and adjustments used to determine the reduction in skeletal muscle mass and impaired muscle function) has not been met yet.⁹⁶

In 1998, Baumgartner and colleagues proposed the first method to assess sarcopenia based on the sum of appendicular skeletal muscle mass (ASM) in both arms and legs divided by the height in metres squared (ASM/height²).⁹⁷ Although, in accordance with the revised definition from the European Working Group on Sarcopenia in Older People (EWGSOP 2), muscle strength moved up as the first criterion to screen for sarcopenia with grip strength < 27 kg for men and grip strength < 16 kg for women, ASM/height² is still used to confirm the diagnosis of sarcopenia (i.e. ASM/height² ≤ 7.0 kg/m² and ≤5.5 kg/m² for men and women, respectively).⁸⁴ In addition, physical performance assessed by gait speed (≤0.8 m/s), the short physical performance battery (SPPB ≤ 8 point score) test, the Timed-Up and Go test (TUG ≥ 20 s), or the 400 m walk test (≥6 min for completion) can be applied to determine the severity of sarcopenia.⁸⁴ However, other authors proposed adjustments for skeletal muscle mass by total body mass,⁹⁸ by body mass index (BMI),⁹⁹ and by total fat mass¹⁰⁰ with the aim to overcome limitations in the equation proposed by Baumgartner and colleagues that underestimated body fat mass, limiting its applicability in patients with combined sarcopenia and obesity, which has lately been termed sarcopenic obesity.¹⁰¹ In patients with chronic HF, a recent study has demonstrated that detecting sarcopenia with three different methods to correct the reduction in skeletal muscle mass (ASM/height² vs. ASM/total body fat vs. ASM/BMI) confirmed earlier prevalence values of sarcopenia around 21% across all methods regardless of BMI.¹⁰² Thus, the methods adjusting ASM for fat mass and BMI may be better to detect sarcopenia in obese patients than Baumgartner’s method with ASM adjusted for height, showing that obese patients can be as affected by sarcopenia as lean patients when appropriate indices are applied.

The methods used to identify frailty and sarcopenia are still evolving to determine precise cut-points for parameters assessed in each condition. Some authors have also described sarcopenia as the central biological substrate for frailty, suggesting that the two conditions should be merged into a new clinical entity, called physical frailty and sarcopenia.¹⁰³ Although there is a complex and multidimensional overlap between sarcopenia and frailty (Figure 1), there are gender differences in the contribution of sarcopenia to the frailty phenotype, and not all frail patients develop sarcopenia.^104,105 Therefore, future studies should focus on applying accurate methods to classify as well as define the border between frailty and sarcopenia in patients with cardiac disease.

3. Involvement of frailty and sarcopenia in cardiac disease

The incidence of cardiovascular disease increases significantly with age, which coincides with changes in functional capacity and body composition due to the ageing process and progressing disease states. Moreover, the improved management of risk factors for cardiovascular disease as well as improved survival in patients with HF and CAD are leading to a longer life expectancy that modified the clinical profile of these patients towards more cumulative age-related conditions. Therefore, all patients with cardiac disease should be screened for frailty and sarcopenia regardless of chronological age.

Comorbidities, such as diabetes mellitus, hypertension, and other conventional risk factors for cardiovascular disease, are frequently associated with frailty in older adults, suggesting that there may be a shared pathophysiological mechanism possibly due to increased inflammation and metabolic dysregulation that can lead to a higher risk of cardiac disease in frail individuals. Indeed, frailty has been independently associated with the risk of developing peripheral vascular disease, acute myocardial infarction, CAD, and HF in the general population,^13,14 suggesting that frailty, and even pre-frailty, can be recognized as risk factors for cardiovascular disease.^106,107 The prevalence of frailty can reach up to 50–75% in patients with HF depending on the assessment tool used,^108,109 whereas the prevalence of frailty in patients with CAD is around 25%.¹¹⁰ Additionally, sarcopenia has been implicated as both cause and consequence of diabetes mellitus,¹¹¹ associated with cognitive impairment and depression,^112,113 and associated with an increased risk for ischaemic heart disease.^15,16 As may be noted, both frailty and sarcopenia are emerging as risk factors of cardiovascular disease and, due to their interweaving relationship, both conditions, associated or not, play an important role in the development of cardiac disease.

In patients with HF, a recent study comparing sex differences in prevalence and prognostic impact of both conditions showed that frailty was somewhat more prevalent in women (i.e. 61% vs. 54%) and sarcopenia had a higher prevalence in men (i.e. 24% vs. 14%), whereas frailty was associated with 1-year mortality only in men, and sarcopenia was associated with 1-year mortality in both sexes.¹¹⁴ Moreover, elderly patients with HF with preserved ejection fraction (HFpEF) showed a higher prevalence of frailty than patients with HF with reduced ejection fraction (HFrEF) (55% vs. 47%).¹¹⁵ Most of the differences between HFpEF and HFrEF were driven by deficits in the physical-functional domains such as handgrip strength (71.4% vs. 52.1%) and gait speed (82.6% vs. 65.2%), whereas no differences were detected in social and cognitive impairment.¹¹⁵ Thus, considering that women have a higher life expectancy, frailty, a condition strongly associated with age, may affect more women than men, whereas sarcopenia should be watched closer in males taking into account that sarcopenia can be an initial sign of alterations in the physical and functional component of frailty in patients with cardiac disease.

Although frailty may be characterized by a decline in reserve and response from many physiological systems to biological stressors, it has been shown that frailty is predominantly associated with left ventricular hypertrophy and impaired left ventricular systolic and diastolic function after accounting for abnormalities in other organ systems.¹¹⁶ Moreover, a SARC-F (Strength, Assistance walking, Rise from a chair, Climb stairs, and Falls) score ≥ 4 was associated with diastolic dysfunction accompanied by increased markers of inflammation in community-dwelling older adults.¹¹⁷ Indeed, there is an extremely strong connection between frailty, sarcopenia, and cardiac disease with a common pathophysiological mechanism that seems to be linked to increased circulating pro-inflammatory cytokines described across all these conditions.¹¹⁸ Below, we elaborate on several of the possible mechanisms that may explain the interplay among frailty, sarcopenia, and especially HF.

4. Biological mechanisms of frailty and sarcopenia

The pathophysiology of frailty and sarcopenia is inextricably involved with ageing, which is characterized by an inevitable time-dependent decline in physiological function. The hallmarks of ageing are classified into three main categories. Primary hallmarks: damage to cellular functions, such as genomic instability, telomere loss, epigenetic changes, and loss of proteostasis. Antagonistic hallmarks: metabolic responses to the primary hallmarks of ageing, include deregulated nutrient sensing, altered mitochondrial function, and cellular senescence. Integrative hallmarks: the physiological consequences of the primary and antagonistic hallmarks of ageing, ultimately resulting in age-related functional decline, which is mainly characterized by stem cell exhaustion and altered intercellular communication.¹¹⁹ These hallmarks of ageing contribute robustly to reduced physical performance and loss of reserve capacity. Environmental factors may also cause or exacerbate many of these mechanisms that may be triggers of frailty and sarcopenia.¹²⁰ At the same time, the pathophysiology described above may be closely associated with the development and/or exacerbation of cardiac disease (Table 2).^{7,27,28,37,121–124} Furthermore, the combination of cardiac disease and geriatric syndromes can exacerbate one another and worsen prognosis significantly,^7,121 making it crucial to comprehend the pathophysiology underlying these conditions in greater depth. The following overview provides possible biological mechanisms of frailty and sarcopenia based on well-established hallmarks of ageing, addressing their relevance to the pathogenesis of HF with recent findings.

Table 2

Shared biological mechanisms between frailty, sarcopenia, and HF

Biological mechanisms	Changes in vivo	Contribution to the pathogenesis of HF	References
Mitochondrial dysfunction	↑ ROS ↓ ATP	Dysfunctional mitochondria increase ROS production, causing a mismatch between ATP production and demand, which can result in cardiac remodelling, inflammation, and diastolic dysfunction.	122,125–127
Oxidative damage	↑ mtDNA damage	Oxidative damage contributes to the severity of HF by causing intracellular Ca2+ overload in cardiac myocytes, cardiac hypertrophy, apoptosis, and endothelial dysfunction.	44–46,125
Increased protein degradation	↑ UPS (MuRF-1 and MAFbx) ↓ Autophagy	MuRF-1 and MAFbx are associated with impaired cardiac contractility under the regulation of TNF. Autophagy impairment leads to the accumulation of abnormal proteins, resulting in cardiac hypertrophy, left ventricular dilatation, and contractile dysfunction.	27,28,123,128–130
Hormonal changes	↓ GH/IGF-1 ↓ Testosterone ↑ RAS ↑ GDF-15	Low GH, IGF-1, and testosterone levels are associated with impaired cardiac performance and exercise capacity in HF patients. Enhanced RAS activity advances cardiac dysfunction/remodelling. GDF-15 is expressed in myocytes in response to myocardial ischaemia and pressure overload.	37,40,59,131–138
Inflammation	↑ IL-1, IL-6, TNF ↑ NF-κB ↑ UPS	HF patients have chronic low-grade systemic inflammation. Inflammation promotes cardiac dysfunction/remodelling and exacerbates HF itself.	55,57,58,139–143

All these mechanisms up-regulate frailty and sarcopenia.

ATP, Adenosine triphosphate; GDF-15, Growth differentiation factor-15; GH, growth hormone; HF, heart failure; IGF-1, insulin-like growth factor-1; IL, interleukin; mtDNA, mitochondrial DNA; MuRF-1, muscle; NF-κB, nuclear factor-kappa B; RAS, renin-angiotensin system; TNF, tumour necrosis factor; UPS, ubiquitin-proteasome system.

4.1 Genomic instability

The integrity and stability of human DNA are always exposed to exogenous stressors, such as radiation and chemicals, and endogenous agents, including DNA replication errors, spontaneous hydrolysis reactions, and reactive oxygen species (ROS).¹⁴⁴ The genetic lesions arising from mutagens vary extensively—small point mutations, translocations, chromosome gains, and breaks, telomere shortening, etc.—the organism has developed a complex network of DNA repair mechanisms that can fix most of these damages inflicted on DNA.¹⁴⁵ However, some lesions are eventually not fully repaired, allowing DNA damage and mutations to accumulate over time. This is why genomic instability is a major hallmark of ageing, and genomic instability has been reported to be involved in a variety of ageing-related cardiovascular and neurodegenerative diseases.^146,147 Skeletal muscle development and regeneration are regulated by skeletal muscle stem cells, called satellite cells (SCs).¹⁴⁸ Therefore, the maintenance of satellite cell genomic integrity is a critical process directly related to the organization of skeletal muscle tissue. However, with ageing, DNA damage protection and repair systems begin to fail, and passenger mutations accumulate throughout the genome of SCs, leading to reduced replication capacity and ultimately to skeletal muscle defects. Taken together, a causal relationship between genomic instability and sarcopenia is expected; however, the ageing process in skeletal muscle is extremely complex, making a causal relationship with genomic instability difficult to clarify. Nevertheless, some evidence links genomic instability to sarcopenia and frailty: Higher levels of 8-oxo-7,8-dihydroguanine (8-oxoG), a key marker of DNA damage, in the vastus lateralis were observed in elderly compared to younger subjects.¹⁷ Sedentary older adults were also identified to have higher levels of 8-oxoG than those who were more active.¹⁷ Moreover, Sánchez-Flores et al.¹⁸ revealed that genomic instability, as assessed by lymphocyte micronucleus frequencies, was associated with frailty in the elderly. These findings are intriguing because they not only indicate that DNA instability, a hallmark of ageing, may be involved in the development of sarcopenia and frailty but also suggest a possible gene-protective effect of physical activity.

4.2 Telomere attrition

Telomeres are gene-poor nuclear protein structures located at the ends of linear chromosomes that shorten with age,^149,150 and are associated not only with cellular ageing but also with many age-related diseases, including cancer, diabetes, and HF.^19,151 In addition, telomere length is associated with disease severity in HF.¹⁹ Therefore, telomere length is widely considered a possible senescence biomarker, although it is still not fully elucidated whether telomere shortening is a cause or a consequence of physiological ageing or age-related diseases. The clinical significance of telomere shortening in sarcopenia and frailty has also been much discussed but still remains inconclusive. Based on nine articles that examined the association between telomere length of leucocytes and sarcopenia and frailty, Lorenzi et al.²⁰ reported that there might be a correlation between telomere length and skeletal muscle mass, but not with muscle strength or frailty. Yet, since then, several findings have also contradicted this report.^21,22 Such inconsistencies may be due not only to the fact that telomere length measured in peripheral blood not accurately reflecting that of skeletal muscle but may also imply that only a single biomarker of telomere shortening, caused by a variety of factors including oxidative stress, inflammation, and repeated cell replication, is insufficient to explain the extreme diversity of pathophysiology underlying the development of sarcopenia and frailty.

4.3 Epigenetic alterations

Epigenetics is defined as the study of mechanisms that can alter gene expression irrespective of changes in the DNA sequence,¹⁵² including DNA methylation, microRNAs (miRNAs), and histone modifications.¹⁵³ These epigenetic mechanisms are influenced by environmental factors and play a part in the adaptive homeostasis of the organism. There is considerable evidence implying that epigenetic changes underlie age-related cellular deterioration,¹⁵⁴ and Pal and Tyler¹⁵⁵ mentioned that reduced bulk levels of the core histones, altered patterns of histone post-translational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered non-coding RNA expression, are the characteristics of the aforementioned changes. DNA methylation has been identified as a possible biomarker of ageing that predicts the age of human cells and tissues, irrespective of health conditions, lifestyle, and other known genetic factors.^156,157 Histone demethylases also regulate lifespan by targeting components such as the insulin/insulin-like growth factor-1 (IGF-1) signalling pathway.¹⁵⁸ Moreover, miRNAs are involved in the regulation of insulin/IGF-1 and mammalian target of rapamycin (mTOR) signalling pathways, and their conserved role in ageing is well established.^159,160 As can be seen from these findings, epigenetic alterations are one hallmark of ageing, whereas it has also been suggested that they are closely related to the degree of frailty and the development of sarcopenia. Some studies have demonstrated that frail individuals have lower levels of global DNA methylation than non-frail individuals and that methylation patterns and miRNA species could be involved in age-related impairment of skeletal muscle function.^23,24 Although the causal relationship between changes in epigenetic patterns during the lifespan and the development of age-related diseases is still unclear, advances in this area of research should lead to a better understanding of the biological mechanisms of frailty in the elderly.

4.4 Loss of proteostasis

Proteostasis is a collection of cellular mechanisms involved in the maintenance of human protein homeostasis.¹⁶¹ Proteostasis fidelity is maintained by a proteostasis network consisting of chaperone-mediated folding, proteasomal degradation, and autophagy. All of these systems function in concert to repair the structure of misfolded polypeptides, degrading and removing them, preventing the accumulation of dysfunctional intracellular proteins, and ensuring the maintenance of proteome integrity.¹¹⁹ Many studies have demonstrated that deterioration of proteostasis with ageing results in misfolded protein aggregates and inclusions in tissues of the aged organisms, contributing to the development of age-related diseases such as Alzheimer's disease, Parkinson's disease, and cataracts.¹⁶² Similarly, skeletal muscle proteostasis impairment contributes significantly to the progression of muscle atrophy in sarcopenia.

Molecular chaperones are small proteins that bind to polypeptide chains in an unfolded, denatured state and assist in their folding into the proper protein structure and acquisition of normal function.¹⁶³ Chaperone synthesis is severely impaired with ageing,¹⁶⁴ and the most important molecular chaperones are the heat-shock family of proteins (HSP). In mammalian animals, the transcription factor heat shock factor 1 (HSF-1) is considered the master regulator of the heat shock response, and deacetylation of HSF-1 by Sirtuin-1 (SIRT-1) is known to potentiate the transcriptional activity of heat shock genes such as Hsp70.¹⁶⁵ Meanwhile, pharmacological induction of the Hsp72, an inducible member of the Hsp70, preserved muscle function and slowed the progression of dystrophic pathology in mice models of Duchenne muscular dystrophy.²⁵ In experiments using treadmill running, Hsp70 was induced in the vastus lateralis in an exercise intensity-dependent manner.²⁶ Activation of SIRT-1 and/or inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) have also been demonstrated to improve skeletal muscle mitochondrial biogenesis and performance in ageing mice.¹⁶⁶ Up-regulation of molecular chaperones may therefore be a promising intervention to improve skeletal muscle performance in conditions such as age-related muscle atrophy and sarcopenia.

Increased protein degradation has been recognized as one of the possible mechanisms of skeletal muscle atrophy, with the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system mainly regulating intracellular protein degradation in skeletal muscle cells (Figure 2).¹²⁸ The degradation process is activated primarily by the p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, as well as the glucocorticoid pathway.^167,168 p38 MAPK activates the expression of a group of enzymes called muscle-specific E3 ubiquitin ligases, such as muscle RING-finger protein-1 (MuRF-1) and muscle atrophy F-Box (MAFbx), which mediate proteolysis by UPS,^129,169 and elevated levels of these ubiquitin ligases are associated with muscle atrophy.¹³⁰ Meanwhile, MuRF-1 and proteasome activity are elevated in the diaphragm and quadriceps of rats with chronic HF.²⁷ Also, MuRF-1 and MAFbx are regulated by tumour necrosis factor (TNF) and associated with impaired cardiac contractility in chronic HF patients.²⁸ These findings suggest that UPS may be one of the shared biological mechanisms in sarcopenia and HF. The transcription factor, NF-κB is activated by oxidative stress and inflammatory cytokines such as TNF,¹⁷⁰ and its role in skeletal muscle atrophy is revealed by its ability to activate MuRF-1 expression.¹⁷¹ Activation of NF-κB in the muscle-specific transgenic expression of activated IkappaB kinase (IKK)-β mice caused marked muscle wasting due to accelerated proteolysis mediated by overexpression of MuRF-1, whereas pharmacological or genetic inhibition of the IKK-β/NF-κB/MuRF-1 pathway reversed muscle atrophy.¹⁷¹

Figure 2

Alterations in skeletal muscle metabolism with ageing and molecular mechanisms of frailty and sarcopenia. Bnip3, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3; FOXO, forkhead box; GSK3, glycogen synthase kinase 3; IGF-1, insulin-like growth factor-1; KLF15, Krüppel-like factor 15; LC3, light chain 3; MAFbx, muscle atrophy F-Box; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex-1; MuRF-1, RING-finger protein-1; NF-κB, nuclear factor-kappa B; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha; PI3-K/Akt, Phosphoinositide 3-kinase/protein kinase B; Smad, suppressor of mothers against decapentaplegic; UPS, ubiquitin-proteasome system.

The glucocorticoid pathway is another major pathway of protein catabolism. The forkhead box (FOXO) family of transcription factors that regulate genes involved in cellular processes such as cell cycle, apoptosis, and metabolism are elevated at gene expression levels in response to glucocorticoid treatment.^172,173 Activated FOXO transcription factors up-regulate MuRF-1 and MAFbx to exert skeletal muscle catabolic effects.^174,175 Glucocorticoids also induce transcription and stability of myostatin,¹⁷⁶ a member of the transforming growth factor (TGF)-β family and a central negative regulator of muscle growth that inhibits protein synthesis by activating suppressor of mothers against decapentaplegic (Smad) proteins (Figure 2),^177,178 thereby further pronouncing proteolysis. Furthermore, glucocorticoids regulate MAFbx and MuRF-1 expression via a transcription factor known as Krüppel-like factor 15 (KLF15).¹⁷⁹ Ligand-bound glucocorticoid receptors induce transcription of KLF15, which interacts with KLF15-responsive elements in the promoter regions of MAFbx and MURF1 and induces their expression.¹⁷⁹ KLF15 also triggers activation of MuRF-1 and MAFbx via stimulation of FOXO1 and FOXO3a expression. Taken together, the glucocorticoid pathway activates MAFbx and MuRF1 through a network of transcription factors, including the FOXO family and KLF15, which ultimately regulate muscle atrophy.^179,180 Thus, UPS is a fundamental mechanism for protein degradation, but there is conflicting evidence for the role of UPS in ageing and sarcopenia. The expression levels of MAFbx and MuRF-1 in aged muscles have shown inconsistent results across studies, with an increase, no change, or even a decrease.^29–31 Because even muscle hypertrophy increases both protein degradation and synthesis, the role of UPS in ageing and sarcopenia needs to be further elucidated, and the present data appear to suggest that other proteolytic pathways besides UPS play a more important role in protein degradation in these pathologies.

The autophagy-lysosome system is another major regulator of proteolysis. Removal of dysfunctional organelles and misfolded proteins by lysosomes plays a pivotal role in maintaining cell and tissue homeostasis.¹⁸¹ Age-related decline of this system is expected to be caused by decreased expression of autophagy-related genes,³² reduced levels of autophagy core components,¹⁸² and sustained mammalian target of rapamycin complex-1 (mTORC1) signalling, a well-established autophagy inhibitor.¹⁸³ Autophagy is likewise important for the regulation of SCs,¹⁸⁴ and age-related decline of autophagy function not only reduces the clearance of damaged and dysfunctional proteins but also leads to loss of SCs function, resulting in skeletal muscle loss from dysfunctional myogenesis.³³ Furthermore, autophagy inhibition in autophagy-related 7 (Atg7) knockout mice induces up-regulation of MuRF-1 and MAFbx, accompanied by loss of myofibre size.¹⁸⁵ This may explain the potential contribution of age-related blunting of lysosomal activity to sarcopenia, accompanied by a compensatory increase in proteolysis by the UPS.

On the other hand, a recent study suggests that general control non-depressible 2 (GCN2)/eukaryotic translation initiation factor 2A (eIF2A) signalling up-regulates autophagy in response to short-term deficiency of single essential amino acid, indicating that this pathway may contribute to cell survival and adaptation by regulating protein homeostasis under nutritional stress conditions.¹⁸⁶ Some autophagy-related markers can be elevated in skeletal muscle cells in the catabolic state,³⁴ and FOXO3 has been established as an important transcription factor that activates autophagy by regulating the expression of many autophagy-related genes, including microtubule-associated protein light chain 3 (LC3) and Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (Bnip3).¹⁸⁷ Therefore, autophagy dysfunction, i.e. both under- and over-activation can contribute to the development of sarcopenia. Several effects of autophagy dysfunction on myocardium have also been reported; inhibition of autophagy in cardiomyocytes by autophagy-related 5 (Atg5) deletion induces hypertrophy, left ventricular dilatation, and contractile dysfunction.³⁵ Administration of the autophagy inhibitor bafilomycin A1 to mice causes marked cardiac dysfunction and left ventricular dilatation in starved mice.³⁶

4.5 Deregulated nutrient sensing

The nutrient-sensing pathway is responsible for regulating protein levels by controlling both protein production and degradation. Various anabolic and neurohormonal hormones are involved in protein metabolism, especially anabolic hormones such as insulin, growth hormone (GH), and its secondary mediator IGF-1, which play a pivotal role in protein synthesis and muscle growth.¹⁸⁸ IGF-1 binding to transmembrane tyrosine kinase receptors on myocyte membranes activates the Phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) pathway, which promotes protein synthesis and muscle hypertrophy by inhibiting glycogen synthase kinase 3 (GSK3) and activation of mTORC1 (Figure 2).¹⁸⁹ In addition, activated PI3K/Akt phosphorylates and inactivates the downstream transcription factors FOXO, preventing protein degradation in skeletal muscle by suppressing MuRF-1 and MAFbx gene expression.¹⁷⁵ Intriguingly, the FOXO transcription factors not only regulate transcription of MuRF-1 and MAFbx, which induce proteolysis by UPS, but also regulate transcription of core components such as Bnip3, which promotes the autophagy-lysosome system,¹⁸⁷ whilst myostatin reverses the PI3K/Akt pathway by inhibiting Akt-phosphorylation and induces atrophy-related genes by increasing FOXO1 expression.¹⁹⁰ Therefore, inhibition of the FOXO transcription factors, which play a crucial role in the development of skeletal muscle proteolysis, is a fascinating approach to sarcopenia, and it was recently reported that vitamin D not only suppresses the transcriptional activity of FOXO1 in myoblasts but also the gene expression of ubiquitin ligase and lysosomal proteolytic enzymes.¹⁹¹ On the other hand, the association of declines in anabolic hormones such as GH, IGF-1, and androgens with sarcopenia and frailty has been widely examined, and the replacement of these anabolic hormones has attracted much interest as a treatment for these pathologies.^{38,39,192,193} Low GH, IGF-1, and testosterone levels are also associated with impaired cardiac performance and exercise capacity in HF patients.^37,40 However, the uncertainty of efficacy, the need for continuous administration, and its side effects, unfortunately, make its practical application controversial.

4.6 Mitochondrial dysfunction

Mitochondrial dysfunction is a common feature of various aspects of ageing, and reduced mitochondrial energy metabolism is associated with the development of various age-related metabolic diseases, including HF.^41,42 A key regulator of mitochondrial biogenesis is the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α),¹⁹⁴ which is modulated by various regulators including AMP-activated protein kinase (AMPK), mTOR, SIRT-1, Akt, and GSK3β.¹⁹⁵ On the other hand, PGC-1α suppresses the transcription factor Foxo3 and prevents proteolysis by controlling UPS (Figure 2).¹⁹⁶ Whilst PGC-1α levels in skeletal muscle decline dramatically with age,¹⁹⁵ there is consensus that exercise increases PGC-1α expression in skeletal muscle through the AMPK-SIRT-1 signalling pathway among others.^197,198 Moreover, in experimental models of HF, mitochondrial dysfunction in cardiac and skeletal muscle has been demonstrated to be associated with lower levels of PGC-1α expression.¹⁹⁹ In light of these findings, PGC-1α may hold promise as a target for preventing the development of sarcopenia and HF through the regulation of mitochondrial biosynthesis.

ROS are generated primarily in mitochondria as a by-product of the electron transfer chain and increase as the organism ages, contributing to mitochondrial degradation and cellular senescence.⁴³ Mitochondrial DNA (mtDNA) is located next to the ROS generator and is more transcriptionally active than nuclear DNA, rendering it more prone to damage than nuclear DNA and a major target for ROS.¹²⁵ Myocytes are inherently susceptible to mitochondria-derived ROS injury because they account for a large proportion of total oxygen consumption in the organism.²⁰⁰ Furthermore, skeletal muscle is composed of post-mitotic cells, making it one of the tissues particularly susceptible to oxidative damage, along with the central nervous system.²⁰¹ It is well known that ROS production is increased in dysfunctional mitochondria of aged muscle.¹²⁶ The accumulation of oxidative stress with ageing alters excitation-contraction coupling and calcium homeostasis in skeletal muscle, causing fibre loss via apoptosis, atrophy of remaining fibres, dysfunction of SCs, and concomitant impairment of muscle degeneration or muscle regeneration, which may eventually lead to sarcopenia.^202,203 Increased ROS production by dysfunctional mitochondria causes a mismatch between ATP production and demand, which can also lead to cardiac remodelling, inflammation, and diastolic dysfunction.^122,127 Moreover, oxidative stress is enhanced in patients with HF, contributing to disease severity and exercise intolerance by causing intracellular Ca²⁺ overload in cardiac myocytes, hypertrophy, apoptosis, and endothelial dysfunction.^44–46 However, against the so-called ‘mitochondrial free radical theory’ described above,⁴³ evidence is also accumulating in the field of intracellular signal transduction regarding the role of ROS in triggering cell proliferation and survival signals in response to physiological signals and stress conditions.^47–49 Recently, Viña et al.²⁰⁴ proposed a ‘free radical theory of frailty’ in which oxidative damage is associated with frailty rather than chronological age, especially in the elderly. Thus, elucidating the details of the role of mitochondrial dysfunction and ROS in ageing remains a significant challenge in ageing research.

4.7 Cellular senescence and stem cell exhaustion

Cellular senescence, defined as the stable arrest of the cell cycle and the concomitant change in canonical phenotype,²⁰⁵ is caused by telomere shortening,²⁰⁶ but several pathways have been implicated in the road to senescence independently of this process. Most prominent among them are the DNA damage response pathways, with the p16^INK4a/Rb and p19^ARF/p53 tumour suppressor pathways appearing to be crucial in age-related senescence.²⁰⁷ Both p16INK4a and p19ARF are encoded at the same genomic locus, the INK4a/ARF locus, which has been identified as the genomic locus most genetically associated with age-related conditions such as frailty, diabetes, and CAD.^50,51,208 Actually, selective removal of INK4a-expressing senescent cells can delay the onset or even halt the progression of age-related diseases in mice.²⁰⁹ Senescent cells are usually eliminated by immune surveillance but accumulate with age.²¹⁰ Whilst cyclin-dependent kinase (CKD) inhibitors such as p16 and p21, tumour suppressor proteins expressed in senescent cells prevent potential cancer cells from proliferating by arresting the cell cycle,²¹¹ senescent cells may also disrupt tissue integrity and make its repair difficult.²¹² As such, excessive senescent cell accumulation plays a crucial role in driving tissue senescence, which contributes to the development of several age-related pathologies such as frailty and sarcopenia.⁵² In addition, senescent cells form what is termed the senescence-associated secretory phenotype (SASP) and secrete pro-inflammatory cytokines, chemokines, matrix-remodelling proteases, TGF-β, and ROS, all of which may contribute to the development of frailty and sarcopenia.^213,214 The SASP can also be induced locally in normal neighbouring cells via autocrine or paracrine mechanisms of senescent cells.²¹⁵ A Recent study in mice has also revealed a ‘bystander effect’ in which transplantation of senescent cells adjacent to normal skeletal muscle increases senescence markers in the muscle and induces thinning of muscle fibres indicative of sarcopenia.²¹⁶

The decline in the regenerative potential of tissues by stem cell exhaustion is one of the obvious features of ageing. While there is a study indicating that depletion of SCs impairs muscle regenerative capacity without affecting sarcopenia,⁵³ a number of studies have reported that exercise therapy, the most effective treatment for sarcopenia and frailty, protects SCs against exhaustion and increases their number and activity.^54,217,218 A better understanding of the role of senescent cells and SCs in sarcopenia and frailty will facilitate the realization of new therapeutic approaches to combat these pathologies.

4.8 Altered intercellular communication

The mechanisms discussed above address alterations at the cellular intrinsic level with ageing. However, ageing also leads to changes at the level of intercellular communication, including endocrine, neuroendocrine, and inflammatory signalling. Age-related chronic low-level inflammation is referred to as ‘inflamm-ageing’,²¹⁹ and several pro-inflammatory cytokines like interleukin (IL)-1, IL-6, and TNF are known to be elevated during the ageing process.²²⁰ Meanwhile, systemic inflammation is related to factors closely associated with physical frailty, such as loss of muscle mass, muscle strength, and bone mineral density, as well as many age-related diseases.^55,56,221 Elevated IL-1, IL-6, and TNF result in impaired protein synthesis from decreased IGF-1 and associated suppression of the PI3K/Akt pathway,²²² and down-regulation of Foxo3 phosphorylation.²²³ They also enhance mechanisms involved in protein catabolism, such as the p38 MAPK pathway,²²⁴ the NF-κB pathway,^140,141 the glucocorticoid pathway via activation of the hypothalamic-pituitary-adrenal (HPA) axis,²²⁵ and UPS via increased levels of E3 ubiquitin ligase,²²⁶ which in turn shifts skeletal muscle towards catabolism altogether (Figure 2). Furthermore, whilst there are some reports of no changes in any inflammatory cytokines in anorexic patients,^139,227 central or peripheral administration of IL-1β or TNF induces anorexia, which has an essential role in the development of cachexia.^228–230 Given the above findings, these pro-inflammatory cytokines have recently emerged as promising candidates for the screening and monitoring of sarcopenia and frailty. Meanwhile, patients with HF have chronic low-grade systemic inflammation, with elevated levels of the aforementioned inflammatory biomarkers involved in skeletal muscle wasting.^57,142,143 Chronic inflammation promotes cardiac dysfunction/remodelling, further exacerbating HF itself.⁵⁸ Therefore, inflammation may also be a shared pathogenesis contributing to the exacerbation of HF itself and the development of physical frailty in patients with HF.

As for the age-related neurohormonal changes, activation of the renin-angiotensin system (RAS) accelerates cellular senescence by inducing the uncontrolled generation of ROS, telomere shortening, and cell cycle arrest by angiotensin II (Ang II).^231–233 Whilst an enhanced RAS is well known to be found in HF patients, there is emerging evidence that it can contribute to muscle wasting through increased production of ROS and induction of TGF-β1 and connective tissue growth factor expression.⁵⁹ Recently, RAS inhibition was also demonstrated to be associated with a lower prevalence of muscle wasting in patients with HF.¹³¹

Growth differentiation factor-15 (GDF-15) is a stress-induced mitokine and not a hormone, but deserves mention here as a potential therapeutic target for frailty.¹³¹ This mitokine is a remote member of the TGF-β superfamily, mirrors inflammation and oxidative stress, and its elevated circulating levels have been identified in ageing, cancer, and cachexia, making it a powerful prognostic biomarker for these conditions.^132,133 GDF-15 is also expressed in myocytes in response to myocardial ischaemia and pressure overload,¹³⁴ and its elevated levels are associated with the severity and prognosis of acute coronary syndromes and chronic HF.^135,136 Furthermore, Bettencourt et al.¹³⁷ demonstrated that higher GDF-15 levels in acute HF were associated with worse prognosis independent of B-type natriuretic peptide (BNP) levels. Most recently, neutralization of GDF-15 with a rat model of monocrotaline-induced cardiac cachexia was reported to prevent anorexia and weight loss, indicating that inhibition of GDF-15 is a potential therapeutic strategy for cardiac cachexia.¹³⁸

4.9 Environmental factors

Frailty is thought to be initiated by a combination of multiple biological mechanisms as mentioned above, yet it can also be induced and exacerbated by a variety of environmental factors from birth onward. Smoking is a predictor of worsening frailty status among community-dwelling elderly people,²³⁴ with possible mechanisms including reduced DNA methylation levels, one of the major forms of epigenetic modification; inflammation induced by various chemicals in cigarettes; and smoking-induced complications such as cardiovascular disease, lung disease, and cancer that ultimately contribute to the development of frailty.^60,61 A good diet throughout the lifespan is critical for the maintenance of skeletal muscle, and poor dietary patterns have been implicated in the development of frailty through their effects on systemic inflammation, oxidative stress, and the composition of the gut microbiota.^62,63 Physical inactivity and sedentary behaviour also cause oxidative damage and chronic inflammation, mitochondrial dysfunction, decreased autophagy, and impaired IGF-1/mTOR signalling pathway, which are implicated in worsening frailty levels.^64,65 Exercise and nutritional therapy both improve the aforementioned drivers of frailty, respectively, but their combination would be more desirable.²³⁵ In the following section, we further provide recent promising treatments for frailty and sarcopenia, including exercise and nutritional therapy.

5. Treatment strategies for frailty and sarcopenia

Patients living with the clinical syndromes of frailty and sarcopenia endure an immense burden, with no particularly effective method available to slow their progression other than exercise training. Since disability is difficult to reverse in the elderly and is extremely devastating for individuals and societies, new strategies should be developed to preserve adequate levels of functional capacity and independence in late life and in chronic illness. The combination of exercise, nutrition, and pharmacological therapy may counteract the development and progression of sarcopenia and frailty.²³⁶ Here we describe the treatment strategies for sarcopenia and frailty in association with pathophysiological mechanisms (Figure 3).

Figure 3

Treatment strategies for frailty and sarcopenia. CAD, coronary artery disease; GDF-15, Growth differentiation factor-15; HF, heart failure.

5.1 Exercise

Physical exercise is now the most effective therapy for slowing the progress of sarcopenia and frailty. Precisely organized and supervised exercise training interventions aim at preventing muscle atrophy, promoting muscle growth, and ultimately, maintaining muscle functions during ageing. Beckwée et al.⁶⁶ reviewed the currently available exercise interventions for the prevention and treatment of sarcopenia using the method of a systematic umbrella review and provided high-quality evidence for the beneficial and significant effect of resistance training on functional capacity, muscle mass, and muscle strength. Given the fact that sarcopenia is omnipresent and is affecting all skeletal muscles in the body with the most functional consequences in the limbs, the authors recommend training that activates the large muscle groups in a total body approach.⁶⁶ Beneficial effects of resistance exercise training are explained through different physiological mechanisms and signalling pathways: vasodilation, antithrombotic effects, inhibition of oxidative stress, anti-inflammatory effects, mTORC1 activation, augmented mitochondrial biogenesis, elevated IGF-1/myostatin ratio, stimulation of peroxisomes, and enhanced insulin sensitivity.^237,238 The molecular biological changes with exercise interventions confirm that the skeletal muscle phenotype is subject to considerable adaptation and plasticity depending on use. Low-intensity training improves mitochondrial function and increases oxygen consumption, whereas high-intensity exercise leads to muscle proliferation and augmentation of contractile proteins.²³⁹ Exercise training stimulates transcriptional up-regulation of the genes involved in Ca²⁺ signalling via the AMPK pathway and influences skeletal myocytes' energy status.²³⁹

With regard to HF, data from multiple exercise intervention trials have shown that supervised exercise training is safe and useful to improve exercise capacity and quality of life in patients with HF, although it failed to reduce mortality and hospitalization rates.⁶⁷ In addition, albeit low-intensity resistance training (≤50% 1-repetition maximum) is sufficient to promote strength gains, high-intensity resistance training (i.e. 80% 1-repetition maximum) is recommended to obtain maximal strength gains, however, different approaches may be necessary for elderly geriatric patients and in patients with HF.

The Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT) project conducted a randomized controlled trial (RCT) to test a multicomponent intervention (MCI) specifically designed to prevent mobility disability in high-risk older people.²⁴⁰ SPRINTT was a phase III, multicentre RCT aimed at comparing the efficacy of MCI, which encompasses long-term structured physical activity, nutritional counselling, and communication technology intervention vs. a standardized healthy ageing lifestyle education programme, designed to prevent adverse outcomes and disability in more than 1500 frail elderly subjects. The primary endpoint of the SPIRINTT trial was mobility disability, defined as the inability to walk 400 m in <15 min, without sitting, help of another person, or the use of a walker. Secondary endpoints included changes in muscle mass and strength, persistent mobility disability, injury and falls, disability in activities of daily living, nutritional status, cognitive function, mood, the use of healthcare resources, cost-effectiveness analyses, quality of life, and the mortality rate. Recently published results of the SPRINTT trial demonstrated that the multicomponent intervention is associated with a reduction in the incidence of mobility disability in frail sarcopenic elderly subjects and an SPPB score of 3–7.⁶⁸ These results imply that physical frailty and sarcopenia can be targeted with multicomponent interventions in order to preserve mobility and functional capacity in vulnerable elderly subjects.⁶⁸ Naturally, there are limitations frequently faced when treating subjects with frailty, as subjects very often do not accept or cannot follow exercise interventions. Another limitation would be that despite the overwhelming proof of the health benefits of regular exercise, there is limited knowledge regarding the proper prescription of exercise regimens as well as predictors of individual responses to exercise interventions in the population of frail elderly. This primarily emanates from broad interindividual differences in the biological responses to exercise.²⁴¹

5.2 Nutrition

Malnutrition and anorexia are per se associated with adverse clinical outcomes. Malnutrition includes all forms of undernutrition (wasting, stunting, underweight), vitamin and mineral deficiencies, obesity, and resulting diet-related non-communicable diseases, whereas anorexia is common in elderly subjects and independently associated with sarcopenia.^242,243 Energy expenditure is reduced as a protective mechanism in malnutrition whereas it remains inappropriately high in sarcopenia and muscle wasting.⁶⁹ Also, increased resting energy expenditure (REE) has been shown in HF,⁷⁰ where a negative balance between energy demand and consumption promotes catabolism and leads to malnutrition, whilst REE in HF patients with muscle wasting is reported to be lower than in those without muscle wasting.²⁴⁴ Dietary deficiencies in micro- (‘nutraceuticals’) and macronutrients (energy storage and substrates) contribute to the progression of a catabolic state in sarcopenia, frailty, and HF. Certainly, deficiency in micronutrients (vitamins and minerals, e.g. vitamin D or iron) impairs muscle physiology.^245,246 Vitamin D deficiency is common in patients with HF and not only exacerbates the pathogenesis of HF by enhancing renin-angiotensin system activity, altering calcium influx, and causing inflammation and endothelial dysfunction but is also associated with reduced muscle mass and impaired physical performance in the elderly with or without HF.²⁴⁷ Thus, vitamin D supplementation could be an attractive strategy for the management of sarcopenia in the setting of HF.²⁴⁸

There is emerging evidence on the pathophysiology of skeletal muscle and nutritional interventions. Adequate nutrition improves muscle function, contributes to muscle anabolism, and regulates muscle protein synthesis, glucose and insulin homeostasis, and neuromuscular and microvascular function.²⁴⁹ Moreover, nutritional interventions regulate nutrient sensing, improve mitochondrial function, and cross-talk between muscle and the immune system.²⁴⁹ While both exercise and nutritional interventions serve as anabolic stimuli to skeletal myocytes, when these strategies are combined, additive effects on muscle mass and function are observed, especially using protein supplantation and resistance training.²⁵⁰

Dietary protein is one of the most important components for frail elderly and HF patients with regard to muscle structure and function as well as to anabolic–catabolic balance.⁷¹ Upon protein intake, essential amino acids (e.g. leucine) exert strong anabolic effects via activation of muscle intracellular signalling pathways that culminate in increased efficiency of mRNA translation and muscle protein synthesis.²⁵¹ Therefore, high protein intake is generally recommended in elderly patients with sarcopenia and patients with HF, but special attention needs to consider chronic kidney disease, which frequently coexists with these conditions.⁷² Additionally, omega-3 polyunsaturated fatty acids could be an alternative anti-sarcopenic therapeutic agent, due to their anti-inflammatory properties.²⁵² Furthermore, SPRINTT trial has shown that multicomponent intervention, based on physical activity and nutritional counselling has various beneficial effects in preserving mobility in older people.⁶⁸

As such, nutritional interventions for patients with sarcopenia and frailty could prevent or ameliorate adverse events associated with these conditions but should be taken into account with the patient's current body weight and comorbidities. Despite being central in treating frailty, nutritional interventions have several important limitations. Common challenges and limitations of dietary interventions comprise the complex nature of food and nutrient interactions, lack of blinding of the treatments, low compliance, high susceptibility to confounding variables (e.g. ethnicity, genotype, and physiological state), diverse dietary behaviours as well as food culture.²⁵³

5.3 Drug therapy

The management of sarcopenia is primarily focused on physical exercise for muscle strengthening, supported by nutritional interventions. There are no pharmacologic agents approved worldwide for the treatment of sarcopenia. However, treating the underlying comorbidities, such as HF, cancer, chronic obstructive pulmonary disease, chronic kidney disease, or dementia may exert beneficial effects on sarcopenia via multiple biological pathways and cross-talks. Some of the potential pharmacological interventions that had been widely studied pre-clinically are hormonal treatment and myostatin inhibition. Hormonal treatment embraces testosterone application, GH, ghrelin, insulin, and thyroid hormones.²³⁶ Due to its well-known metabolic, anabolic, and peripheral effects, testosterone replacement therapy has been considered as a potential anti-sarcopenic therapy. Randomized controlled trials have demonstrated that testosterone therapy could moderately improve functional capacity and muscle function in sarcopenic HF patients.⁷³ However, given the various androgen side effects, including the risk of prostatic hyperplasia, large-scale trials are needed to confirm the efficacy and safety of testosterone application. GH replacement therapy could pre-clinically ameliorate muscle wasting through anabolic, anti-inflammatory, and antioxidant effects.⁷⁴ However, the clinical effectiveness of GH has not been confirmed yet. Due to its beneficial effects on appetite and gastric motility, ghrelin may be a promising therapeutic target for sarcopenia. Its effectiveness has been shown in animal models as well as in a clinical study, which demonstrated that ghrelin administration could improve functional capacity, muscle strength, and mass as well as left ventricular ejection fraction in sarcopenic HF patients.⁷⁵ Insulin stimulates muscle protein synthesis by increasing amino acid delivery and intramuscular blood flow.⁷⁶ However, a large-scale clinical study displayed that insulin therapy might be associated with worse outcomes in patients with chronic HF and diabetes.²⁵⁴ Thyroid hormone is an essential metabolic regulator, whose major target is skeletal myocytes. It has been shown that overt and latent thyroid dysfunction has been associated with muscle wasting and reduced muscle function.²⁵⁵ Over the past decade, myostatin has been a primary pharmacological target in sarcopenia. Myostatin is an extracellular cytokine and a member of the TGF-β family, and it is highly expressed in skeletal myocytes.²⁵⁶ The results of several trials with myostatin inhibitors were disappointing, and there was only limited therapeutical effectiveness. However, a study with bimagrumab in sarcopenic elderly subjects has shown beneficial effects and improved functional capacity and independence.⁷⁷

Currently, a new star in the field is certainly GDF-15, which is important in muscle pathophysiology and has been described as a global regulator of stress. Contemporary evidence suggests that GDF-15 is associated with decreased muscle mass and performance and increased inflammation.²⁵⁷ Therefore, GDF-15 neutralization is a transformative therapeutic approach with effects on restoring muscle function and physical performance. Anti-GDF-15 treatment in experimental models increased muscle mass by increasing appetite and food intake and markedly improved muscle function and physical performance.⁷⁸ Clinical studies with industrial engagement and knowledge transfer in the field presented recently a novel drug BIO101, a small molecule and a leading drug candidate, administered orally, and its effectiveness in treating sarcopenia.⁷⁹ This candidate molecule showed promising results for the improvement of mobility disability in the gait speed from the 400 m walking test. The primary endpoint was the ability to complete a 400 m walk test in less than 15 min, and the secondary endpoint: gait speed of 4 m from SPPB, hand grip strength test, and patient-reported outcome.

6. Conclusions

With the ageing of the population, the prevalence of frailty and sarcopenia, causing a variety of adverse outcomes, is on the rise. The biological mechanisms of these geriatric syndromes are multifactorial and overlap considerably with the pathophysiology of cardiac disease, particularly HF, and their frequent concomitant and complex interactions clearly deteriorate prognosis. Whilst exercise training, nutritional therapies, and disease-specific therapies are certainly the primary treatments for such a complex condition, further research into therapies devised from pathophysiologies, such as drugs that enhance the regenerative capacity of SCs and regulate autophagy, anabolic hormone replacement therapy, myostatin inhibitors, and anti-GDF-15 therapy, is warranted to improve prognosis.

Data availability

No new data were generated or analysed in support of this research.

Author notes

Conflict of interest: R.S. reports grants from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad, during the conduct of the study. S.D.A. reports grants and personal fees from Vifor Int, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Servier, grants and personal fees from Abbott Vascular, personal fees from Cardiac Dimensions, personal fees from Actimed, personal fees from Astra Zeneca, personal fees from Amgen, personal fees from Bioventrix, personal fees from Janssen, personal fees from Respicardia, personal fees from V-Wave, personal fees from Brahms, personal fees from Cordio, personal fees from Occlutech, outside the submitted work. S.v.H. has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor. S.v.H. reports research support from Amgen, Boehringer Ingelheim, IMI, and the German Center for Cardiovascular Research (DZHK).