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INTRODUCTION
Sarcopenia is a progressive skeletal muscle disorder characterized by age-related loss of muscle mass and function, leading to frailty and adverse health outcomes [1,2]. Even when conservative diagnostic criteria are applied, sarcopenia affects an estimated 5% to 10% of the general older population. The condition increases the risk of falls, fractures, and premature mortality, representing a growing public health and socioeconomic burden. Once regarded solely as a deficiency in muscle mass, sarcopenia is now recognized as a complex geriatric syndrome—essentially an age-related state of muscle failure—with multifactorial causes spanning neuromuscular, metabolic, hormonal, and inflammatory domains. It often coexists with other age-associated conditions such as osteoporosis and frailty, underscoring its systemic nature and motivating terms like ‘osteosarcopenia’ to describe concurrent bone and muscle loss [3,4]. In both research and clinical practice, sarcopenia has gained recognition as a distinct pathological entity and an emerging target for therapeutic intervention [5].
In this article, we provide a comprehensive overview of sarcopenia and muscle aging, updating and expanding upon previous summaries of the field. We integrate recent advances in diagnostic criteria, molecular pathogenesis, and inter-organ cross-talk, while highlighting new developments in biological omics research. We also critically examine current and emerging therapeutic strategies—spanning lifestyle modification, pharmacologic intervention, and novel biologic approaches—and discuss the translational barriers that have limited clinical progress. The goal is to inform clinicians and researchers about the current state of sarcopenia research and to highlight promising pathways for translating mechanistic insights into effective therapies for this increasingly burdensome condition.
UPDATED DIAGNOSTIC FRAMEWORKS AND CLINICAL CRITERIA
Consensus definitions and evolving criteria
Our understanding of sarcopenia has advanced markedly over the past decade, resulting in evolving definitions and diagnostic frameworks (Table 1). Early consensus definitions (circa 2010) emphasized low muscle mass, with inconsistent inclusion of weakness or impaired function. More recently, definitions have converged toward prioritizing muscle strength and physical performance as the key diagnostic elements. The 2019 update by the European Working Group on Sarcopenia in Older People (EWGSOP2) redefined sarcopenia primarily as a deficit in muscle strength, with low muscle mass confirming the diagnosis and poor physical performance indicating severe sarcopenia [6,7]. Parallel efforts from Asian (Asian Working Group for Sarcopenia [AWGS]) [8], American (Foundation for National Institutes of Health [FNIH], Sarcopenia Definitions and Outcomes Consortium [SDOC]) [9,10], and other working groups [11,12] have provided region- and population-specific refinements. Nevertheless, these efforts largely align with the central concept that sarcopenia reflects compromised muscle strength, quantity, and function. Collectively, these consensus frameworks have established the foundation for a globally unified definition, and the ongoing Global Leadership Initiative on Sarcopenia (GLIS) aims to harmonize diagnostic criteria worldwide in the near future [13].
Diagnostic workflow in practice
In clinical practice, a stepwise diagnostic workflow enables efficient identification of sarcopenia (Fig. 1). The process generally follows four steps: screen→assess strength→confirm mass→grade performance. This structured approach ensures accurate and timely diagnosis. In real-world settings, clinicians often employ a simplified version. For example, an older adult with evident muscle wasting and slow gait may first undergo a grip strength test; if strength is markedly reduced, sarcopenia can be provisionally diagnosed and intervention initiated even before formal dual-energy X-ray absorptiometry (DXA) testing. Measurement tools such as DXA and bioelectrical impedance analysis (BIA) are commonly used to assess muscle mass, but their availability and accuracy vary. DXA cannot distinguish contractile muscle from fat infiltration, while BIA results are affected by hydration status. New modalities, such as muscle ultrasound and computed tomography (CT) or magnetic resonance imaging (MRI)-based assessments, are under investigation for evaluating muscle quality, though they are not yet widely adopted in clinical settings. Consequently, recent guidelines allow for a diagnosis of ‘probable sarcopenia’ based on reduced strength alone, an important shift since low strength alone warrants clinical intervention. Objective confirmation of reduced muscle mass remains ideal but can be pursued opportunistically. Clinicians must also apply judgment to rule out alternative causes of poor performance, such as osteoarthritis or neurological disease.
Diagnostic cut-offs for sarcopenia vary among populations. Asian populations typically exhibit lower average muscle mass, leading the AWGS to establish lower appendicular lean mass thresholds for DXA and BIA. However, differences in lifestyle and culture also contribute to sarcopenia risk beyond baseline muscularity [2]. Ethnic-specific validation of gait speed and grip strength cut-offs is ongoing. For example, the Korean Working Group on Sarcopenia (KWGS 2023) found that a slightly higher gait speed cut-off of 1.0 m/sec improved diagnostic sensitivity in their population [12]. Clinicians should be aware of the reference values used, as criteria continue to evolve. Ultimately, diagnosis should be individualized, taking into account the patient’s baseline physique and functional capacity—for instance, comparisons with their midlife status or adjustments for body size [5].
PATHOPHYSIOLOGICAL MECHANISMS
Sarcopenia develops through the interplay of intrinsic muscle aging processes and extrinsic systemic factors (Fig. 2A). Aging skeletal muscle undergoes multiple molecular and cellular alterations, often described in terms of the ‘hallmarks of aging’ as they manifest in muscle tissue. In addition, changes in neuromuscular, hormonal, and inflammatory systems further accelerate muscle decline. The mechanisms discussed below are broadly categorized into muscle-intrinsic and muscle-extrinsic factors, acknowledging that these categories overlap and interact. Understanding these mechanisms is crucial, as they form the biological basis for existing and emerging therapeutic strategies.
Muscle cell-extrinsic factors
Chronic low-grade inflammation
Chronic, systemic, low-grade inflammation that accompanies aging is a well-recognized contributor to sarcopenia [14]. Older adults frequently exhibit elevated circulating inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein [15]. These cytokines exert catabolic effects on muscle tissue. TNF-α and IL-6, for instance, activate nuclear factor kappa B and other intracellular pathways that enhance protein degradation and suppress anabolic signaling, promoting muscle atrophy [16]. Elevated IL-6 levels have been associated with accelerated muscle loss and weakness in epidemiologic studies. Notably, IL-6 has a dual role: it can act as a beneficial myokine acutely released during exercise to support metabolism, yet chronically elevated IL-6 contributes to muscle wasting [17]. The aging immune system exhibits a pro-inflammatory shift due to factors such as the accumulation of senescent cells that secrete cytokines (the senescence-associated secretory phenotype [SASP]), reduced sex hormone levels, chronic infections, and increased visceral adiposity [18]. This persistent inflammatory milieu—often termed ‘inflammaging’— creates a hostile environment that continuously stresses skeletal muscle. Furthermore, chronic inflammatory diseases common in older adults exacerbate sarcopenia through heightened cytokine burden. Consequently, anti-inflammatory interventions are under active investigation as potential strategies to slow or mitigate sarcopenia progression [19].
Endocrine and metabolic changes
Aging is accompanied by declines in multiple anabolic hormones essential for maintaining muscle mass and function [20]. Testosterone levels decrease in older men, and estrogen levels fall in postmenopausal women, reducing both muscle protein synthesis and satellite cell activation potential. Low testosterone in men is strongly associated with sarcopenia and frailty, whereas hormone replacement therapy can modestly increase muscle mass and strength, although it carries potential adverse effects. Growth hormone (GH) and its downstream mediator, insulin-like growth factor-1 (IGF-1), also decline with age, leading to reduced stimulation of anabolic processes through the GH/IGF-1 axis. Insulin resistance is another hallmark of aging. Skeletal muscle in older individuals often exhibits impaired insulin signaling and diminished glucose uptake, which not only disrupt metabolism but also impairs protein turnover. Insulin resistance and type 2 diabetes are both linked to lower muscle strength and poorer muscle quality in older adults, in part through exacerbation of inflammatory and oxidative stress pathways [21]. Vitamin D deficiency is prevalent in the elderly and has been associated with muscle weakness and an increased risk of falls. Because vitamin D receptors are expressed in muscle tissue, vitamin D may influence calcium handling and protein synthesis within muscle cells [22]. Clinical studies have shown that correcting vitamin D deficiency improves muscle function, particularly in individuals with severely deficient levels. Aging and chronic stress may also increase cortisol levels or tissue sensitivity to cortisol, promoting catabolic activity and muscle breakdown [23]. Additionally, age-related anabolic resistance means that older adults require higher protein intake and stronger exercise stimuli to achieve the same protein synthesis response as younger individuals [24]. Overall, the hormonal milieu of aging shifts toward catabolism, with elevated myostatin and cortisol, and away from anabolism, with reductions in sex steroids, GH/IGF-1, and thyroid hormones. This shift creates a permissive environment for muscle loss. Although treating underlying endocrinopathies can help, hormone-based therapies for sarcopenia have achieved only limited success due to side effects and the multifactorial nature of muscle aging.
Physical inactivity
Although intrinsic biological aging is critical, behavioral factors— most notably reduced physical activity—play a major contributory role. Many features of sarcopenia resemble accelerated disuse atrophy. Sedentary lifestyles become common in later life due to retirement, mobility limitations, or comorbid illnesses, reducing the mechanical and metabolic stimuli necessary to preserve muscle mass [25,26]. Muscle tissue requires regular contractile loading to sustain protein synthesis and neuromuscular connectivity. Lack of both resistance and aerobic activity leads to atrophy of type II fibers, reduced capillary density, and metabolic inflexibility. Periods of enforced inactivity, such as bed rest or hospitalization, can cause abrupt and profound muscle losses that older adults struggle to recover from because of impaired regenerative capacity. Recurrent hospital stays can therefore compound chronic sarcopenia. Moreover, insufficient dietary protein intake—common among older adults due to appetite decline, dental problems, or socioeconomic constraints—further aggravates muscle loss. Without adequate amino acid supply, aged muscle cannot effectively rebuild tissue, particularly since anabolic resistance necessitates higher per-meal protein doses (approximately 25 to 30 g) to maximally stimulate synthesis [27]. In summary, lifestyle factors such as low physical activity and suboptimal nutrition accelerate muscle aging beyond intrinsic biological processes. Consequently, exercise and nutritional interventions remain first-line treatments for sarcopenia, as they directly address these modifiable extrinsic contributors.
Chronic diseases and multimorbidity
Sarcopenia frequently coexists with chronic illnesses such as chronic kidney disease (CKD), chronic heart failure, chronic obstructive pulmonary disease, and cancer—conditions that promote muscle wasting through diverse mechanisms [28]. For instance, sarcopenia is highly prevalent among end-stage renal disease patients on dialysis, where uremic inflammation and metabolic disturbances complicate both diagnosis and management. In obesity, ‘sarcopenic obesity’ may occur, in which excess fat mass conceals underlying muscle loss; adipose-derived inflammatory mediators and mechanical strain further impair muscle function [29]. Each chronic condition imposes additional stress on muscle through pathways such as inflammation, nutritional derangements, or restricted mobility. As individuals age, multimorbidity becomes common, and sarcopenia often forms part of a vicious cycle: illness induces inactivity and inflammation that exacerbate sarcopenia, while sarcopenia, in turn, worsens disease outcomes. Thus, effective sarcopenia management requires a comprehensive approach addressing both primary muscle aging and the interacting disease processes that amplify it.
Muscle cell-intrinsic mechanisms
Impaired protein homeostasis
The fundamental driver of sarcopenia is an imbalance between muscle protein synthesis and degradation. Skeletal muscle maintenance depends on continuous remodeling, wherein old or damaged proteins are degraded through proteolytic systems, primarily the ubiquitin-proteasome and autophagy–lysosome pathways, while new proteins are synthesized to sustain muscle structure. In aging muscle, anabolic signaling via the IGF-1/Akt/mechanistic target of rapamycin (mTOR) pathway is blunted, leading to reduced protein synthesis capacity [2]. Simultaneously, proteolytic activity is often upregulated by catabolic stimuli such as proinflammatory cytokines and glucocorticoids, accelerating protein breakdown. This dual effect results in a progressive net loss of muscle protein. One well-characterized example is the age-related rise in myostatin, a transforming growth factor-beta (TGF-β) family myokine that powerfully inhibits muscle growth. Elevated myostatin and related ligands activate suppressor of mothers against decapentaplegic 2/3 (Smad2/3) signaling, suppressing protein synthesis and upregulating atrophy-related genes such as muscle atrophy F-box (atrogin-1/MAFbx) and muscle RING-finger protein-1 (MuRF1) [30]. Studies have shown higher myostatin expression and reduced levels of its natural inhibitor, follistatin, in aged muscle [31,32]. Aging is also associated with anabolic resistance, wherein older muscle exhibits diminished responsiveness to nutrients and exercise stimuli. This blunted effect arises partly from impaired mTORC1 signaling and reduced activation of satellite cells, which are essential for muscle regeneration [33]. On the catabolic side, aging cells accumulate damaged proteins and organelles, yet autophagy efficiency declines. Inadequate clearance of dysfunctional cellular components triggers muscle fiber damage and atrophy. Consistent with this, aged muscle demonstrates reduced expression of autophagy regulators and proteasome subunits, along with visible aggregates of misfolded proteins.
Mitochondrial dysfunction
Mitochondria are essential for muscle energy production, and their dysfunction represents a central mechanism of muscle aging [34]. Aging muscle fibers exhibit reduced mitochondrial content, diminished enzyme activity, impaired oxidative phosphorylation, and increased generation of reactive oxygen species (ROS). The resulting chronic oxidative stress damages cellular components, including proteins, lipids, and DNA. Over time, mitochondrial DNA mutations accumulate within muscle tissue, compromising electron transport chain efficiency and energy output [35]. Importantly, aging muscle displays impaired mitophagy—the selective autophagic removal of damaged mitochondria— which allows dysfunctional, ROS-producing mitochondria to persist [36,37]. In older adults, lower mitochondrial respiratory capacity correlates with reduced walking speed, greater fatigue, and decreased strength. Conversely, interventions that enhance mitochondrial quality—such as exercise, caloric restriction, or pharmacologic agents that stimulate mitochondrial biogenesis—can improve muscle endurance. Nicotinamide adenine dinucleotide (NAD+), a critical cofactor for metabolic and DNA repair enzymes, declines with age in skeletal muscle, contributing to metabolic inefficiency and mitochondrial dysfunction. Preclinical studies suggest that restoring NAD+ levels through supplementation or precursor administration can rejuvenate mitochondrial function in aged muscle [38]. Overall, mitochondrial impairment not only diminishes cellular energy production but also triggers pro-atrophy pathways through ROS and inflammatory signaling, making it a pivotal contributor to sarcopenia pathogenesis.
Satellite cell exhaustion
Muscle regeneration throughout adult life depends on satellite cells—the resident muscle stem cells located beneath the basal lamina of myofibers [39]. With aging, satellite cells experience both quantitative and qualitative decline. Their numbers decrease, and the remaining cells exhibit signs of senescence and quiescence defects, including elevated expression of cell-cycle inhibitors such as p16INK4a and diminished proliferative capacity [40]. Consequently, aged satellite cells are less effective in repairing muscle after injury or promoting hypertrophy in response to exercise [41]. Mechanistically, aged satellite cells show impaired activation of regenerative pathways, reduced responsiveness to growth factors, and accumulation of DNA damage. They may also possess shortened telomeres, which limit their replicative potential [42]. Recent single-cell transcriptomic analyses of human muscle aging have identified distinct subsets of aged muscle stem cells characterized by downregulation of ribosomal biogenesis genes, indicative of reduced protein synthesis capacity, and upregulation of proinflammatory factors such as C-C motif chemokine ligand 2 (CCL2) [43]. These molecular changes shift the cells toward dysfunctional phenotypes, resulting in incomplete regeneration and progressive fiber atrophy. Furthermore, the microenvironment (‘niche’) surrounding satellite cells deteriorates with age. Aged muscle fibers and fibroblasts provide fewer pro-regenerative cues and more inhibitory or fibrotic signals, compounding stem cell dysfunction [44]. The net outcome is impaired muscle repair and a gradual decline in the tissue’s regenerative capacity, leading to cumulative muscle loss over time.
Denervation and fiber-type transitions
Aging is also characterized by the gradual loss of motor neurons, particularly the large, fast alpha-motor neurons that innervate type II (fast-twitch) fibers. This neuronal loss leads to denervation of muscle fibers, which, if not reinnervated by collateral sprouting from surviving neurons, undergo atrophy and eventual degeneration [45]. Type II fibers are preferentially affected, resulting in a shift toward a higher proportion of type I (slow-twitch) fibers in aging muscle [46]. The denervation–reinnervation process induces motor unit remodeling: surviving motor neurons may reinnervate some denervated fibers, producing larger, mixed-type motor units, while others remain abandoned and atrophy. In advanced aging, this leads to fiber-type grouping observed on muscle biopsy and an overall reduction in total fiber number. The preferential loss of fast-twitch fibers helps explain the disproportionate decline in power and high-intensity strength with age. Interestingly, recent human muscle atlas studies have reported an expansion of specialized nuclei associated with neuromuscular junctions (NMJs) in aged muscle, possibly reflecting compensatory reinnervation efforts [43]. However, these adaptive responses eventually plateau, and continued motor neuron loss results in irreversible muscle fiber dropout. Exercise can partially mitigate denervation effects by enhancing NMJ stability and stimulating collateral reinnervation, whereas inactivity accelerates motor unit loss [47]. Thus, maintaining neural integrity is an essential component of preserving muscle function with aging.
Myokines and muscle-organ crosstalk
Skeletal muscle is not merely a passive target of systemic endocrine regulation; it also functions as an active secretory organ that produces myokines—cytokines, growth factors, and peptides that exert autocrine, paracrine, and endocrine effects. These molecules mediate communication between muscle and other organs, influencing systemic metabolism and aging. In sarcopenia, the myokine secretion profile becomes dysregulated, contributing to both local muscle decline and broader systemic deterioration.
Apelin
Apelin is a peptide myokine, also produced in adipose tissue, that plays an important role in muscle regeneration and metabolism. Apelin levels decline in sedentary older adults. Animal studies show that apelin supplementation improves muscle function in aged mice by enhancing mitochondrial activity and autophagy. In humans, higher circulating apelin levels are associated with better muscle perfusion and aerobic capacity. Apelin is also an exercise-inducible factor and may mediate some of the pro-regenerative and metabolic benefits of physical activity. The age-related reduction in apelin thus represents a potentially reversible deficit. Indeed, preclinical studies administering apelin mimetics have demonstrated improvements in muscle function and endurance in older mice. Apelin additionally promotes angiogenesis, helping counteract the age-related reduction in muscle capillary density [48,49].
Brain-derived neurotrophic factor
Although best known for its roles in the nervous system, brain-derived neurotrophic factor (BDNF) is also produced by skeletal muscle during contraction. Within muscle, BDNF enhances fatty acid oxidation and may help preserve NMJ integrity. Circulating and muscle BDNF levels decline with age, and reduced muscle-derived BDNF may contribute to impaired metabolic adaptation in older individuals. BDNF is also a key component of the muscle–brain axis, influencing both cognition and neural plasticity. Its contribution to sarcopenia remains under active investigation, but it represents another dimension of muscle-secreted signaling that interconnects muscular and neural health [50,51].
Cathepsin B
Cathepsin B (CTSB), a lysosomal cysteine protease traditionally known for its degradative role in proteostasis, has recently been identified as a novel exercise-induced myokine [52]. In skeletal muscle, CTSB contributes to autophagy regulation, tissue remodeling, and maintenance of proteostasis. Notably, CTSB can cross the blood–brain barrier, where it promotes neurogenesis and memory formation through the upregulation of BDNF expression. This dual action highlights its role in the muscle– brain axis. With aging, both CTSB expression and responsiveness to exercise decline, reducing autophagic efficiency and regenerative capacity. Experimental upregulation of CTSB in aged mice has been shown to improve muscle quality and cognitive performance, indicating broad anti-aging effects [53]. CTSB thus exemplifies an exercise-responsive myokine that integrates muscle maintenance, neuroprotection, and systemic resilience, making it a promising target for interventions addressing both sarcopenia and cognitive frailty.
Fibroblast growth factor 21
Fibroblast growth factor 21 (FGF21) is a hormone-like protein primarily secreted by the liver during fasting, but skeletal muscle can also produce FGF21 under conditions of stress, earning it the designation of a ‘mitokine.’ In aging, muscle FGF21 expression increases in response to mitochondrial dysfunction, and circulating FGF21 levels are often elevated in frail older adults. Although transient FGF21 elevation may initially promote metabolic adaptation—enhancing energy expenditure and insulin sensitivity—chronic overexpression is frequently associated with metabolic stress and muscle loss. The relationship between FGF21 and sarcopenia is therefore complex: while some studies report protective effects against diet-induced muscle loss, others link high FGF21 levels to poorer muscle strength and endurance [54,55]. Collectively, FGF21 illustrates how muscle-derived stress signals influence systemic metabolism and aging.
Growth differentiation factor 11
Growth differentiation factor 11 (GDF11) is closely related to myostatin (both are TGF-β family members). Early parabiosis experiments suggested that GDF11 administration might reverse certain age-related cardiac changes. However, its role in muscle aging remains controversial. Evidence indicates that GDF11, like myostatin, can inhibit myogenesis and muscle regeneration. In animal models, blocking both myostatin and GDF11 with a ligand trap resulted in significant muscle hypertrophy. In humans, GDF11 levels appear to rise with age, but whether this increase is adaptive or deleterious remains unclear. Current consensus suggests that excessive GDF11 activity likely suppresses muscle growth, paralleling myostatin’s effects [56,57]. Ongoing studies aim to clarify whether modulating GDF11 signaling will be beneficial or harmful in sarcopenia management.
Growth differentiation factor 15 (GDF15)
GDF15, also known as macrophage inhibitory cytokine-1 (MIC-1), is a stress-responsive cytokine that increases in numerous aging tissues and disease states. It is strongly induced by mitochondrial dysfunction and is often elevated in chronic inflammation and cancer cachexia. GDF15 has emerged as an important biomarker of aging and frailty. Elevated circulating GDF15 levels are associated with weight loss, reduced muscle strength, and overall physical decline. Although its direct effects on skeletal muscle are not yet fully understood, GDF15 may act on central appetite-regulating pathways to induce anorexia at high concentrations, indirectly contributing to malnutrition. It may also exert direct autocrine effects on muscle metabolism. In older adults, elevated GDF15 levels correlate with sarcopenia severity, positioning it as a potential target and biomarker for sarcopenia management [58].
Humanin
Humanin is a mitochondrial-derived peptide originally identified in neuronal tissue but now recognized for its systemic cytoprotective functions, including roles in skeletal muscle. Acting as both a mitokine and a myokine, humanin is secreted in response to mitochondrial stress and mediates anti-apoptotic and insulin-sensitizing effects. Within muscle, it enhances mitochondrial efficiency, reduces oxidative stress, and mitigates apoptotic signaling—mechanisms that are crucial for preserving muscle integrity during aging [59]. Animal studies show that exogenous humanin administration improves muscle mass and endurance in aged models, while human studies associate higher circulating humanin levels with reduced frailty and better metabolic resilience [60]. Humanin also interacts with IGF-1 signaling and may indirectly modulate myogenesis and proteostasis [61]. Notably, humanin expression declines with advancing age, suggesting a loss of this protective signaling axis in older muscle. Thus, restoring humanin levels or mimicking its activity represents a promising therapeutic approach for sarcopenia and age-related mitochondrial dysfunction.
IL-6
IL-6 is unique in functioning both as a myokine and as a proinflammatory cytokine. During acute exercise, contracting skeletal muscle releases IL-6, which mobilizes energy substrates and exerts anti-inflammatory effects—actions considered beneficial in metabolic adaptation. In contrast, chronically elevated IL-6, particularly from non-muscle sources such as adipose tissue or immune cells, contributes to muscle wasting. Aging muscle may also produce excess IL-6 at rest as part of the SASP. This duality underscores the importance of context: transient, exercise-induced IL-6 supports metabolic health and adaptation, whereas persistently high basal IL-6 levels promote catabolism and atrophy. In sarcopenia, an imbalance often occurs in which baseline IL-6 is elevated while the acute, exercise-induced IL-6 response is blunted, reflecting diminished muscle plasticity and contractile adaptability [62,63].
Irisin
Irisin is a hormone-like myokine produced by proteolytic cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) membrane protein, which is upregulated in skeletal muscle by exercise. It gained attention for its ability to induce ‘browning’ of white adipose tissue and improve systemic metabolic homeostasis. In muscle, irisin exerts autocrine effects that promote fiber hypertrophy, mitochondrial biogenesis, and regenerative activity. However, circulating irisin levels decline with age, and several studies have reported lower irisin concentrations in older adults with sarcopenia, suggesting an impaired muscle-secretory response. Although human evidence is still developing, animal studies indicate that increasing irisin levels can help maintain both muscle and bone mass. Irisin therefore exemplifies a beneficial myokine that diminishes with aging; sustaining exercise-induced irisin secretion may be one mechanism through which physical activity protects against sarcopenia [64,65].
Myostatin (GDF-8)
A master negative regulator of muscle mass, myostatin is produced by muscle and acts in an autocrine and paracrine manner to inhibit muscle growth. It binds to the activin receptor type IIB on muscle cells, activating Smad signaling to suppress protein synthesis and satellite cell activity. Elevated myostatin expression with aging and in chronic diseases promotes muscle atrophy. In contrast, naturally occurring myostatin mutations or genetic knockout models result in marked muscle hypertrophy, highlighting its potent regulatory effect. Myostatin also circulates systemically as an endocrine signal, potentially influencing energy metabolism. With age, its antagonist follistatin declines, shifting the balance toward catabolic signaling. Consequently, the myostatin/activin axis represents a major therapeutic target, and multiple strategies to inhibit this pathway have been tested in efforts to combat sarcopenia [66,67].
Vascular endothelial growth factor A
Vascular endothelial growth factor A (VEGF-A) is a potent angiogenic myokine secreted by skeletal muscle, especially during exercise or hypoxic stress [68]. As a myokine, VEGF-A regulates local vascularization, enhancing oxygen and nutrient delivery to active myofibers. This is critical for mitochondrial oxidative capacity and recovery from fatigue. In aging muscle, VEGFA expression declines, resulting in capillary rarefaction, reduced tissue perfusion, and impaired regeneration [69]. Mouse models with muscle-specific VEGF-A knockout exhibit microvascular loss and muscle atrophy, whereas overexpression enhances endurance capacity and confers protection against sarcopenic decline. Beyond its vascular effects, VEGF-A indirectly influences satellite cell activation and mitochondrial biogenesis via hypoxia-inducible signaling pathways [70]. Importantly, VEGF-A expression is highly responsive to endurance training, and circulating levels correlate positively with aerobic fitness in both young and older adults. Thus, enhancing VEGF-A signaling may help counteract vascular and metabolic deterioration in aging muscle, positioning it as a promising target for improving physical performance and tissue resilience in sarcopenia.
Others
Several additional myokines have been identified as potential modulators of muscle tissue interactions. Decorin, a muscle-secreted proteoglycan, binds directly to myostatin and may inhibit its activity, thereby promoting muscle growth; its expression increases following exercise [71]. Secreted protein acidic and rich in cysteine (SPARC; osteonectin) is another exercise-induced myokine that may mediate beneficial effects on adipose tissue metabolism and possibly bone remodeling [72]. IL-15 promotes muscle anabolism and supports muscle–fat crosstalk; however, IL-15 expression tends to decrease with age. Irisin and IL-15 together are considered key mediators of muscle maintenance and metabolic homeostasis, both of which decline in the absence of regular exercise. Additionally, brain natriuretic peptide, typically recognized as a cardiac hormone, has been detected as a muscle-derived signal under specific conditions and may influence lipid mobilization and muscle energy balance [73].
The aging muscle environment
Cellular senescence and the SASP
Aging skeletal muscle progressively accumulates senescent cells that have permanently exited the cell-cycle and secrete pro-aging factors. These senescent populations include myogenic progenitor cells, as well as infiltrating immune and stromal cells. Senescent cells release a complex mixture of inflammatory, fibrotic, and proteolytic mediators collectively termed the SASP. In muscle tissue, SASP factors—such as IL-6, IL-1β, TNF-α, and matrix metalloproteinases—impair neighboring cell function and promote fibrosis. Markers of senescence increase in aging muscle stem cells and fibro-adipogenic progenitors (FAPs), correlating with functional decline. Experimental studies in progeroid mouse models have demonstrated that pharmacologic clearance of senescent cells using senolytic agents restores muscle function and regenerative capacity, underscoring the causal role of senescence in muscle aging. The SASP creates a chronic inflammatory microenvironment that continuously exposes myofibers to catabolic signals, suppresses regeneration, and accelerates atrophy. Consequently, targeting senescent cells or modulating their SASP profile represents a promising therapeutic strategy to rejuvenate aged muscle and mitigate sarcopenia [74,75].
Fibrosis and extracellular matrix remodeling
With age, the skeletal muscle extracellular matrix—which normally provides structural support for myofibers—undergoes excessive collagen deposition and cross-linking, resulting in fibrosis. This process is largely driven by dysregulated FAPs, which, under healthy conditions, transiently aid regeneration by producing temporary scaffolding for new fibers. In aged muscle, however, FAPs become chronically activated, proliferating excessively and differentiating into fibrogenic or adipogenic cells [76]. Persistent low-level TGF-β signaling in old muscle further stimulates collagen synthesis by FAPs and impairs their clearance [77]. The outcome is stiff, inelastic muscle tissue with greater passive tension and reduced force transmission. Fibrotic remodeling also hinders satellite cell mobility and limits effective myofiber regeneration. In sarcopenic obesity, intramuscular fat infiltration often co-occurs with fibrosis, compounding the loss of muscle quality. Experimental anti-fibrotic therapies have shown potential—such as losartan, which improved muscle regeneration and reduced fibrosis in aged mice—but human trials have yet to demonstrate consistent functional benefits [78]. Anti-fibrotic approaches remain a potential adjunct in sarcopenia therapy.
NMJ degradation
Beyond motor neuron loss, the NMJs themselves exhibit structural and functional deterioration with aging [47]. Age-related NMJ changes include partial withdrawal of motor nerve terminals, fragmentation and reduced density of acetylcholine receptors on the postsynaptic membrane, and aberrant proliferation of Schwann cells at the junction. This partial denervation leads to impaired muscle activation and reduced contractile efficiency even before complete fiber denervation occurs. An expanded pool of NMJ-associated myonuclei observed in aged muscle likely reflects chronic remodeling or ongoing synaptic injury. The functional consequence of NMJ degeneration is reduced muscle power and delayed contraction initiation. Regular physical activity, particularly resistance and motor learning exercises, helps preserve NMJ integrity by stimulating synaptic signaling and neurotrophic factor production [79]. Conversely, prolonged inactivity accelerates NMJ destabilization. While NMJ decline is not the sole cause of sarcopenia, it exacerbates weakness and functional loss. Emerging research on NAD+ precursors and neurotrophic compounds aims to preserve NMJ structure and function, offering a novel avenue for mitigating neuromuscular aging [80].
Systemic factors
Beyond local muscle-specific alterations, aging is accompanied by systemic changes in circulating factors that profoundly affect muscle health. The term gerokines has been introduced to describe age-associated circulating molecules that influence multiple aging phenotypes. For instance, resistin levels increase with age and may promote insulin resistance within skeletal muscle. Adiponectin, typically a muscle-sensitizing hormone, paradoxically rises in older adults, possibly reflecting a failed compensatory mechanism. Alterations in cortisol circadian rhythm further expose muscle tissue to prolonged catabolic signaling [81]. Additionally, age-related declines in renal function and the frequent occurrence of anemia in older adults reduce oxygen and nutrient delivery to skeletal muscle, exacerbating fatigue and impairing regeneration [82]. Collectively, these circulating factors constitute a biochemical milieu that can either accelerate or buffer the trajectory of muscle decline. There is growing interest in characterizing the plasma ‘secretome’ of older individuals with and without sarcopenia to identify circulating molecules that distinguish protective from deleterious aging profiles. Proteomic studies have already identified panels of age-associated factors elevated in sarcopenic individuals, several of which may serve as both biomarkers and therapeutic targets [83]. In summary, the aging muscle exists within a progressively hostile systemic environment—one that is proinflammatory, pro-fibrotic, and deficient in regenerative growth signals. Interventions capable of rejuvenating this environment, such as senescent cell clearance, TGF-β inhibition, supplementation of anabolic growth factors, or exposure to ‘young blood’ factors, are being actively explored. Remarkably, several of these strategies have demonstrated rejuvenating effects in preclinical models, underscoring that muscle aging may indeed be modifiable if the systemic environment can be recalibrated toward a more youthful state.
EMERGING INSIGHTS FROM OMICS AND SYSTEMS BIOLOGY
Recent advances in high-throughput omics technologies have dramatically expanded our understanding of muscle aging and sarcopenia. Large-scale analyses integrating transcriptomic, proteomic, metabolomic, and epigenomic data have revealed complex molecular networks governing muscle degeneration (Fig. 2B). When combined with computational modeling, these approaches allow for a systems biology perspective—viewing sarcopenia not as the result of isolated pathways, but as a dynamic network disorder. The following sections summarize major insights from these studies and their implications for biomarker discovery and precision interventions.
Transcriptomics and gene expression signatures
Whole-transcriptome analyses of human muscle biopsies consistently demonstrate age-related shifts in gene expression [84]. In general, aged muscle shows downregulation of genes involved in mitochondrial oxidative phosphorylation, ribosomal biogenesis, and contractile apparatus components, accompanied by upregulation of genes related to extracellular matrix remodeling, proteolysis, and inflammation. More refined single-cell RNA sequencing (scRNA-seq) approaches have provided celltype–specific resolution, profiling individual populations such as myofibers, satellite cells, immune cells, fibroblasts, and endothelial cells. A landmark single-cell atlas of human muscle aging profiled tens of thousands of cells from young and aged donors [85,86]. This work revealed distinct aging signatures, including subsets of satellite cells characterized by reduced protein synthesis capacity and heightened inflammatory signaling (e.g., CCL2 expression). It also identified fiber-type–specific transcriptional shifts, reflecting fiber conversion and compensatory remodeling. Moreover, scRNA-seq analyses uncovered an age-related enrichment of NMJ-associated gene programs, indicating persistent reinnervation attempts. Single-nucleus RNA sequencing (snRNA-seq), which captures transcriptional changes within multinucleated myofibers, has further refined these observations by identifying distinct myonuclear domains affected by aging. Together, these techniques reveal that muscle aging is a heterogeneous, cell-type–specific process, with implications for targeted rejuvenation therapies that address specific cellular vulnerabilities.
Spatial transcriptomics
Spatial transcriptomics, an emerging methodology not yet widely applied to sarcopenia, offers the ability to map transcriptional activity within intact tissue architecture. This technique could identify the spatial organization of proinflammatory versus healthy fibers and characterize the infiltration of immune or fibrotic cells within aging muscle.
Proteomics
Although transcriptomics provides valuable insight, proteins are the direct effectors of muscle structure and metabolism. Proteomic studies of aging skeletal muscle reveal substantial remodeling of the muscle proteome. Aging is associated with decreases in mitochondrial enzymes, myofibrillar proteins (e.g., actin and myosin isoforms), and glycogen-metabolizing enzymes, alongside increases in extracellular matrix components, collagens, and stress response proteins [87,88]. Mass spectrumetry-based proteomics of human muscle biopsies can quantify hundreds of proteins simultaneously, revealing consistent patterns of impaired bioenergetic capacity and increased proteostasis stress in older tissue. Beyond tissue-level analyses, plasma proteomics has emerged as a noninvasive strategy to identify circulating markers of muscle health [89]. For example, large-scale proteomic screens have identified circulating GDF15 as strongly correlated with muscle weakness and frailty [90]. Other candidate plasma biomarkers of sarcopenia include collagen fragments, C-reactive protein, IL-6, insulin-like growth factor-binding proteins, and various myokines. A recent multi-omics study combining proteomic, metabolomic, and clinical data identified a distinct panel of plasma proteins that discriminated sarcopenic from non-sarcopenic older adults [91]. As such panels are refined and validated, they may pave the way toward a simple blood test for sarcopenia risk stratification and monitoring of therapeutic response—a long-sought goal in clinical geroscience.
Metabolomics
Metabolomic analysis measures small-molecule metabolites in biological samples such as blood or muscle tissue. In sarcopenia research, metabolomics has revealed characteristic alterations in amino acid and lipid metabolism [92]. Individuals with sarcopenia often exhibit lower circulating levels of essential amino acids and elevated concentrations of catabolic intermediates, reflecting impaired protein turnover. Altered lipid metabolite profiles, including increased acylcarnitines and ceramides, suggest inefficiencies in mitochondrial β-oxidation in aging muscle. Additionally, changes in tricarboxylic acid cycle intermediates and antioxidant molecules have been identified in individuals with reduced muscle strength, consistent with the involvement of mitochondrial dysfunction and oxidative stress [93]. Intramuscularly, aging is associated with increased intramyocellular lipid accumulation and altered phosphocreatine kinetics, both indicative of impaired energy metabolism. Certain bile acid derivatives and uremic toxins, which accumulate in older adults and in those with CKD, may directly disrupt muscle metabolism [94]. Moreover, metabolomic studies have highlighted the emerging importance of the gut–muscle axis: age-related shifts in gut microbiota composition alter the production of metabolites that influence muscle physiology. For example, lower levels of the gut-derived metabolite 3-indoxyl sulfate were associated with better muscle mass, suggesting that microbiome modulation could represent a therapeutic avenue for sarcopenia [95]. Metabolomic profiles thus provide a dynamic readout of muscle metabolic health. Distinct metabolic responses to exercise, protein supplementation, and pharmacologic interventions have been observed, raising the possibility that future sarcopenia treatments could be individualized according to each patient’s metabolic signature.
Epigenomics
Epigenetic modifications regulate gene expression without altering DNA sequence, and growing evidence indicates that both aging and lifestyle factors leave lasting epigenetic imprints on skeletal muscle. Genome-wide DNA methylation studies reveal that older muscle exhibits distinct methylation patterns at genes related to muscle structure, metabolism, and regeneration [96]. Some methylation changes may be deleterious, whereas others could represent adaptive compensations to metabolic stress. Epigenetic clock analyses—where specific DNA methylation sites are used to estimate biological age—have shown that muscle tissue often displays accelerated epigenetic aging in individuals with sarcopenia. In one study, participants with low grip strength demonstrated significantly higher DNA methylation age relative to their chronological age [97]. Specific loci, such as the promoter region of the FGF2 gene, have shown methylation patterns correlating with sarcopenia severity [98]. Beyond DNA methylation, histone modifications regulating chromatin accessibility are also altered by both exercise and aging, influencing the expression of metabolic and structural genes [99]. Another emerging area involves small noncoding RNAs—particularly microRNAs (miRNAs)—which post-transcriptionally regulate gene expression. Circulating, muscle-enriched miRNAs such as miR-1, miR-133, and miR-206 show consistent age-related changes and are being explored as blood-based biomarkers of muscle health [100,101]. For instance, elevated levels of miRNAs that suppress IGF-1 signaling have been linked to muscle atrophy in aging and disease [102]. Understanding epigenetic and miRNA regulation may lead to new targets for interventions: drugs or lifestyle changes that reverse harmful epigenetic marks or boost beneficial ones. An emerging concept is that exercise exerts many of its pro-muscle effects by reprogramming the muscle epigenome to a more youthful state.
Integrative multi-omics and precision medicine
Each omics layer provides one dimension of data; the next challenge is integrating them to achieve a holistic picture. Multiomics approaches now combine genomic and molecular data with physiological and clinical phenotypes to identify key regulatory networks that drive muscle degeneration [103]. Advanced computational modeling and machine learning (ML) techniques are being employed to manage high-dimensional data, uncovering networks of genes, proteins, and metabolites most strongly predictive of muscle decline. Such analyses have already revealed novel candidate mediators, including specific sphingolipids whose abundance correlates with both gene expression alterations and reduced muscle strength. Network-based analyses can also identify ‘hub’ molecules that occupy central roles in the muscle aging interactome—potentially serving as therapeutic targets. These systems biology approaches align closely with the emerging paradigm of precision medicine in sarcopenia. Not all cases share the same pathophysiological drivers; multi-omics profiling may enable stratification of sarcopenia into distinct molecular subtypes. Preliminary clustering studies have identified patient subgroups with differing biomarker patterns and clinical outcomes, suggesting the feasibility of individualized treatment strategies [86,104].
Artificial intelligence in sarcopenia research
With the rapid growth of omics datasets, artificial intelligence (AI) and ML are increasingly central to sarcopenia research. AI models are being trained to predict the onset, progression, and treatment response of sarcopenia based on complex molecular and clinical data [105]. In addition, AI-driven image analysis enables automated quantification of muscle quality and volume from CT or MRI scans, and even gait or video-based analysis to infer muscle function and frailty [106]. In drug discovery, AI is being utilized to screen and optimize compounds targeting sarcopenia-related pathways, accelerating the identification of therapeutically promising molecules [107]. Although still in its infancy, AI integration across molecular, imaging, and functional domains promises a future in which sarcopenia diagnosis and management are guided by comprehensive, computationally derived precision profiles.
Omics and systems biology have transformed our conceptualization of sarcopenia from a simple muscle mass deficit into a multisystem network disorder [104]. These technologies are revealing actionable biomarkers—such as specific proteins, metabolites, or miRNAs—that could enable earlier detection of muscle decline and more precise monitoring of interventions [108]. Moreover, they are accelerating translational discovery by identifying novel molecular targets for therapeutic development. As integrative omics and AI-based analytics move toward clinical implementation, they pave the way for precision geroscience: individualized, data-driven strategies to preserve muscle health and function across the lifespan [103].
THERAPEUTIC INTERVENTIONS: BENCH TO BEDSIDE
Managing sarcopenia requires a multifaceted strategy that addresses its diverse etiologies (Fig. 3). While the cornerstone of therapy remains exercise and nutrition, extensive research has explored pharmacologic and biological interventions to augment muscle mass and function. To date, no drug has received formal regulatory approval for sarcopenia, and clinical trial outcomes remain heterogeneous. Lifestyle interventions, particularly resistance training combined with adequate protein intake, consistently improve muscle strength and performance across populations. However, adherence, personalization, and interindividual variability in response remain key challenges. Pharmacologic strategies under investigation include several mechanistic classes. Myostatin/activin inhibitors (e.g., bimagrumab) effectively increase lean mass but have shown limited improvements in functional endpoints. Selective androgen receptor modulators such as enobosarm demonstrate anabolic benefits with improved safety profiles compared to traditional hormone therapy, although long-term data are pending. GH and ghrelin mimetics (e.g., anamorelin) have produced mixed results and carry metabolic and cardiovascular risks. Given the central role of mitochondrial dysfunction in sarcopenia, NAD+ precursors such as nicotinamide riboside and nicotinamide mononucleotide have been evaluated in early trials, showing modest improvements in fatigue and muscle performance. Nutraceuticals like creatine and β-hydroxy-β-methylbutyrate, particularly when combined with resistance exercise, can enhance muscle strength and reduce loss in older adults. Emerging gerotherapeutics, including senolytics (dasatinib plus quercetin), aim to eliminate senescent cells and attenuate chronic inflammation; early-phase studies report improvements in physical capacity and endurance. Vitamin D supplementation provides benefit mainly in individuals with deficiency, while excessive dosing shows no added advantage. Increasing attention has also focused on the gut–muscle axis, where prebiotic and probiotic interventions may enhance nutrient absorption, reduce systemic inflammation, and indirectly improve muscle metabolism. Future management of sarcopenia will likely involve combination therapies integrating behavioral, nutritional, and molecular interventions. Below, we summarize both established and experimental strategies— from lifestyle modifications to cutting-edge molecular therapeutics—and discuss outcomes of pivotal clinical trials and their implications for next-generation treatment development (Table 2) [109–149].
LIMITATIONS AND TRANSLATIONAL CHALLENGES
From a systems-biology perspective, the principal translational challenge in sarcopenia is its irreducible heterogeneity—spanning etiologic drivers (inflammaging, metabolic inflexibility, neuromuscular degeneration), comorbidity burden, and lifecourse exposures—coupled with inconsistent case definitions and threshold criteria that introduce sampling bias and effectsize variability across studies. The GLIS has provided a unifying conceptual framework, yet operational definitions remain plural, sustaining variability in prevalence estimates, inclusion criteria, and trial endpoints [13]. Measurement discordance compounds this issue: ‘muscle quantity’ and ‘muscle quality/strength’ are not interchangeable constructs, and differences in imaging platforms (DXA vs. CT/MRI), anatomical reference levels (L1 vs. L3), and segmentation algorithms can alter quantitative readouts and prognostic accuracy. Automated CT-based analyses have underscored that vertebral level choice alone can shift the prognostic signal, highlighting the need for methodological standardization. The biomarker landscape remains nascent despite rapid growth. Umbrella reviews indicate that most circulating candidates— including inflammatory, hormonal, metabolic, and noncoding RNA markers—demonstrate low-to-moderate diagnostic performance, high interstudy heterogeneity, and criterion dependence. Consequently, none yet meet the evidentiary threshold for regulatory qualification as surrogate endpoints, pending prospective validation across large, diverse cohorts [150]. Finally, although AI and ML models show promise for risk prediction and response stratification, meta-research reveals variable labeling standards, poor generalizability, and performance degradation in out-of-sample testing. Harmonized reference datasets and multicenter external validation are essential before such models can support trial enrichment or population screening. Bridging these gaps will require integrative frameworks that combine standardized phenotyping with longitudinal multi-omics profiling and analytically robust endpoints centered on functional outcomes—consistent with EWGSOP2’s emphasis on muscle strength as the primary diagnostic anchor [6,7]. Only by aligning mechanistic signals with clinically meaningful change can translational progress accelerate from bench to bedside.
FUTURE PERSPECTIVES
A credible path toward precision medicine in sarcopenia begins with global harmonization and progresses through deeply phenotyped, longitudinal, multi-omics cohorts linking molecular mechanisms to hard functional endpoints. GLIS provides the necessary lexical and conceptual foundation for interoperability across regions and research platforms [13]. At the discovery level, next-generation reference maps such as the multimodal human skeletal muscle atlas integrate transcriptomic, proteomic, and epigenomic layers to reveal cell-type–specific networks and niche microenvironments not discernible in bulk analyses [86]. Translational acceleration occurs when these atlases are combined with causal inference and perturbational studies: recent cross-species multi-omics analyses have identified branched-chain amino acid (BCAA) catabolic dysfunction as a modifiable driver of sarcopenia, while a single-nucleus senescence atlas of aging human muscle implicated C-C chemokine receptor type 5 (CCR5) antagonism (maraviroc) as a potential senotherapeutic—both exemplars of target discovery pipelines bridging molecular stratification to actionable interventions [105]. On the implementation side, clinically proximal AI applications continue to mature. Automated CT-based muscle quantification and emerging cardiothoracic CT workflows enable opportunistic risk phenotyping and longitudinal monitoring at population scale. These tools dovetail with adaptive clinical trial designs that use ML to predefine responder-enriched subgroups, optimizing trial efficiency and precision [150]. Looking forward, the most plausible therapeutic architecture is multimodal and subtype-aware—combining resistance exercise and optimized nutrition with pathway-directed agents emerging from network-guided discovery—evaluated in platform trials that integrate digital function phenotypes and omics-based response biomarkers to iteratively refine treatment rules toward individualized, durable gains in muscle function [86].
CONCLUSIONS
Sarcopenia is a multifactorial and progressive condition of aging that undermines independence, resilience, and quality of life. While progressive resistance training and optimized nutrition remain the foundation of management, advances in geroscience and mechanism-based therapeutics—such as modulation of the myostatin/activin pathway, senescence-targeting interventions, and mitochondrial or metabolic restoration—are opening new avenues for treatment. Nonetheless, translation to clinical practice remains limited by substantial patient heterogeneity, inconsistencies in operational definitions and endpoints, the persistent discordance between muscle mass and function, immature biomarker validation pipelines, and methodological constraints that attenuate effect detection in many trials.
A credible path forward lies in the evolution toward precision muscle medicine. This will require harmonized diagnostic criteria to stabilize case identification, longitudinal and deeply phenotyped cohorts, and validated multi-omics and imaging biomarkers capable of enabling subtype classification and identifying treatable molecular networks. Clinically, the most effective model will likely combine lifestyle-based interventions with biomarker-guided pharmacologic strategies, supported by AI-enabled assessments—including opportunistic CT/MRI quantification and digital gait or function analytics—to shift care from reactive to proactive. Future clinical trials should prioritize patient-centered functional outcomes, employ adaptive and responder-enriched designs, and adopt transparent data standards to facilitate regulatory acceptance and equitable implementation. If achieved, such an integrated framework could translate mechanistic discoveries into individualized, durable improvements in muscle strength, mobility, and overall healthspan.
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