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].

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.

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.

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.

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.

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.

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 p16^INK4a 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.

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.

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].

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 (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 (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 (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.

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 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 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 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].

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 (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.

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].

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].

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.

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].

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.