Exercise, Exerkines, and Sarcopenia
Article information
Abstract
Sarcopenia is a progressive age-related musculoskeletal disorder characterized by loss of skeletal muscle mass, strength, and physical function. Closely associated with aging and physical inactivity, it significantly compromises mobility, independence, and quality of life in older adults. Exercise is widely recognized as an effective non-pharmacological intervention for managing sarcopenia. However, the underlying molecular mechanisms remain incompletely elucidated. Among the emerging mediators, exerkines, physical exercise-induced signaling molecules, are secreted by multiple tissues, including the skeletal muscle, bone, liver, and adipose tissue, and mediate the systemic beneficial impacts of exercise via autocrine, paracrine, and endocrine signaling. These factors play critical roles in interorgan communication, regulation of muscle regeneration, mitochondrial function, inflammation, and metabolic homeostasis. Importantly, the secretion profiles and biological functions of exerkines are modulated by exercise-specific parameters such as mode, intensity, and duration. Understanding the regulatory dynamics of exerkine signaling may offer novel therapeutic avenues, particularly for individuals unable to engage in regular physical activity. This review focuses on the recently identified exerkines relevant to skeletal muscle physiology and their implications in the pathophysiology of sarcopenia. We also provided a comprehensive overview of exerkine responses to various exercise modalities in the prevention and treatment of sarcopenia.
Highlights
• Sarcopenia is age-related loss of muscle mass and strength via multifactorial causes.
• Exerkines mediate interorgan crosstalk and regulate muscle mass in sarcopenia.
• Apelin, LIF, follistatin, and 12,13-diHOME have pleiotropic effects associated with sarcopenia.
• Exercise mode, intensity, and duration modulate exerkine secretion and action.
• Targeting exerkines enables precision exercise prescriptions and mimetic therapies.
The Sulwon Award for Scientific Achievement is the Korean Diabetes Association’s highest scientific award and honors an individual who has excellently contributed to the progress in the field of diabetes and metabolism. The Sulwon Award is named after emeritus professor Eung Jin Kim, who founded Korean Diabetes Association. Prof. Kyung Mook Choi received the 17th Sulwon Award at the 38th Spring Congress of Korean Diabetes Association, May 8- to 10 in 2025, at Gyeongju, Korea.
INTRODUCTION
In Korea, the prevalence of sarcopenia among adults aged 65 years and older varies widely—from 3% to 24%—reflecting differences in diagnostic criteria and cut-off thresholds [1]. Using the Korean Sarcopenic Obesity Study, the prevalence of sarcopenia was more than twofold higher in individuals with type 2 diabetes mellitus (T2DM) compared with their non-diabetic counterparts (15.7% vs. 6.9%, respectively) [2]. A bidirectional impact between sarcopenia and T2DM has been suggested, as each condition exacerbates the progression of the other [3].
Sarcopenia is a progressive musculoskeletal disorder defined by a decline in skeletal muscle volume, strength, and functional capacity, predominantly observed in aging populations and individuals with physical inactivity and chronic comorbidities [4]. Its pathophysiology involves a complex interplay of mechanisms including aging-related insulin resistance, chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, hormonal imbalances, and impaired muscle protein synthesis [5–8]. Reduced satellite cell activity and increased muscle catabolism also contribute to muscle degeneration [9]. Moreover, physical inactivity and nutritional deficiencies exacerbate the progression of sarcopenia [10]. In turn, this geriatric syndrome significantly compromises physical performance and quality of life while markedly increasing the risk of falls, frailty, hospitalization, cardiometabolic-related morbidity, neurodegenerative disorders, and all-cause mortality. Given the accelerating global demographic shift toward an aging population, the development of evidence-based therapeutic strategies for sarcopenia has become increasingly urgent [11].
Exercise is widely recognized not only as a cornerstone intervention for the prevention and management of sarcopenia but also as a powerful therapeutic modality for various chronic diseases, including metabolic, cardiovascular, neurological, pulmonary, psychiatric disorders, and cancer [12]. In particular, numerous studies have demonstrated that both resistance and endurance training induce beneficial adaptations in skeletal muscle physiology, including hypertrophy, improved neuromuscular function, and enhanced metabolic efficiency [13]. Furthermore, exercise training corrects hormonal imbalances, ameliorates inflammation and oxidative stress, and improves mitochondrial dysfunction [14]. Guidelines firmly recommend increasing physical activity or regular exercise as the primary approach for managing sarcopenia, based on research evidences [15]. Beyond these traditional physiological outcomes, emerging evidence highlights the pivotal role of exercise-induced humoral factors, collectively termed exerkines, in mediating the systemic benefits of physical activity [16].
Exerkines comprise a diverse group of bioactive molecules, such as myokines, adipokines, hepatokines, osteokines, metabolites, and extracellular vesicles, that are secreted by contracting skeletal muscles and other organs in response to physical exercise [17]. These molecules act through autocrine, paracrine, and endocrine pathways to regulate muscle homeostasis, modulate inflammatory responses, enhance mitochondrial function, and influence interorgan communication [18]. In a meta-analysis including 40 randomized controlled trials, exercise training induced changes in exerkines, such as adiponectin, leptin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, fetuin-A, and fibroblast growth factor-21 (FGF-21), in patients with T2DM, accompanied by anti-inflammatory effects and improvement of metabolic parameters [19]. Furthermore, recent studies have reported that some exerkines have anti-tumor effects. Irisin, in particular, is known to have potential anti-cancer properties in breast and colorectal cancers by enhancing apoptosis and suppressing cancer cell proliferation [20].
This review aimed to comprehensively synthesize the current understanding of the interplay between physical exercise, exerkines, and sarcopenia (Fig. 1). Specifically, we examined the role of exerkines as molecular mediators in mitigating sarcopenia through their effects on skeletal muscle. We explored the impact of various exercise modalities on musculoskeletal health in aging populations. Finally, we discuss the translational potential of exerkine-based therapeutic strategies and highlight critical gaps in knowledge that warrant further investigation.
Different exercise modes, intensities, and durations regulate the expression and systemic release of diverse exerkines. These exert pleiotropic benefits by stimulating muscle anabolism, preserving mitochondrial homeostasis, attenuating pro-inflammatory signaling and oxidative stress, and enhancing fatty acid oxidation and glucose metabolism. Collectively, these adaptations improve metabolic, cardiovascular, neurological, and skeletal health, thereby mitigating the pathophysiological progression of sarcopenia.
IMPLICATIONS OF EXERKINES FOR SKELETAL MUSCLE MASS AND FUNCTION
Despite the increasing diversity of exerkine types identified using advancements in discovery techniques [21], their precise responsiveness and specific exercise modalities that elicit the most pronounced responses remain unclear. Exerkines secreted by various tissues, such as skeletal muscle, bone, liver, and adipose tissue, in response to physical exercise have been reported to exert multifaceted biological effects, including the regulation of mitochondrial homeostasis, attenuation of pro-inflammatory signaling and oxidative stress, enhancement of fatty acid oxidation and glucose metabolism, as well as promotion of muscle anabolism [7,18,22]. Ultimately, exerkines play a central role in orchestrating interorgan communication, facilitating systemic adaptations to physical activity, and contributing significantly to the preservation of muscle mass and function, particularly in older adults at a heightened risk of sarcopenia [23].
Apelin
Apelin has emerged as a critical myokine involved in maintaining and enhancing skeletal muscle and exerts beneficial effects on cognitive performance during aging [24]. Apelin production is stimulated by muscle contraction and progressively diminished with age in both humans and rodents [25]. Besse-Patin et al. [26] reported that exercise-activated signaling pathways significantly upregulated apelin mRNA expression and secretion in cultured human primary myotubes in vitro, and 8 weeks of endurance training upregulated skeletal muscle apelin expression in male subjects in vivo. In senescent rodent models, deficiency of apelin or its receptor significantly accelerates muscle aging [25]. Notably, in aged mice, chronic high apelin level exposure—achieved either through systemic administration or muscle-specific overexpression—has been shown to ameliorate age-associated muscle function decline by promoting mitochondriogenesis, autophagy, and anti-inflammation through increasing AMP-activated protein kinase (AMPK) and protein kinase B (AKT) phosphorylation and inducing a mechanistic target of rapamycin (mTOR)-P70 S6 kinase (P70S6K)-4E-binding protein-1 (4E-BP1) cascade in myofibers while also improving regenerative capacity through activation of muscle stem cells [25]. A meta-analysis of nine studies demonstrated that exercise increases blood apelin levels and is associated with beneficial effects on metabolic disorders, particularly in the elderly [27]. Moreover, apelin plays a pivotal role in bone-muscle crosstalk, and exercise-induced apelin induces bone formation by promoting osteoblast differentiation and mineralization [20]. Apelin also augments muscle hypertrophy and contractility in skeletal muscle, thereby amplifying anabolic effects on muscle and bone [20]. These findings underscore the therapeutic potential of apelin as a molecular target for the diagnosis of early sarcopenia and pharmacological strategies for preserving muscle and bone mass in aging populations.
Leukemia inhibitory factor
Leukemia inhibitory factor (LIF) is another multifunctional myokine belonging to the IL-6 superfamily [28,29], originally identified for its ability to suppress the proliferation of myeloid leukemia cells [30]. LIF plays various roles in the regeneration of stem cells across multiple somatic tissues, including the nervous system, intestine, and skeletal muscle, as well as in the regulation of immune cell function [31]. In skeletal muscle, LIF expression is rapidly upregulated following contraction through the well-known exercise-induced signaling molecules phosphoinositide 3-kinase (PI3K), Akt, and mTOR [32]. LIF promotes skeletal muscle satellite cell and myoblast proliferation, partly through induction of transcription factors JunB and c-Myc [32]. Reduced regenerative responses following muscle injury have been reported in LIF-deficient mice, whereas local administration of LIF significantly enhances muscle repair [33]. LIF also exerts potent anti-inflammatory effects during muscle regeneration [34]. It downregulates lipopolysaccharide-induced TNF-α and prevents inflammatory overactivation; in contrast, antagonism of LIF receptor-α during the inflammatory phase of skeletal muscle regeneration augments the inflammatory response, which subsequently impairs myotube formation [34]. Collectively, LIF promotes skeletal muscle regeneration through dual mechanisms: suppression of excessive inflammation and direct enhancement of skeletal muscle satellite cell activation and myogenic cell proliferation [32,34].
Myostatin
Myostatin (also known as growth differentiation factor-8 [GDF-8]), a member of the transforming growth factor-β (TGF-β) superfamily, functions as a potent negative regulator of skeletal muscle growth [35–37]. Exercise induced downregulation of myostatin expression has been consistently linked to enhanced satellite-cell activity and increased muscle fiber size [36]. Inhibition of myostatin leads to upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased mitochondrial biogenesis in muscle [38]. In animal models, myostatin blockade, particularly via receptor-blocking antibodies, markedly increases muscle mass and has been proposed as a therapeutic strategy for common muscle-degenerative conditions, including age-related sarcopenia [39]. Concurrent training has been shown to enhance muscle mass and function by reducing myostatin levels and improving body composition in elderly men with sarcopenia [40]. Beyond skeletal muscle, various adipokines and hepatokines are also modulated by exercise and exert paracrine and endocrine effects on skeletal muscle physiology. Follistatin, a liver-derived exerkine, directly antagonizes myostatin by binding to and neutralizing its biological activity, thereby promoting myogenic growth [41]. Both acute and chronic exercise elevate circulating follistatin levels in rodents and humans [41–44] and amplify the muscle anabolic environment induced by reduced myostatin signaling [41]. The follistatin-myostatin axis plays a pivotal role in regulating muscle mass and metabolic health, including glycemic control and lipid metabolism [37,41].
12,13-Dihydroxy-9Z-octadecenoic acid
Adipose tissue crosstalk with other organs, including skeletal muscle and heart, occurs through peptide hormones (adipokines) and bioactive lipids (lipokines) [45]. 12,13-Dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a lipokine whose circulating levels rise after a single bout of exercise in both rodents and humans regardless of sex (male and female), age (young and older adults), and activity status (sedentary and physically active) [46]. Functionally, 12,13-diHOME enhances skeletal muscle free fatty acid uptake and promotes subsequent mitochondrial β-oxidation in rodents and humans [46]. In mice, brown adipose tissue (BAT) is the principal source of exercise-induced increases in circulating 12,13-diHOME, as surgical ablation of BAT abolishes this response [46]. Notably, although both cold exposure and exercise elevate BAT-derived 12,13-diHOME, their physiological roles appear context-dependent [46,47]: Stanford et al. [46] suggested that cold stimulates 12,13-diHOME release to act in an autocrine manner to fuel BAT thermogenesis, whereas exercise triggers endocrine release that targets working skeletal muscle to augment fatty acid uptake, oxidation, and mitochondrial activity. 12,13-diHOME has a favorable impact on cardiac function via nitric oxide synthase type 1 (NOS1) and its blood levels are reduced in patients with heart disease, suggesting that it exerts beneficial effects on the myocardium in an endocrine-like manner [48,49].
Summary
Overall, exerkines have emerged as critical mediators of the exercise-induced adaptation of skeletal muscle mass and function. Their pleiotropic actions, ranging from the autocrine regulation of muscle remodeling to the endocrine modulation of systemic physiology, underscore their therapeutic potential in improving sarcopenia and other muscle-wasting conditions. A deeper understanding of exerkine biology, including secretion dynamics, receptor specificity, and tissue-specific actions, is essential for optimizing exercise-based therapeutic strategies and designing targeted exercise-mimetic interventions.
IMPACTS OF EXERCISE ON EXERKINES AND SARCOPENIA
Physical inactivity is a key contributor to the attenuation of skeletal muscle protein synthesis, reduction of lean body mass, and impairment of muscular function, thereby exacerbating the incidence and progression of sarcopenia [10]. According to the World Health Organization 2020 Physical Activity Guidelines, older adults—including those with functional limitations or at risk of sarcopenia—are encouraged to engage in at least 150 to 300 minutes of moderate-intensity aerobic activity per week, or 75 to 150 minutes of vigorous-intensity activity, or an equivalent combination. In addition, muscle-strengthening exercise on ≥2 days per week and multicomponent training incorporating balance and functional movements ≥3 days per week are recommended to improve mobility and reduce fall risk [50]. Although these recommendations are not specific to sarcopenia, they may provide a practical framework for exercise-based management in this population. Many human studies have shown that exercise interventions, including aerobic training, resistance training, or a combination thereof, have profound effects on maintaining skeletal muscle mass and enhancing physical performance and muscle strength, which are the main components of sarcopenia [51,52]. The beneficial effects of exercise on sarcopenia are mediated by a range of complex mechanisms, including increasing muscle mass [53], stimulating muscle regeneration [54], attenuating reactive oxygen species [55], increasing hormone secretion [8], and improving mitochondrial homeostasis [7]. PGC-1α, which is regulated by exercise, is a core transcriptional coactivator that controls mitochondrial biogenesis [56]. In old mice, a sarcopenia model, long-term aerobic exercise activates the AMPK/PGC-1α pathway, promoting mitochondrial biogenesis and improving sarcopenia [57]. Mitochondria undergo a continuous process of fusion and fission to maintain homeostasis, known as mitochondrial dynamics. Knockout of sestrin2 results in an imbalance of mitochondrial dynamics as well as impaired mitophagy, and aerobic exercise alleviates these negative effects on sarcopenia through the sestrin2-AMPKα2 pathway [58]. High-intensity interval training (HIIT) augments mitochondrial biomass and muscle mass, improves grip strength, and increases treadmill endurance and gait speed in aged mice [59]. Notably, several exerkines released in response to exercise can modulate key mitochondrial quality control processes—such as mitophagy, mitochondrial biogenesis, dynamics, and redox regulation [7]. These processes collectively contribute to the preservation of mitochondrial homeostasis, which is essential for maintaining mitochondrial health and overall skeletal muscle metabolic balance [7].
Emerging evidence suggests that the secretion profiles and biological functions of exerkines are modulated by exercise duration, intensity, and mode. In the following section, we provide a comprehensive summary of the current findings regarding differential exerkine responses and associated skeletal muscle metabolic adaptations elicited by various exercise paradigms.
Duration of exercise
The physiological response to exercise varies substantially, depending on the duration of exposure. Acute exercise, defined as a single bout of either aerobic or resistance activity, primarily induces transient responses aimed at maintaining metabolic homeostasis. These include temporary elevations in inflammatory cytokine levels that are counterbalanced by anti-inflammatory mediators, as well as increased fuel utilization [21]. For example, IL-6 levels can increase up to 100-fold following acute exercise, triggering a compensatory anti-inflammatory response characterized by the release of molecules such as IL-10, IL-1 receptor antagonist (IL-1RA), and soluble TNF receptor [60]. Animal and human studies have demonstrated that acute exercise stimulates the expression of various exerkines, such as 12,13-diHOME, adiponectin, apelin, FGF-21, follistatin, musclin, IL-6, IL-8, IL-10, IL-13, and IL-1RA [21,61]. Unfortunately, meta-analytical findings suggest that, due to substantial inter-study variability, many of these changes in exerkine levels (e.g., IL-15, irisin, secreted protein acidic and rich in cysteine [SPARC], oncostatin M [OSM], and decorin) were not statistically significant [61]. The responses typically manifest as modest to substantial increases observed immediately after exercise and up to 60 minutes after exercise, with exerkine levels generally returning to baseline between 180 minutes and 24 hours [61].
Chronic or regular exercise induces a cumulative effect of exerkine secretion related to a single bout of exercise as well as more sustained physiological adaptations [21]. These adaptations are characterized by enhanced metabolic efficiency, including increased glucose uptake, fatty acid oxidation, and attenuation of oxidative stress and inflammation [21]. In association with these mechanisms, chronic exercise has been shown to upregulate several beneficial exerkines, including 12,13-diHOME, apelin, follistatin, and IL-13, while downregulating others such as fetuin-A, musclin, and IL-6 [21].
Importantly, the response of exerkines to acute exercise does not necessarily mirror that of chronic exercise. For instance, whereas acute bouts of exercise are known to transiently elevate circulating IL-6 levels, sustained exercise training regimens are typically associated with a reduction in plasma IL-6 concentrations, potentially accompanied by a compensatory upregulation of IL-6 receptor mRNA expression within skeletal muscle tissue in humans [21].
Exercise intensity
Exercise intensity is also important for modulating exerkine secretion [62]. Ji et al. [63] demonstrated that HIIT elicits significantly greater increases in brain-derived neurotrophic factor (BDNF), FGF-21, follistatin-like 1 (FSTL1), and cathepsin B than moderate-intensity continuous training (MICT). Similarly, He et al. [64] reported that the magnitudes of FGF-21 and follistatin responses were significantly elevated with higher aerobic exercise intensity. Furthermore, other studies have documented greater elevations in TGF-β1, follistatin, and activin A following high-intensity resistance training compared to lower-intensity protocols [65]. In human experiments, increased exercise intensity boosted plasma IL-6 concentrations compared with low-intensity exercise, but the anti-inflammatory IL-10 response was not significantly increased [66]. Riahy [67] reported that HIIT and MICT similarly decreased myostatin levels, but only HIIT significantly increased irisin levels in men with T2DM.
Exercise training modes
Aerobic exercise is closely linked to the upregulation of key exerkines including irisin, IL-6, BDNF, meteorin-like protein (METRNL), and FGF-21 [68–70]. These exerkines collectively enhance mitochondrial function, increase fatty acid oxidation, improve insulin sensitivity, and exert anti-inflammatory effects [70]. Through these mechanisms, aerobic exercise serves as a primary intervention for enhancing muscle quality, metabolic efficiency, and physical performance, particularly in populations at risk of age-related muscle decline [71]. Emerging evidence suggests that aerobic exercise may also have an anabolic potential [72,73]. In line with this, intermittent aerobic exercise increases the levels of serum apelin, a myokine associated with mitochondrial biogenesis and muscle regeneration [74].
Resistance exercise predominantly stimulates muscle anabolic signaling pathways [71] and is characterized by the elevated expression of insulin-like growth factor-1 (IGF-1) [75], apelin [74], and IL-15 [76], while concurrently suppressing myostatin, a potent inhibitor of muscle growth [77]. Additionally, decorin and follistatin are secreted in response to mechanical loading, thereby promoting satellite cell activation and muscle regeneration [77,78]. In addition to hypertrophic adaptations, resistance exercise regulates glucose and lipid metabolism and contributes to mitochondrial health. Animal studies have demonstrated that FGF-21 protein expression in skeletal muscle is stimulated by both aerobic and resistance training [79]. A recent meta-analysis of 34 studies reported that acute resistance exercise had immediate positive effects on IL-6, IL-1RA, and IL-15 [80].
Combined or multimodal training, which integrates both aerobic and resistance components, is particularly effective in enhancing multiple domains of musculoskeletal and metabolic functions. This exercise modality stimulates a broader exerkine profile, amplifying synergistic effects on muscle hypertrophy, metabolic regulation, and anti-sarcopenic responses [23]. Meta-analyses further support that combined training is superior to either modality alone in reducing systemic inflammatory markers such as C-reactive protein (CRP) and IL-6 and confers more pronounced anti-inflammatory and sarcopenia-ameliorating benefits [81,82].
Despite these promising findings, many exercise intervention studies are limited by a heterogeneous study design, small sample size, and variability in methodological quality, which compromise the generalizability and reproducibility of their results. Moreover, the physiological outcomes elicited by structured exercise programs exhibit considerable inter-individual variability, reflecting complex interactions between extrinsic factors (e.g., nutritional composition, timing of meals and exercise, environmental conditions, and sampling time of blood or tissue) and intrinsic determinants such as genetic background [62]. Despite these limitations, a comprehensive characterization of exercise-induced effects is essential for the development of personalized exercise prescriptions tailored to the physiological needs of an aging population. Therefore, for patients with sarcopenia, an appropriate combination of exercise type, duration, intensity, and frequency should be optimized and recommended for each individual.
CONCLUSIONS AND FUTURE PERSPECTIVE
Sarcopenia is a progressive musculoskeletal disorder closely associated with aging and physical inactivity that poses a significant threat to functional independence and longevity in older adults. Accumulating evidence has consistently demonstrated broad-spectrum health benefits of physical exercise. However, significant challenges remain in elucidating the molecular mechanisms underlying these benefits.
Among these insights, exerkines have attracted considerable attention as key mediators of exercise-induced physiological adaptations, particularly through their roles in orchestrating interorgan communication and maintaining systemic homeostasis [21]. In addition to promoting gains in muscle mass and strength, exerkine secretion in response to physical activity plays a central role in mediating a wide array of intramuscular and systemic effects [21]. Recent advances in multiomics microsampling during exercise are expected to facilitate the dynamic profiling of exerkines [83]. Exerkines, including myokines such as apelin, LIF, and IL-15; hepatokines such as FGF-21 and follistatin; and adipokines/lipokines such as adiponectin and 12,13-diHOME, exert diverse biological functions. They range from stimulating satellite cell proliferation and enhancing mitochondrial biogenesis to ameliorating inflammation, improving insulin sensitivity, and regulating lipid metabolism. Notably, the type and quantity of secreted exerkines, as well as their functional roles, appear to be influenced by the mode, intensity, and duration of exercise.
Metabolic comorbidities such as T2DM, obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and chronic kidney disease—conditions that commonly coexist with sarcopenia—are increasingly recognized as significant modulators of exerkine biology [84,85]. In these disease states, insulin resistance, chronic low-grade inflammation, oxidative stress, and dysregulated hormonal signaling substantially distort exerkine secretion patterns and reduce receptor sensitivity and downstream pathway signaling [84,85]. These metabolic alterations collectively blunt the anabolic, anti-inflammatory, and mitochondrial regulatory actions of exerkines, thereby diminishing their physiological efficacy and potentially accelerating muscle catabolism in vulnerable patients [84,85]. Accordingly, individualized exercise prescriptions matching specific metabolic comorbidities are required and further mechanistic and clinical studies are needed to define optimal strategies in these populations.
As our understanding of exerkine biology advances, its potential therapeutic application in the treatment of age-related diseases has become increasingly compelling, particularly in individuals with physical limitations that preclude regular exercise. In this context, the development of exercise mimetics such as AMPK activators, estrogen-related receptor α (ERRα)/PGC-1α agonists, myostatin inhibitors, SIRT1 activators, irisin/fibronectin type III domain containing 5 (FNDC5) pathway modulators, or apelin analogues [86], which are pharmacological agents designed to replicate the beneficial effects of exercise, represents a promising frontier in anti-aging medicine. Such interventions may enable targeted modulation of key molecular pathways, thereby promoting healthy aging at the cellular and systemic levels. However, these agents predominantly act on a single signaling axis and therefore cannot reproduce the broad, integrated metabolic, musculoskeletal, and cardiovascular adaptations induced by natural exercise [86]. Additional concerns regarding long-term safety, off-target effects, and limited clinical evidence further constrain their clinical use. Accordingly, current exercise-mimetic candidates may be considered as adjunctive strategies rather than perfect substitutes for regular exercise [86].
Looking ahead, the convergence of exercise physiology, molecular biology, and therapeutic innovation offers a transformative opportunity to reframe aging, not merely as a decline to be endured but also as a process that can be actively modulated. Through the continued exploration of exerkine-mediated mechanisms and translational strategies, we edge closer to a future in which an extended health span, rather than a lifespan alone, becomes the principal goal of geriatric healthcare.
Notes
CONFLICTS OF INTEREST
Kyung Mook Choi has been an honorary editor of the Diabetes & Metabolism Journal since 2024. He was not involved in the review process of this article. Otherwise, there was no conflict of interest.
FUNDING
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT; RS-2023-00220894), and a grant funded by Korea University (K2508621).
ACKNOWLEDGMENTS
Artificial intelligence (AI) assistance. ChatGPT (GPT-5 Thinking; OpenAI) was used solely to assist with English-language editing and clarity review of the manuscript. All AI-assisted text was reviewed and verified by the authors.