Prevalence of sarcopenia, which was officially classified as a disease by the World Health Organization (WHO) in 2016 using the International Classification of Diseases (ICD-10) code M62.84, varies based on age, sex, race, and measurement method [10]. Understanding these pathogenic mechanisms will allow for the design of practical therapeutic approaches for sarcopenia. Therefore, this paper discusses treatment and prevention strategies for sarcopenia, focusing on three factors that recent research has emphasized on: exercise, nutrition, and antioxidant compounds (monoterpenes). It is estimated that approximately 10-20% of individuals over 60 years of age experience sarcopenia, with the prevalence increasing with age and affecting over 50% of people over 80 years of age [11]. In addition, men showed a higher prevalence compared to women [12]. The reported prevalence of sarcopenia can vary based on the country and research institution, and the exact prevalence may change over time owing to different research methods. In Europe, the prevalence ranges from approximately 11% to 20%. In the European Union, the social, health, and economic impacts of sarcopenia are significant owing to the large elderly population [13]. Japan, with its rapidly aging population, has a high prevalence of sarcopenia, with more than 20% of the elderly experiencing it [14]. Similarly, in Korea, prevalence is increasing with approximately 10-20% of people over 60 years of age being affected, although exact statistics are limited [15].

Sarcopenia occurs through various complex physiological processes. Major factors contributing to sarcopenia include hormonal changes, chronic inflammation, neuromuscular junction changes, mitochondrial dysfunction, and oxidative stress (Figure 1). The Forkhead box O3 (FOXO3) transcription factor is a significant signaling pathway that regulates muscle protein breakdown. Regulated by the insulin/IGF-1 pathway, FOXO3, when activated, induces the expression of genes that promote muscle protein breakdown upon activation. Insulin/IGF-1 activation leads to FOXO3 phosphorylation via the PI3K/AKT pathway, thereby maintaining FOXO3 inactivity in the cytoplasm. Reduced insulin/IGF-1 signaling suppresses AKT activation, causing FOXO3 dephosphorylation and nuclear translocation, and increasing MURF-1 and Atrogin-1 gene expression. Nuclear FOXO3 promotes the transcriptional activation of these ligases, enhancing muscle protein breakdown, and resulting in muscle atrophy. FOXO3 regulates autophagy in response to cellular stress and is crucial for removing damaged organelles and proteins.

Accumulation of senescent cells in the muscles leads to increased secretion of inflammatory molecules [16]. Inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor-α (TNF-α) activate the intracellular nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [17]. Activated NF-kB promotes skeletal muscle protein degradation by increasing the expression of MURF-1 and Atrogin-1 [18]. Additionally, it promotes the expression of inflammatory factors IL-6 and TNF-a, further activating inflammation and increasing the production of endogenous reactive oxygen species (ROS) [19].

Muscle cells have numerous mitochondria because of the high energy demand for contractile activity [20]. It generates a large amount of ROS within muscle cells and activates protein breakdown metabolism [21]. ROS damages mitochondrial DNA and proteins, which results in mitochondrial dysfunction [22]. Additionally, ROS phosphorylates MAPKs, which activate NF-κB. Activated proteins induce pro-cytokines or increase the expression of the protein degradation biomarkers, MURF-1 and Atrogin-1 [23].

Reduced muscle fiber synthesis due to inflammation, as well as decreased testosterone and estrogen hormone levels, inhibit muscle synthesis and cause muscular atrophy. Decreasing testosterone and estrogen levels also contribute to a reduction in muscle mass and function [24]. Inflammatory cytokines, such as TNF-α, IL-6, etc., accelerate the progression of sarcopenia by promoting muscle protein breakdown and interfering with muscle cell regeneration [25].

Exercise exerts mechanical stress on muscle cells, promotes muscle growth, and increases protein synthesis [26]. Resistance training, in particular, strengthens muscle fibers stronger and larger, improves mitochondrial function, and increases metabolic activity in muscle cells [27]. Exercise also regulates hormone secretion and promotes the production of growth hormones and IGF-1, aiding the recovery and regeneration of muscle cells [28].

Table 1 shows clinical results on the effects of exercise and nutrition on muscle growth. Monti et al. investigated the effects of exercise in 45 older adults with decreased muscle function [29]. The study was conducted over two years divided into a control group and an exercise group. The exercise was a combination of aerobic exercise and strength training and was trained three times a week for two years. The aerobic and strength exercises reduced the concentration of the C-terminal agrin fragment in the serum and were effective in maintaining neuromuscular junction stability and muscle structure, thereby improving physical performance in elderly people with sarcopenia. Similarly, Leuchtmann et al. investigated the effects of resistance exercise on skeletal muscle vascularization in older adults [30]. Healthy elderly men performed resistance training and high-intensity intermittent exercises for 12 weeks. The findings revealed enhanced capillary action and increased oxidase activity in the skeletal muscle, suggesting that exercise not only prevents muscle atrophy but also promotes vascular health, which is critical for sustaining muscle function.

Jhang et al. sought to determine the effects of lower extremity muscle exercises in middle-aged people [31]. The survey was conducted among residents aged 55 years or older. Fifty participants were randomly assigned to control and experimental groups. The experimental group exercised for 50 min three times a week for 12 weeks. These findings in middle-aged adults showed that lower-extremity exercises improved muscle functional fitness, physiological indices, sleep quality, and mental health. This holistic improvement highlights the systemic benefits of targeted muscle exercises.

Vikberg S et al. studied the effects of resistance exercise in sarcopenic patients over 70 years of age [32]. The participants were divided into a control group (n=34) and a physical training and diet control group (n=36). The diet was provided as a 250 mL supplement containing 19 g carbohydrates, 21 g protein, and 1.5 g fat. Resistance exercise was performed for 45 minutes three times a week for 10 weeks. Their results suggest that dietary protein supplementation synergizes with resistance training to maintain strength and increase muscle mass.

Hofmann M et al. investigated the effects of resistance training and nutritional supplementation on 91 women with an average age of 63.6 divided into resistance training, resistance training and nutritional supplementation, and control groups [33]. These results show that personalized approaches that integrate exercise and nutrition significantly improve muscle quality and physical performance in older women, emphasizing the need for tailored interventions.

These exercise protocols show a personalized approach in which each patient with sarcopenia is unique with their own health status, physiological characteristics, and exercise levels.

However, treatment of sarcopenia alone has some limitations. Exercise plays a crucial role in muscle growth and function; however, muscle cells may require proper nutrients [34]. Proteins, vitamin D, and omega-3 fatty acids are essential for muscle health [35]. Muscle recovery and growth are limited in the absence of these nutrients. Sarcopenia is caused by various physiological changes that occur with aging. These factors are challenging to address by using simple exercises alone. For instance, hormonal imbalance or chronic inflammation can significantly cause a decline in muscle cell function. Patients with sarcopenia who attempt exercise may experience a severe functional decline in their muscle cells. Representative resistance exercises and their effects on protein synthesis are summarized in Table 2.

Choline is an essential nutrient for cell membrane metabolism and signaling, and is known to have antioxidant properties. Lee et al. studied the effects of choline intake and resistance exercise on the strength and muscle mass of elderly people [36]. Healthy adults were divided into three groups: low-, medium-, and high-choline intake groups. In all groups, resistance exercise was performed 3 times a week in 3 sets of 8-12 repetitions. Low choline intake did not increase muscle strength; however, high choline intake led to significant increases in strength after 12 weeks of training.

Kim et al. investigated the effects of combined exercise and nutrition in 26 elderly women with spinal sarcopenia patients [37]. A comparative analysis was conducted before and after the 13 weeks of exercise. All participants exercised for 50 min once every two weeks for 12 weeks. The diet consisted of liquid supplements and energy bars were consumed daily for 12 weeks. Physical and back performance, as measured using the Short Physical Performance Battery, significantly improved after exercise.

Leucine is an essential amino acid that decreases protein breakdown and increases protein synthesis [38]. Vitamin D is a potent antioxidant that reduces liposomal lipid peroxidation and regulates intracellular GSH and SOD [39]. Combining leucine and vitamin D intake with exercise increases muscle function and mass in elderly individuals and patients with muscular dystrophy. Rondanelli et al. analyzed the effects of nutrition and exercise in 161 sarcopenic older adult [40]. They were divided into two groups: a placebo group and a group wherein leucine and vitamin D-based whey protein food (150 kcal) was consumed. Additionally, all groups performed the exercise 20 minutes a day, 5 times a week, for 8 weeks. Consuming a whey protein-based diet rich in leucine and vitamin D improves physical performance and function and increases muscle mass. Nilsson et al. investigated the effects of five nutritional supplements containing vitamin D on muscle strength in older adult [41]. The participants were divided into two groups: an exercise-only group and an exercise and intake of the five nutritional supplements group. Nutritional supplements (proteins, micellar casein, creatine, vitamin D3, and omega-3) were administered in the mornings for 12 weeks. Additionally, all participants underwent home-based resistance training using elastic bands three times a week for 12 weeks. Muscle mass, strength, and tone improved in the group that received the five nutritional supplements. Finally, Molnár et al. investigated the effects of exercise and nutrition in 34 older adults [42]. They were divided into two groups: the resistance training group and the exercise and nutrition intake (containing 20 g protein, 10 g essential amino acids, 3 g leucine, 9 g carbohydrates, 3 g fat, vitamins, and minerals) group. Resistance exercises were performed twice a week for 3 months. In the resistance exercise group, skeletal muscle mass and strength did not improve, whereas exercise and intake significantly improved skeletal muscle mass and strength.

Monoterpenes are abundant in oranges, lemons, grapefruits, rosemary, thyme, and mint [43]. Monoterpene is a substance that has anti-inflammatory, analgesic, antibacterial, antibacterial, antiviral, anticancer, antituberculous, and antioxidant effects [44]. Monoterpenes include thymol, p-cymene, linmonene, camphor, sabinene, and camphene. Table 3 lists the types and effects of monoterpenes. Thymol showed anti-inflammatory effects in acutely inflamed mice and in an acute periodontitis mouse model [45]. Additionally, P-cymene reduced the expression of inflammatory cytokines and increased the expression of superoxide dismutase in the serum of obese mice induced by a high-fat diet [46]. Monoterpenes are known to inhibit oxidative stress associated with mitochondrial dysfunction [47]. In addition, (R)-(+)-limonene regulates both glucose uptake and lipolysis [48]. Sarcopenia is caused by excessive generation of ROS, resulting in mitochondrial dysfunction and changes in lipid metabolism [49]. Recently, we reported that camphene alleviates muscular dystrophy by regulating mitochondrial dysfunction and MURF-1, and Atrogin-1 expression in muscular dystrophy cells and animal models [50]. Ryu et al. reported that sabinene was effective against muscular dystrophy in animal models of muscular dystrophy [51]. Therefore, monoterpenes, which have strong anti-inflammatory and antioxidant effects, may be potential candidates for clinical treatment of sarcopenia.