The dysregulation of endocrine hormones, such as insulin-like growth factor (IGF), growth hormone (GH), testosterone, estrogen, and cortisol, during aging is closely associated with sarcopenia and cognitive impairment (Zeng et al., 2020; Dabin et al., 2022). A decrease in IGF expression with advancing age leads to limited IGF/PI3K/Akt signaling-mediated protein synthesis, a reduction in the number of satellite cells available for damage repair, and ultimately, a decrease in muscle mass and strength (Serra et al., 2007). IGF-1 plays a crucial role in preventing cell death, promoting neurogenesis in the hippocampus, facilitating the normal phosphorylation of tau proteins, and clearing Aβ. Therefore, reduced IGF-1 levels in the bloodstream of patients with AD have been linked to increased Aβ deposition in the brain of these individuals (Westwood et al., 2014). GH, on the other hand, promotes muscle growth directly via GHR or indirectly by stimulating IGF-1 production. In the brain, GH activation in the hypothalamus triggers the release of GH-releasing hormone (GHRH), leading to elevated circulating levels of IGF-1, thereby supporting neuronal growth and survival, regulating tau protein phosphorylation, and counteracting the negative effects of Aβ in vivo (Winston et al., 2018). Furthermore, in the context of aging, a decrease in the level of testosterone, a critical sex hormone, has been associated with a decrease in muscle mass and strength (Mouser et al., 2016). Testosterone also plays a role in inhibiting SMAD-mediated protein degradation through the ubiquitin-proteasome system, thus reducing protein atrophy. While age-related decreases in testosterone levels appear to increase disease risk in humans, estrogen activates dormant muscle satellite cells, aiding in the repair of damaged muscle tissues (Morley, 2017a; Liao et al., 2019). However, compared to testosterone, estrogen, which possesses potential neuroprotective functions, appears to have a reduced ability to protect microglia from Aβ toxicity and promote microglial Aβ clearance (Keyvani et al., 2018).

In addition to anabolic hormones, glucocorticoids, particularly cortisol, also play a significant role in influencing human skeletal muscles (Kaplan and Shimizu, 1963). Cortisol levels are regulated at both the systemic and tissue levels to maintain glucocorticoid homeostasis. Elevated cortisol levels can result in muscle atrophy by increasing proteolysis through the ubiquitin-proteasome and lysosome systems (Sato et al., 2017). Additionally, glucocorticoids can decrease muscle protein synthesis by inhibiting IGF-I signaling and increasing myostatin signaling. This dual effect of cortisol on the muscles can impact muscle function and overall muscle health (Schakman et al., 2013). Furthermore, studies have revealed a correlation between plasma cortisol levels and cognitive impairment in individuals with AD, suggesting that the hyperactivity of the hypothalamic-pituitary-adrenal axis, which leads to elevated cortisol levels, may contribute to the progression of cognitive decline in these individuals (Zvěřová et al., 2013; Popp et al., 2015). Moreover, cortisol levels tend to increase with age, and higher levels of cortisol are associated with poorer cognitive function (Roelfsema et al., 2017; Qiu et al., 2021). These findings highlight the importance of understanding the impact of hormone levels on both muscle health and cognitive function, especially in the context of aging and neurodegenerative diseases.

The increased production of reactive oxygen species (ROS) during aging is associated with increased damage to biomolecules (Radak et al., 2016). This increase in oxidative damage results in the development of different pathophysiological states, such as aging-related skeletal muscle loss and neurodegenerative disorders (Naudí et al., 2007; Tang et al., 2019). Additionally, the decrease in antioxidant activity with aging leads to the activation of nuclear factor kappa-B (NF-κB) and forkhead box O (FoxO) through the ROS pathways, thus triggering apoptosis and protein degradation in skeletal muscles. These transcription factors subsequently promote the expression of the muscle atrophy F-box protein (MAFbx/Atrogin-1) and the muscle-specific ring finger protein 1 (MuRF1), ultimately resulting in skeletal muscle atrophy.

Compromised mitochondrial function leads to the expression of oxidative stress markers, such as IL-6, CRP, and IL-1RA, which are closely associated with reduced physical function and muscle strength in elderly individuals (Bellanti et al., 2018). Therefore, the maintenance of mitochondrial health is crucial for the viability and functioning of neurons, as their structural and functional integrity are closely intertwined (Rugarli and Langer, 2012). Moreover, the maintenance of normal mitochondrial function is essential for maintaining the stability of the internal environment in mammals, and any disruption in the ROS scavenging system during mitochondrial oxidative phosphorylation can lead to brain aging and neurodegenerative disorders (Bernardo et al., 2013). Recent studies have highlighted a strong relationship between oxidative stress, aging, and neurodegenerative conditions. These findings suggest that the accumulation of Aβ triggers detrimental cellular changes, including oxidative damage to the mitochondria (Bozner et al., 1997; Pappolla et al., 1998). However, the precise mechanisms by which Aβ operates in vivo are not fully understood. Some studies have proposed that the translocase of the outer mitochondrial membrane 40 (TOMM40) plays a role in regulating the entry of Aβ into the mitochondria through the Tom40 outer membrane pore, underscoring its role as a potential target for the treatment of cognitive impairment (Yu et al., 2007). Collectively, these reports suggest that the restoration of mitochondrial function is crucial for the effective management of nerve disorders, especially cognitive dysfunction.

Aging is commonly associated with a chronic low-grade inflammation known as inflammaging, which results in an elevation in the levels of inflammatory factors, which in turn cause the heightened metabolic degradation of skeletal muscles (Sato et al., 2016). Multiple potential mechanisms underlie chronic low-grade inflammation and its negative impacts on muscle health during the aging process. Age-related redox imbalances can lead to the upregulation of pro-inflammatory cytokines, which are key players in inflammatory pathways. Additionally, ROS can trigger inflammation, causing the release of TNF-α, leptin, and GH, and this cascade ultimately results in insulin resistance, accelerated muscle breakdown, and the loss of muscle mass (Thoma and Lightfoot, 2018). Proinflammatory cytokines, on the other hand, can counteract the anabolic effects of GH and IGF-1, causing a negative muscle protein balance, thereby affecting muscle function and strength (Kim et al., 2018). Recent evidence suggests that age-related chronic inflammation is correlated with elevated levels of circulating biomarkers, such as TNF-alpha, IL-1beta, IL-6, COX-2, iNOS (Chung et al., 2009). The findings reveal that this inflammatory response contributes to increased muscle breakdown and depletion through various pathophysiological pathways, thus contributing significantly to the aging of skeletal muscles (Kedlian et al., 2024). TNF-α, another key cytokine, has also been implicated in chronic inflammation and the onset of neurodegeneration (Hofman et al., 1989; Mogi et al., 1994). Furthermore, inflammatory cytokines have been shown to interfere with insulin function at the cellular level and worsen its neurotoxic effects, thus exacerbating cognitive decline (Fava et al., 2017). Therefore, chronic inflammation may serve as a shared pathogenic factor for aging-associated muscular dystrophy as well as MCI.

Aging-associated muscular dystrophy is a distinct disease associated with malnutrition. Reduced dietary intake and protein synthesis in patients with cognitive impairment can result in muscle loss, exacerbating the development of skeletal muscle atrophy (Cederholm et al., 2017). Malnutrition in elderly individuals, on the other hand, can result in decreased physical fitness and muscle strength and fitness, thus creating a vicious cycle. Inadequate nutritional intake can downregulate the Akt/mTORC1 signaling pathway, thus reducing muscle protein synthesis by inhibiting the phosphorylation of the downstream markers p70S6K and rpS6, and ultimately resulting in sarcopenia (Margolis et al., 2016). Inadequate nutrient intake can also increase oxidative stress or inhibit antioxidant mechanisms, contributing to the onset and progress of dementia. Evidence suggests that decreased food intake and activity in elderly individuals can cause vitamin D deficiency, which in turn impacts muscle protein synthesis and its metabolism through disturbances in the calcium and phosphorus levels and via insulin imbalance, ultimately leading to the development of sarcopenia (Ceglia et al., 2010). Moreover, since vitamin D and physical activity act synergistically and promote muscle protein ubiquitination and degradation, physical inactivity and vitamin D deficiency can worsen muscle atrophy (Yang et al., 2020). Furthermore, the risk of cognitive impairment is also greater in individuals with vitamin D deficiency, as vitamin D regulates calcium balance and Aβ deposition and displays antioxidant and anti-inflammatory properties in patients with AD.

Autophagy plays a crucial role in breaking down dysfunctional organelles and damaged macromolecules in aging cells, thus aiding in the maintenance of the internal environment of the muscle cells. Evidence suggests that the inhibition of autophagy in skeletal muscles can lead to neuromuscular synaptic issues and reduced muscle strength, potentially impacting the quality of life and the lifespan of animals (Carnio et al., 2014). This close association between autophagy and aging results in reduced autophagy or disrupted autophagic flux, leading to the excessive degradation of muscle proteins, thus exacerbating skeletal muscle loss. The age-associated reduction in neuronal autophagy, on the other hand, hinders mitochondrial renewal, causing the accumulation of impaired mitochondria, accelerated cell death, and inflammation (Sheng et al., 2010). Mounting evidence indicates that the interplay between cellular autophagy and mitochondrial dysfunction can contribute to the onset of various age-associated disorders (Green et al., 2011).

Similar to replicating cells, neurons, which are terminally differentiated post-mitotic cells during early development, do not possess the ability to eliminate misfolded proteins and damaged organelles through cell division (Metaxakis et al., 2018). Therefore, the dysfunction of the autophagic lysosomal degradation process disrupts neuroendocrine homeostasis, causes lipofuscin accumulation, inhibits autophagy, and establishes a detrimental cycle. Evidence suggests that the accumulation of autophagosomes in the hippocampus of aged mice due to reduced degradation is possibly linked with cognitive impairment (Soontornniyomkij et al., 2012). In addition, brain aging is also characterized by a gradual decline in neuronal autophagic lysosome function, which plays a crucial role in the progression from normal aging to pathological aging, ultimately resulting in neurodegeneration in patients with AD (Ling and Salvaterra, 2011). These findings suggest that impaired autophagy can contribute significantly to cognitive decline in elderly individuals.

Prolonged exercise leads to the production and release of IL-6, which is classified as a myokine, by the skeletal muscles. However, the release of IL-6 during exercise is associated with muscle damage (Bruunsgaard et al., 1997), and increased levels of circulating IL-6 have been linked to mortality in healthy elderly individuals (Harris et al., 1999). In a previous study, individuals with elevated levels of both IL-6 and CRP exhibited increased fibrinogen levels, indicating the potential presence of a chronic low-level inflammation associated with aging (Cohen et al., 1997). While elevated levels of IL-6 in the plasma lead to skeletal muscle atrophy through the STAT3/5 signaling pathway, the inhibition of the IL-6 receptor reduces muscle atrophy by suppressing the expression of MuRF1 (Yakabe et al., 2018). Therefore, IL-6 not only impedes muscle growth and disrupts energy balance but also actively contributes to muscle breakdown and subsequent atrophy (Goodman, 1994; Tsujinaka et al., 1995). Studies on transgenic mice with increased expression levels of human IL-6 have demonstrated significant muscle wasting in the mice by 10 weeks of age, along with the activation of lysosomal enzymes and increased expression of proteasomal subunits (Tsujinaka et al., 1995; Tsujinaka et al., 1996). However, the inhibition of IL-6 signaling by the prolonged administration of an IL-6R antibody led to the reversal of the muscular alterations observed in the IL-6 transgenic mice, and the alleviation of muscle atrophy in wild-type mice with tumors. Various studies have indicated that the Otago exercise program (Gde Agung Mahendra et al., 2022) and moderate-intensity strengthening resistance exercise (Heo and Jee, 2024) effectively decrease the risk of falls among elderly individuals by increasing muscle strength and stability and lowering the levels of IL-6.

IL-6, a key player in the early stages of amyloid plaque formation in the brain of patients with AD (Huell et al., 1995), has also been linked to tau phosphorylation, synapse loss, and cognitive impairment in mouse models of AD (Quintanilla et al., 2004). Despite certain conflicting opinions from the academic community, previous meta-analyses have shown that IL-6 levels are elevated in both the cerebrospinal fluid (CSF) and the plasma of individuals with MCI and AD compared to that in the CSF and plasma of control subjects (Brosseron et al., 2014). In individuals with AD, the elevation in the levels of IL-6 in both the brain and the bloodstream is associated with the severity of dementia (Huell et al., 1995; Kálmán et al., 1997). However, recent research has shown that the neutralization of IL-6 and the inhibition of the STAT3 signaling pathway in the brain of AD mouse models can improve memory impairment (Lyra et al., 2021). Despite its proinflammatory properties, IL-6 displays different effects during physiological and pathological conditions. One study revealed that the positive effects of Nordic walking are manifested by a decreased concentration of proinflammatory proteins such as HMGB1 and IL-6 and increased irisin (Gmiat et al., 2017). IL-6 can be considered both a pro-inflammatory protein and an anti-inflammatory protein. Previous research has reported significant variations in IL-6 levels in response to exercise, which are influenced by factors such as intensity, duration, working muscle mass, and an individual’s endurance capacity (Febbraio and Pedersen, 2005; Petersen and Pedersen, 2005). Overall, regular exercise has been associated with a significant reduction in inflammation by decreasing the circulating levels of specific inflammatory markers, including IL-6 (Bautmans et al., 2021).

IGF-1 plays a crucial role in promoting mesenchymal stem cell differentiation and migration, as well as enhancing muscle fiber proliferation, differentiation, and contraction. IGF-1 also contributes to nerve remodeling and skeletal muscle regeneration by acting as a powerful neurotrophic factor that supports nerve regeneration and facilitates neuromuscular repair (Apel et al., 2010). The IGF-1/Akt/mTOR signaling pathway is known to regulate skeletal muscle hypertrophy (Rommel et al., 2001), and higher levels of IGF-1 can inhibit the expression of the protein degradation markers Atrogin-1 and MuRF1, thereby alleviating skeletal muscle atrophy (Schulze et al., 2005). Nevertheless, research indicates that this age-related decrease in IGF-1 levels in the skeletal muscles can be partially counteracted by progressive resistance training (Urso et al., 2005).

In addition to its role in the growth and development of the body, IGF-1 plays a key role in the development and metabolism of the CNS. A recent study in male mice has shown that the overexpression of IGF-1 in the CNS can protect against age-related cognitive dysfunction (Farias Quipildor et al., 2019). For example, in a rat model of sporadic Alzheimer’s disease (sAD), adenovirus-mediated IGF-1 gene transfer into the brain led to an increase in the levels of synaptic markers, leading to enhanced hippocampal synaptic plasticity, thereby improving recognition and spatial memory (Zappa Villar et al., 2021). In humans, on the other hand, IGF-1 deficiency results in cognitive dysfunction, which can be improved by interventions that increase circulating IGF-1 levels (Sonntag et al., 2013). Additionally, exercise has also been found to counteract the negative effects of MCI by regulating the serum IGF-1 levels (Tsai C. L. et al., 2018). In aging rats, an 8-week swimming training program led to the activation of the IGF-1/PI3K/Akt signaling pathway in the hippocampus, resulting in the reduced apoptosis of the hippocampal neurons and improved hippocampal function (Lin et al., 2020). In humans, while studies on older women have shown that 16 weeks of aquatic exercise and 24 months of progressive resistance exercise can increase serum IGF-1 levels (Kang et al., 2020; Molina-Sotomayor et al., 2020), a study on 30 elderly males demonstrated that strength and endurance training can elevate the serum IGF-1 levels and enhance cognitive function in elderly individuals (Arazi et al., 2021).

BDNF, a protein belonging to the neurotrophic family, is primarily found in the brain and skeletal muscles and is vital for the development and differentiation of myoblasts and myofibers. It has also been detected in various tissues and body parts, including the periphery and the CNS, suggesting the presence of a neurotrophic connection between the different systems of the body and the blood-brain barrier (BBB) (Ribeiro et al., 2021). The level of BDNF decreases during myoblast maturation and myogenic differentiation, thus impacting the satellite cells or muscle progenitor cells (MPCs) and supporting the early differentiation of myoblasts (Mousavi and Jasmin, 2006). A study on a murine injury model revealed that BDNF functions via the tropomyosin-related kinase-B receptor (TrkBR) and the p75 neurotrophin receptor (p75NTR), both of which are markers of highly differentiated muscle precursor cells, thus enhancing myogenesis and myofiber maturation. Moreover, the expression of BDNF in the muscle satellite cells is upregulated during muscle injury, thereby facilitating the activation of the satellite cells (Yarrow et al., 2010).

BDNF also plays a crucial role in the CNS, overseeing neuronal survival, growth, and maintenance. It also regulates synaptic plasticity, cell survival, and brain cell differentiation (Aguado et al., 2003). Studies in mice have shown that BDNF positively affects brain function by promoting hippocampal cell regeneration, increasing BDNF gene expression, enhancing spatial memory, improving motor performance, and preserving the overall functionality of the brain (Marlatt et al., 2012). BDNF also acts as a key factor in exercise-induced neuroprotection, mediating the changes in synaptic strength and enhancing neurotransmitter release. Even in case of advanced memory impairment, cardiovascular exercise has been found to elevate BDNF levels, which in turn enhance hippocampal neuroplasticity and memory function in mice across various age groups from young to old (Tsai S. F. et al., 2018). Both human and animal studies have shown that acute/long-term cardiovascular/resistant exercise elevates circulating BDNF levels. In women, high-intensity cardiovascular exercise results in increased insulin sensitivity and reduced circulating levels of cortisol and BDNF, along with cognition-enhancing effects that are most pronounced for executive control tasks (Baker et al., 2010). In aging rats, cardiovascular exercise and strength training improve spatial memory by inducing neuroplasticity through distinct molecular mechanisms. Both exercise protocols also led to an increase in BDNF levels after training. While cardiovascular exercise specifically increased the levels of glutamatergic proteins (the NMDA receptor and PSD-95), strength training increased the levels of PKCα and the pro-inflammatory factors TNF-α and IL-1β (Vilela et al., 2017). These results suggest that cardiovascular exercise can positively impact brain functionality by affecting BDNF levels.

A study from 2012 revealed that prolonged exercise training in mice led to a significant increase in the expression of PGC-1α in the muscles, which in turn led to the enhanced expression of the target gene, FNDC5, resulting in the production of irisin, a myokine that converts white adipose tissue to brown fat (Boström et al., 2012). Irisin is a novel cytokine that is primarily found in the brain and skeletal muscles. Although its secretion decreases with age, it can be partially restored by resistance exercise training (Kim et al., 2015). Generally, individuals with sarcopenia exhibit lower levels of skeletal muscle protein biomarkers, including irisin, compared to those without sarcopenia (Yen et al., 2022). Irisin, an exercise-induced polypeptide secreted by skeletal muscles, crosses the blood-brain barrier and brings about certain exercise-mediated effects in the brain. Previous studies have shown a positive correlation between irisin levels and aging-induced cognitive dysfunction^. The primary pathological process of AD involves the over-accumulation of Aβ in the brain due to an imbalance in Aβ production and clearance (Lourenco et al., 2019). This excessive accumulation of Aβ leads to neurotoxicity, resulting in a decrease in the number of neurons, loss of synapses, and impaired nerve signal conduction, ultimately leading to cognitive impairment. Notably, FNDC5, the irisin precursor, has been found in various regions of the brain and is associated with neural differentiation (Hashemi et al., 2013). Physical exercise has been shown to enhance FNDC5 expression (Wrann et al., 2013) and irisin levels (Siteneski et al., 2018) in the hippocampus. In a study involving rats, the administration of Aβ1‒42 to the hippocampus led to spatial learning and memory impairments, along with reduced hippocampal FNDC5 expression. However, 4 weeks of moderate-intensity running exercise increased the hippocampal FNDC5 mRNA levels and improved spatial learning and memory loss in the rats.

Cathepsin B (CTSB), which is expressed in various tissues, including the skeletal muscles and the brain, can play a crucial role in brain flexibility. Moon et al. identified CTSB as a myokine in a study utilizing rat myotubes treated with the AMPK agonist AICAR (Moon H. Y. et al., 2016). Typically, physical activity increases the CTSB level in the blood and the CTSB gene expression in the hippocampus, indicating that CTSB impacts brain function both directly and indirectly. In mice, the deletion of the CTSB gene prevented the exercise-induced improvement in spatial memory retention and adult neurogenesis, reduced the inhibitory signals transmitted to dentate granule cells (GCs), and reduced the levels of hippocampal P11, a crucial protein necessary for the effect of CTSB on the differentiation and migration of neurons (Moon H. Y. et al., 2016). Additionally, CTSB also possessed the ability to penetrate the blood-brain barrier. While CTSB administration did not affect hippocampal cell proliferation in the mice, it increased the BDNF mRNA and protein expression levels. Additionally, CTSB treatment also elevated the level of doublecortin, a protein known for its neuroprotective effect and ability to promote neuronal migration.

CTSB is a potential therapeutic target for neurodegenerative diseases such as AD. Plasma levels of CTSB increased after adults at high risk for AD participated in 26 weeks of moderate-to-vigorous intensity cardiovascular exercise, with this alteration in CTSB positively correlated with cognitive performance (Gaitán et al., 2021). In a mouse model of AD, CTSB was found to reduce the levels of Aβ42 and improve behavioral abnormalities (Hwang et al., 2019). Conversely, another study revealed a correlation between an increase in the plasma CTSB levels and the progression of MCI and AD from the mild to the severe forms of the disease, with the pathological worsening of the disease being mediated by protein accumulation (Morena et al., 2017). However, CTSB also possesses neuroprotective and anti-amyloidogenic properties (Mueller-Steiner et al., 2006), and mice studies have revealed neuronal loss and brain atrophy in double-KO mice lacking both CTSB and CTSL (Felbor et al., 2002). Additionally, CTSB may also be involved in the exercise-mediated enhancement of hippocampal neurogenesis, memory, and learning. However, further research is needed to determine the extent to which this myokine influences the exercise-mediated improvement in cognitive function in humans.

LIF was first identified as a factor that promotes macrophage differentiation. It is produced by cardiac, neural, and skeletal muscles and acts as a versatile myokine (Hilton, 1992). LIF plays a role in controlling the proliferation and differentiation of satellite cells, which are crucial for muscle hypertrophy (Spangenburg and Booth, 2006). Studies have shown that LIF stimulates human myoblast proliferation and induces JunB and c-Myc expression in human myotubes. Conversely, the suppression of the LIF receptor has been shown to reduce myoblast proliferation (Broholm et al., 2011). LIF also has the ability to cross the blood‒brain barrier and enter the nervous system, where it plays a role in astrocyte development and oligodendrocyte survival. Treatment of mouse hippocampal cells with LIF has been found to activate the Akt/mTOR and STAT3 signaling pathways, downregulate LC3-II, increase c-fos expression (a marker of neuronal activation), and enhance cell survival. Similar results have also been observed in a Drosophila model of AD wherein LIF was found to inhibit LC3-II (Lee et al., 2019). Multiple studies have revealed elevated LIF levels in patients with AD, suggesting a possible connection between Aβ and the initiation of LIF-induced inflammation (Soilu-Hänninen et al., 2010). Theoretically, Aβ acts as a trigger for LIF, leading to an inflammatory response in individuals with AD. However, LIF also possesses neuroprotective properties, which it exerts by inducing oligodendrocyte apoptosis via TNF-α (Vanderlocht et al., 2006). In a drug trial involving rats with CNS injury, LIF was found to boost neurotrophin expression and facilitate corticospinal axon growth (Pan et al., 2000). However, owing to its potential instability, the impact of LIF on neural tissues was limited to a short duration. Further exploration is needed to address these limitations and establish LIF as a promising therapeutic option for the treatment of AD.