Wen Kong

Skeletal muscle aging is a conserved biological process characterized by progressive declines in muscle mass, strength, regenerative capacity, and metabolic adaptability, contributing to impaired mobility, frailty and age-related diseases. Beyond its canonical role in locomotion, skeletal muscle functions as an endocrine and metabolic organ that actively regulates organismal aging through myokines, metabolites, extracellular vesicles, thermogenic activity, and dynamic communication with distant organs. In this review, we summarize the intrinsic mechanisms driving skeletal muscle aging, including protein turnover imbalance and anabolic resistance, myosteatosis, denervation and motor unit loss, and cellular composition remodeling. We also discuss how aging skeletal muscle influences systemic aging through bidirectional interactions with metabolic organs, brain, cardiovascular system, and bone via endocrine signaling and interorgan communication. Finally, we highlight emerging interventions targeting skeletal muscle aging, including exercise, nutritional strategies, pharmacological approaches, and other novel therapies. Understanding skeletal muscle as both a target and regulator of systemic aging provides a framework for developing strategies to promote healthy aging and reduce the burden of age-associated diseases.

Obesity leads to a chronic inflammatory state throughout the body, with increased infiltration of immune cells and inflammatory factors in skeletal muscle tissue, and, at the same time, the level of intracellular mitochondrial oxidative stress rises. Meanwhile, obesity is closely related to the development of skeletal muscle fibrosis and can affect the metabolic function of skeletal muscle, triggering metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D). However, whether there is a mutual regulatory effect between the two pathological states of inflammation and fibrosis in obese skeletal muscle and the specific molecular mechanisms have not been fully clarified. This review focuses on the pathological changes of skeletal muscle inflammation and fibrosis induced by obesity, covering the metabolic changes it causes, such as lipid deposition, mitochondrial dysfunction, and dysregulation of inflammatory factors, aiming to reveal the intricate connections between the two. In terms of intervention strategies, aerobic exercise, dietary modification, and pharmacotherapy can improve skeletal muscle inflammation and fibrosis. This article provides insight into the important roles of inflammation and fibrosis in the treatment of obesity and the management of skeletal muscle diseases, aiming to provide new ideas for the diagnosis and treatment of metabolic diseases such as obesity and IR.

Central presbycusis is caused by degradation of the auditory centre during ageing. Its main characteristics are difficulties in understanding language and localizing sound. Presbycusis is an increasingly critical public health problem, but the underlying molecular mechanism has not been fully elucidated. Ferroptosis is a form of regulated cell death caused by iron‐ and reactive oxygen species‐induced lipid peroxidation. Ferroptosis is related to many pathological processes, but whether it participates in the degeneration of the auditory system remains unclear. To investigate this, we measured iron levels in a simulated ageing model established by the addition of d‐galactose (d‐gal). We found, for the first time, that iron accumulated within cells and that the ultrastructural features of ferroptosis appeared in the auditory cortex with ageing. These changes were accompanied by upregulation of iron regulatory protein 2 (IRP‐2), which led to an increase in transferrin receptor 1 (TfR‐1), thus increasing iron entry into cells and potentially leading to ferroptosis. In addition, the malondialdehyde (MDA) content and the occurrence of mitochondrial DNA common deletions (CDs) increased, neuron degeneration appeared, and glutathione (GSH) and superoxide dismutase (SOD) activity decreased. Furthermore, we found that treatment with the iron chelator deferoxamine (DFO) and knockdown of IRP‐2 both relieved ferroptosis during the simulated ageing process, thus achieving a partial protective effect to delay ageing. In summary, we describe here the first discovery that age‐related iron deposition and ferroptosis may be associated with auditory cortex neurodegeneration. Relieving ferroptosis might thus be a new intervention strategy for age‐related hearing loss.