Core Viewpoint - The study highlights the role of senescent macrophages in inducing ferroptosis in skeletal muscle, which accelerates muscle atrophy related to osteoarthritis (OA) [3][8][10]. Group 1: Osteoarthritis and Muscle Atrophy - Osteoarthritis (OA) is characterized by pathological changes including cartilage damage, subchondral bone remodeling, and synovial inflammation, with muscle atrophy being a common manifestation [2]. - Muscle atrophy associated with OA is strongly correlated with knee joint symptoms and the deterioration of joint pathology [2]. Group 2: Mechanisms of Muscle Atrophy - Senescent macrophages induce ferroptosis in skeletal muscle, leading to quadriceps atrophy associated with OA [3][8]. - The mechanism involves iron overload in senescent macrophages causing mitochondrial damage in muscle cells, which reduces aspartate metabolites and inhibits the mTORC1-HMGCR signaling pathway, ultimately decreasing endogenous coenzyme Q10 (CoQ10) synthesis [3][10]. Group 3: Role of CoQ10 - CoQ10 is crucial for maintaining muscle integrity and quality, with its levels positively correlating with antioxidant capacity, muscle mass, strength, and endurance in OA patients [6]. - Exogenous supplementation of CoQ10 has been shown to alleviate muscle atrophy by inhibiting ferroptosis, significantly increasing quadriceps mass and reducing pathological damage to OA joints [10].

Core Viewpoint - The article discusses the development of a human universal senescence index (hUSI) that accurately predicts cellular senescence across various conditions, addressing the challenges of identifying heterogeneous senescent cells [3][7][9]. Group 1: Background on Cellular Senescence - Cellular senescence (CS) is characterized by irreversible cell cycle arrest and is considered a key factor in age-related diseases [2]. - Senescent cells secrete pro-inflammatory proteins and other paracrine factors, which can stimulate immune responses and intercellular communication, leading to diverse effects in various tissues [2]. Group 2: Development of hUSI - The research team from Fudan University developed hUSI, a transcriptome-based index for assessing cellular senescence reliably across different cell types and conditions [3][7]. - The study compiled and standardized single-cell transcriptome sequencing data from 73 published studies, resulting in a comprehensive dataset of 770 senescent and non-senescent cell samples covering 34 cell types and 13 senescence types [3][9]. Group 3: Significance and Applications of hUSI - hUSI demonstrates a strong correlation with senescence phenotypes and shows robustness in predicting senescence states [9]. - The technology has identified potential senescence regulatory factors and mapped the accumulation of senescent cells in different cell types during COVID-19, as well as decoded the heterogeneous senescence states in melanoma tumors [9][10]. - The hUSI method has broad applications in aging research and clinical practice, with an open-source software package and user guide available for further use [10].

Core Viewpoint - Cellular senescence is a stable state of growth arrest closely related to age-related diseases and cancer development, characterized by an intrinsic anti-apoptotic ability and a unique secretory phenotype known as the senescence-associated secretory phenotype (SASP) [1][2]. Group 1 - Senescent tumor cells release mitochondrial DNA (mtDNA), which enhances immunosuppression mediated by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) through the cGAS-STING pathway [3][9]. - The release of mtDNA from senescent cells can exacerbate inflammation associated with tissue damage or disease progression, indicating a potential mechanism linking cellular senescence to age-related diseases and cancer [2][6]. - The study highlights that targeting the release of mtDNA could reprogram the immunosuppressive tumor microenvironment, thereby improving cancer treatment outcomes for patients undergoing chemotherapy [9][10]. Group 2 - The research team found that both naturally senescent primary cells and tumor cells undergoing senescence due to treatment actively release mtDNA into the extracellular environment [5][7]. - Extracellular mtDNA is encapsulated in extracellular vesicles and selectively transferred to PMN-MDSC, enhancing their immunosuppressive activity through the cGAS-STING-NF-κB signaling pathway [5][10]. - Pharmacological inhibition of voltage-dependent anion channels (VDAC) can reduce extracellular mtDNA levels and reverse PMN-MDSC-driven immunosuppression, improving chemotherapy efficacy in prostate cancer mouse models [6][10].