BACKGROUND: Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual\'s auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions.
METHODS: We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression.
RESULTS: The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor).
CONCLUSIONS: The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.

Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence-associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G-quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence-associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence.

UNASSIGNED: Cellular senescence is a common biological process with a well-established link to cancer. However, the impact of cellular senescence on tumor progression remains unclear. To investigate this relationship, we utilized transcriptomic data from a senescence gene set to explore the connection between senescence and cancer prognosis.
UNASSIGNED: We developed the senescence score by the Least Absolute Shrinkage and Selection Operator (LASSO) Cox model. We obtained transcriptomic information of the senescence gene set from The Cancer Genome Atlas (TCGA) program. Additionally, we created a nomogram that integrates these senescence scores with clinical characteristics, providing a more comprehensive tool for prognosis evaluation.
UNASSIGNED: We calculated the senescence score based on the expression level of 42 senescence-related genes. We established the nomogram based on the senescence score and clinical characteristics. The senescence score showed a positive correlation with epithelial-to-mesenchymal transition, cell cycle, and glycolysis, and a negative correlation with autophagy. Furthermore, we carried out Gene Ontology (GO) analysis to explore the signaling pathways and biological process in different senescence score groups.
UNASSIGNED: The senescence score, a novel tool constructed in this study, shows promise in predicting survival outcomes across various cancer types. These findings not only highlight the complex interplay between senescence and cancer but also indicate that cellular senescence might serve as a biomarker for tumor prognosis.

Cathepsin L (CTSL) has been implicated in aging and age-related diseases, such as cardiovascular diseases, specifically atherosclerosis. However, the underlying mechanism(s) is not well documented. Recently, we demonstrated a role of CUT-like homeobox 1 (CUX1) in regulating the p16INK4a-dependent cellular senescence in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via its binding to an atherosclerosis-associated functional SNP (fSNP) rs1537371 on the CDKN2A/B locus. In this study, to determine if CTSL, which was reported to proteolytically activate CUX1, regulates cellular senescence via CUX1, we measured the expression of CTSL, together with CUX1 and p16INK4a, in human ECs and VSMCs undergoing senescence. We discovered that CUX1 is not a substrate that is cleaved by CTSL. Instead, CTSL is an upstream regulator that activates CUX1 transcription indirectly in a process that requires the proteolytic activity of CTSL. Our findings suggest that there is a transcription factor in between CTSL and CUX1, and cleavage of this factor by CTSL can activate CUX1 transcription, inducing endothelial senescence. Thus, our findings provide new insights into the signal transduction pathway that leads to atherosclerosis-associated cellular senescence.

BACKGROUND: Intervertebral disc (IVD) degeneration (IVDD) is a prevalent condition contributing to back pain and disability. Periostin (POSTN) has emerged as a potential molecular marker and therapeutic target in IVDD, prompting further investigation into its role and mechanisms.
METHODS: This study employs bioinformatics analysis combined with experimental validation to explore the role of POSTN in IVDD. Gene expression datasets from the GEO database were analyzed to identify genes associated with IVDD, and the effects of POSTN on rat nucleus pulposus (NP) cells senescence and extracellular matrix (ECM) metabolism were assessed both in vitro and in vivo.
RESULTS: Elevated POSTN expression was observed in degenerated discs from IVDD patients, correlating with disease severity. In vitro experiments demonstrated that POSTN promotes NP cells senescence and ECM metabolism in a dose- and time-dependent manner. In vivo studies confirmed that POSTN inhibition can ameliorate the progression of IVDD. Further mechanistic insights revealed that POSTN may exert its effects by activating the NF-κB and Wnt/β-catenin signaling pathways.
CONCLUSIONS: POSTN plays a significant role in the pathogenesis of IVDD, with its upregulated expression closely linked to NP cells senescence and ECM metabolism. Targeting POSTN could offer a novel therapeutic strategy for IVDD. Additionally, the study predicts small molecules that may inhibit POSTN expression, providing potential candidates for the development of new drug treatments.

BACKGROUND: Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
METHODS: Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
RESULTS: We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
CONCLUSIONS: In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.

Metabolic disorders are considered the hallmarks of cancer and metabolic reprogramming is emerging as a new strategy for cancer treatment. Exogenous and endogenous stressors can induce cellular senescence; the interactions between cellular senescence and systemic metabolism are dynamic. Cellular senescence disrupts metabolic homeostasis in various tissues, which further promotes senescence, creating a vicious cycle facilitating tumor occurrence, recurrence, and altered outcomes of anticancer treatments. Therefore, the regulation of cellular senescence and related secretory phenotypes is considered a breakthrough in cancer therapy; moreover, proteins involved in the associated pathways are prospective therapeutic targets. Although studies on the association between cellular senescence and tumors have emerged in recent years, further elucidation of this complex correlation is required for comprehensive knowledge. In this paper, we review the research progress on the correlation between cell aging and metabolism, focusing on the strategies of targeting metabolism to modulate cellular senescence and the progress of relevant research in the context of anti-tumor therapy. Finally, we discuss the significance of improving the specificity and safety of anti-senescence drugs, which is a potential challenge in cancer therapy.

Intracerebral hemorrhage (ICH) is the cerebrovascular disease with the highest disability and mortality rates, causing severe damage to the health of patients and imposing a significant socioeconomic burden. Aging stands as a foremost risk factor for ICH, with a significant escalation in ICH incidence within the elderly demographic, highlighting a close association between ICH and aging. In recent years, with the acceleration of the \"aging society\" trend, exploring the intricate relationship between aging and ICH has become increasingly urgent and worthy of in-depth attention. We have summarized the characteristics of ICH in the elderly, reviewing how aging influences the onset and development of ICH by examining its etiology and the mechanisms of damage via ICH. Additionally, we explored the potential impacts of ICH on accelerated aging, including its effects on cognitive abilities, quality of life, and lifespan. This review aims to reveal the connection between aging and ICH, providing new ideas and insights for future ICH research.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease characterized by unknown causes and a poor prognosis. Recent research indicates that age-related mechanisms, such as cellular senescence, may play a role in the development of this condition. However, the relationship between cellular senescence and clinical outcomes in IPF remains uncertain.
METHODS: Data from the GSE70867 database were meticulously analyzed in this study. The research employed differential expression analysis, as well as univariate and multivariate Cox regression analysis, to pinpoint senescence-related genes (SRGs) linked to prognosis and construct a prognostic risk model. The model\'s clinical relevance and its connection to potential biological processes were systematically assessed in training and testing datasets. Additionally, the expression location of prognosis-related SRGs was identified through immunohistochemical staining, and the correlation between SRGs and immune cell infiltration was deduced using the GSE28221 dataset.
RESULTS: The prognostic risk model was constructed based on five SRGs (cellular communication network factor 1, CYR61, stratifin, SFN, megakaryocyte-associated tyrosine kinase, MATK, C-X-C motif chemokine ligand 1, CXCL1, LIM domain, and actin binding 1, LIMA1). Both Kaplan-Meier (KM) curves (p = 0.005) and time-dependent receiver operating characteristic (ROC) analysis affirmed the predictive accuracy of this model in testing datasets, with respective areas under the ROC curve at 1-, 2-, and 3-years being 0.721, 0.802, and 0.739. Furthermore, qRT-RCR analysis and immunohistochemical staining verify the differential expression of SRGs in IPF samples and controls. Moreover, patients in the high-risk group contained higher infiltration levels of neutrophils, eosinophils, and M1 macrophages in BALF, which appeared to be independent indicators of poor prognosis in IPF patients.
CONCLUSIONS: Our research reveals the effectiveness of the 5 SRGs model in BALF for risk stratification and prognosis prediction in IPF patients, providing new insights into the immune infiltration of IPF progression.

Smoking is a pathogenic factor for pulmonary hypertension (PH). Our previous study showed that serum miR-21 levels are elevated in smokers. miR-21 is considered as engaged in the PH process; however, its mechanisms remain unclear. In this investigation, we found that in the lung tissue of smoking-induced PH patients, the levels of miR-21 and aging markers (p21 and p16) were upregulated, and the function of pulmonary vascular endothelial cells was also impaired. Exposure of mice to cigarette smoke (CS) for four months caused similar changes in lung tissues and increased pulmonary arterial pressure, which were attenuated by knockout of miR-21. Further, human umbilical vein endothelial cells (HUVECs) exposed to cigarette smoke extract (CSE) revealed upregulation of miR-21 levels, depression of PTEN, activation of PI3K/AKT/mTOR signaling, an increase in senescence indexes, and enhanced dysfunction. Inhibiting miR-21 overexpression reversed the PTEN-mTOR signaling pathway and prevented senescence and dysfunction of HUVECs. In sum, our data indicate that miR-21-mediated endothelial senescence and dysfunction are involved in CS-induced PH through the activation of PI3K/AKT/mTOR signaling, which suggests that selective miR-21 inhibition offers the potential to attenuate PH.