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Aim: Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter‐organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling. Methods: In a first experiment, 10‐week‐old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%–21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild‐type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT‐qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy. Results: CIH‐induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH‐induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH‐induced myocardial fibrosis. Conclusion: Short‐term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA‐related cardiac disorders. [ABSTRACT FROM AUTHOR]

Addressing adipose niche senescence is crucial for preventing obesity‐related aging. Telomerase reverse transcriptase (TERT) is a promising target for gene therapy, but traditional methods lack precision and safety. A novel mitochondrion‐located TERT (mito‐TERT) activating approach is presented by injectable gene/short‐fiber complexes (gene/fiber‐plexes) to safely reverse adipose niche senescence from mitochondrial enhancement. The gene/fiber‐plexes are prepared from polydopamine‐coated short‐fibers to adsorb cationic dendrimers (PAMAM G3, PG3) carrying TERT plasmids and Coenzyme Q10 (CoQ10), termed PG3‐TERT@CoQ10. Upon intraperitoneal injection, the gene/fiber‐plexes adhere to the peritoneum and release PG3‐TERT@CoQ10, precisely targeting the adipose niche. Transient active oxygen scavenging by CoQ10 activates TERT transfection and endogenous mitochondrion translocation sequentially, enhancing mitochondrial function. In vitro and in vivo studies shows that gene/fiber‐plexes effectively targeted visceral adipose tissue, increased mito‐TERT levels and restored mitochondrial function. In an obese mouse model, they restored adipose tissue homeostasis and metabolic stability. RNA sequencing indicated reduced senescence‐related genes and restored cell cycle. This mito‐TERT activation strategy shows great promise for treating premature aging and metabolic diseases linked to adipose tissue senescence. [ABSTRACT FROM AUTHOR]

Cellular senescence, traditionally associated with aging and chronic diseases, has recently been identified as a potential facilitator of tissue regeneration via a senescence‐associated secretory phenotype (SASP). In rodents, the meniscus is known to regenerate spontaneously from the surrounding synovium, but the mechanism, and especially its relationship to cellular senescence, remains unclear. This study investigated the contribution of cellular senescence to spontaneous repair of the rat meniscus. We created a rat partial medial meniscectomy (pMx) model to evaluate time‐course changes in regenerative tissue. Immunohistochemistry revealed marked increases in p16 expression and senescence‐associated beta‐galactosidase (SA‐β‐gal) activity in the regenerating tissue at the early phase after pMx surgery. RNA sequencing of regenerating tissues identified the upregulation of genes related to aging, extracellular matrix organization, and cell proliferation. Fluorescence staining identified high expression of SOX9, a master regulator of cartilage/meniscus development, adjacent to p16‐positive cells. In vitro investigations of the effect of SASP factors on synovial fibroblasts (SFs) demonstrated that conditioned medium from senescent SFs stimulated the proliferation and chondrogenic differentiation of normal SFs. In vivo histological evaluation to determine whether selective elimination of senescent cells with a senolytic drug (ABT‐263) retarded spontaneous repair of meniscus in vivo confirmed that ABT‐263 decreased the meniscus score and expression of SOX9, aggrecan, and type 1 collagen. Our findings indicate that transient senescent cell accumulation and SASP in regenerating tissues beneficially contribute to spontaneous repair of the rat meniscus. Further research into the molecular mechanism will provide a novel strategy for meniscus regeneration based on cellular senescence. [ABSTRACT FROM AUTHOR]

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA‐damage protein 훾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence‐related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo. [ABSTRACT FROM AUTHOR]

The risk of developing type 2 diabetes (T2D) is heterogeneous among individuals with obesity. Functional decline of adipocyte precursor cells (APCs) and accumulation of senescent cells in the subcutaneous adipose tissue contributes to the progression toward T2D. LncRNAs regulate cell senescence and may be implicated in determining this abnormality in APCs. Here, we report that APCs from individuals with obesity show a gradual increase in multiple senescence markers, which worsens in parallel with the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) or T2D. Transcriptomic analysis identified PANDAR as the top‐ranked lncRNA differentially expressed in APCs from individuals with obesity and T2D and non‐obese subjects. Q‐PCR confirmed PANDAR up‐regulation in APCs from individuals with obesity, at progressively increased levels in those who developed, respectively, IGT and T2D. Bisulfite sequencing and luciferase assays revealed that, in parallel with glucose tolerance deterioration, the −1317 CpG at the PANDAR promoter became hypo‐methylated in obesity, resulting in enhanced PANDAR induction by p53. PANDAR silencing in senescent APCs from individuals with obesity and T2D caused repression of senescence programs and cell cycle re‐entry. PANDAR transcription in white blood cells (WBCs) mirrored that in APCs. Also, individuals with obesity exhibited rescue of PANDAR transcription in WBCs following bariatric surgery, accompanied by enhanced methylation at the regulatory PANDAR −1317 CpG. In conclusion, PANDAR dysregulation is a newly identified mechanism determining the early senescence of APCs from individuals with obesity, which worsens along the progression toward T2D. In the future, PANDAR targeting may represent a valuable strategy to delay this progression. [ABSTRACT FROM AUTHOR]

Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence. Synopsis: Heterochromatin plays an essential role in the regulation of genome stability, gene expression, and cellular functions, but the factors responsible for its formation and maintenance remain incompletely characterized. This study shows that insulin receptor tyrosine kinase substrate (IRTKS) can undergo liquid‒liquid phase separation and counteract cellular senescence by regulating heterochromatin organization. IRTKS is required for heterochromatin architecture. IRTKS undergoes liquid-liquid phase separation and infiltrates into heterochromatin condensates. IRTKS facilitates HP1α SUMOylation by Ubc9 and its subsequent stabilization. IRTKS deficiency accelerates cellular senescence. IRTKS contributes to the formation and maintenance of HP1α-driven heterochromatin condensates by promoting HP1α SUMOylation. [ABSTRACT FROM AUTHOR]

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging. [ABSTRACT FROM AUTHOR]

Single‐cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell‐intrinsic and ‐extrinsic stressors. With an atlas of single‐cell RNA‐sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin‐specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non‐replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age‐related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age‐related skin sequelae. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," and "CELLULAR SENESCENCE." Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as "DNA DAMAGE," "OXIDATIVE STRESS," and "AUTOPHAGY." According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro‐inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients' quality of life. [ABSTRACT FROM AUTHOR]

The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age‐associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence‐associated secretory phenotype, exacerbate the aging process through pro‐inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging‐associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age‐related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging‐related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population. [ABSTRACT FROM AUTHOR]

Recent evidence suggests an association between age‐related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age‐related osteoporosis and the mechanism remain unknown. Results revealed that age‐related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast‐specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age‐related osteoporosis. Histomorphometrically, Men1‐knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age‐related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein‐indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age‐related osteoporosis and that osteoblast‐specific inducible Men1‐knockout mice offer a promising model for developing therapeutics for age‐related osteoporosis. [ABSTRACT FROM AUTHOR]

Therapy‐induced senescence can regulate both the innate and adaptive immune systems, thereby affecting therapeutic efficacy. Bleomycin is a major component of combined chemotherapy regimens, utilized for the treatment of multiple tumors, whereas pulmonary toxicity severely restricts its clinical benefits. As a member of the bleomycin family, boningmycin (BON) exhibits potent anticancer activity with minimal pulmonary toxicity, making it a potential alternative to bleomycin. Low concentrations of BON can induce senescence, but the impact of BON‐induced senescence on anticancer immunity remains unclear. This study investigates the effects of BON‐induced senescence on PD‐L1 expression and the underlying mechanisms in human cancer cells. Firstly, the elevation of PD‐L1 protein during BON‐induced senescence was confirmed by a senescence β‐galactosidase staining assay, detection of the senescence‐associated secretory phenotype (SASP), western blot and flow cytometry in human lung cancer NCI‐H460 cells and breast cancer MDA‐MB‐231 cells. Subsequently, it was shown that the increase in PD‐L1 protein is mediated by SASP, as evidenced by the use of conditional media, knockdown of cyclic GMP‐AMP synthase and inhibition of stimulator of interferon genes. Ultimately, it was demonstrated that SASP‐mediated PD‐L1 up‐regulation is dependent on the activation of the JAK/STAT pathway through the use of specific inhibitors and siRNAs. These findings clarify the impact of BON‐induced senescence on PD‐L1 expression and may contribute to the optimization of the therapeutic efficacy of bleomycin‐related compounds and the clinical transformation of BON. [ABSTRACT FROM AUTHOR]

The evidence of the correlation between cellular senescence and aging has increased in research with animal models. These models have been intentionally generated to target and regulate cellular senescent cells with the promoter activity of p16Ink4a or p19Arf, genes that are highly expressed in aging cells. However, the senolytic efficiency in various organs and cells from these models represents unexpected variation and diversity in some cases. We have generated a novel knock‐in model, p16tdT‐hDTR mice, which possess tdTomato and human diphtheria toxin receptor (hDTR) downstream of Cdkn2a, an endogenous p16Ink4a gene. We successfully demonstrated that p16‐derived tdTomato and hDTR expressions are observed in these mouse embryo fibroblasts and following treatment with diphtheria toxin (DT) eliminates those cells. Furthermore, we demonstrated the efficacy of eliminating p16‐positive cells in vivo, and also observed a tendency to decrease their cutaneous SA‐β‐gal activity after subcutaneous DT injection into p16tdT‐hDTR mice. In particular, comprehensive gene expression analysis in skin revealed that upregulated genes related to lipid metabolisms with aging exhibited remarkable expressions under the senolysis. These results clearly unveiled p16‐positive senescent cells contribute to age‐related changes in skin. [ABSTRACT FROM AUTHOR]

GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF‐β signaling. In this study, we investigated the role of TGF‐β‐signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of GorabPrx1 conditional knockouts with the TGF‐β neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF‐β overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF‐β dysregulation was not a cell‐intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF‐β signaling caused elevated Nox4 expression in GorabPrx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN‐mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating GorabPrx1 mutants with the antioxidant N‐acetylcysteine ameliorated the osteoporosis phenotype. TGF‐β induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the GorabPrx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF‐β‐Nox4‐senescence axis and therapeutic strategies for GO. [ABSTRACT FROM AUTHOR]

The accumulation of senescent cells is thought to play a crucial role in aging‐associated physiological decline and the pathogenesis of various age‐related pathologies. Targeting senescence‐associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence‐specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or “surfaceome”, in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age‐related diseases. [ABSTRACT FROM AUTHOR]

The number of senescent vascular endothelial cells increases during aging and their dysfunctional phenotype contributes to age‐related cardiovascular disease. Identification of senescent cells is challenging as molecular changes are often tissue specific and occur amongst clusters of normal cells. Here, we established, benchmarked, and validated a new gene signature called EndoSEN that pinpoints senescent endothelial cells. The EndoSEN signature was enriched for interferon‐stimulated genes (ISG) and correlated with the senescence‐associated secretory phenotype (SASP). SASP establishment is classically attributed to DNA damage and cyclic GMP–AMP synthase activation, but our results revealed a pivotal role for RNA accumulation and sensing in senescent endothelial cells. Mechanistically, we showed that endothelial cell senescence hallmarks include self‐RNA accumulation, RNA sensor RIG‐I upregulation, and an ISG signature. Moreover, a virtual model of RIG‐I knockout in endothelial cells underscored senescence as a key pathway regulated by this sensor. We tested and confirmed that RIG‐I knockdown was sufficient to extend the lifespan and decrease the SASP in endothelial cells. Taken together, our evidence suggests that targeting RNA sensing is a potential strategy to delay vascular aging. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis is a progressive and age‐related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL‐2 and BCL‐XL, leading to BAX inactivation. We further showed that high levels of inactive BAX‐mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl‐valyl‐O‐methylaspartyl‐[2,6‐difluorophenoxy]‐methyl ketone (QVD‐OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1‐activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment. [ABSTRACT FROM AUTHOR]

Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence‐associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy. [ABSTRACT FROM AUTHOR]

Since the 12 major signs of aging were revealed in 2023, people's interpretation of aging will go further, which is of great significance for understanding the occurrence, development, and intervention in the aging process. As one of the 12 major signs of aging, cellular senescence refers to the process in which the proliferation and differentiation ability of cells decrease under stress stimulation or over time, often manifested as changes in cell morphology, cell cycle arrest, and decreased metabolic function. Interferon (IFN), as a secreted ligand for specific cell surface receptors, can trigger the transcription of interferon‐stimulated genes (ISGs) and play an important role in cellular senescence. In addition, IFN serves as an important component of SASP, and the activation of the IFN signaling pathway has been shown to contribute to cell apoptosis and senescence. It is expected to delay cellular senescence by linking IFN with cellular senescence and studying the effects of IFN on cellular senescence and its mechanism. This article provides a review of the research on the relationship between IFN and cellular senescence by consulting relevant literature. [ABSTRACT FROM AUTHOR]

Chondrocyte senescence and reduced lubrication play pivotal roles in the pathogenesis of age‐related osteoarthritis (OA). In the present study, highly lubricated and drug‐loaded hydrogel microspheres are designed and fabricated through the radical polymerization of sulfobetaine (SB)‐modified hyaluronic acid methacrylate using microfluidic technology. The copolymer contains a large number of SB and carboxyl groups that can provide a high degree of lubrication through hydration and form electrostatic loading interactions with metformin (Met@SBHA), producing a high drug load for anti‐chondrocyte senescence. Mechanical, tribological, and drug release analyses demonstrated enhanced lubricative properties and prolonged drug dissemination of the Met@SBHA microspheres. RNA sequencing (RNA‐seq) analysis, network pharmacology, and in vitro assays revealed the extraordinary capacity of Met@SBHA to combat chondrocyte senescence. Additionally, inducible nitric oxide synthase (iNOS) has been identified as a promising protein modulated by Met in senescent chondrocytes, thereby exerting a significant influence on the iNOS/ONOO‐/P53 pathway. Notably, the intra‐articular administration of Met@SBHA in aged mice ameliorated cartilage senescence and OA pathogenesis. Based on the findings of this study, Met@SBHA emerges as an innovative and promising strategy in tackling age‐related OA serving the dual function of enhancing joint lubrication and mitigating cartilage senescence. [ABSTRACT FROM AUTHOR]

In recent years, there has been increasing attention towards understanding the relationship between age‐related alterations in the oral microbiota and age‐associated diseases, with reports emphasizing the significance of maintaining a balanced oral microbiota for host health. However, the precise mechanisms underlying age‐related changes in the oral microbiota remain elusive. We recently reported that cellular senescence of ileal germinal center (GC) B cells, triggered by the persistent presence of commensal bacteria, results in diminished IgA production with aging and subsequent alterations in the gut microbiota. Consequently, we hypothesize that a similar phenomenon may occur in the oral cavity, potentially contributing to age‐related changes in the oral microbiota. Examination of p16‐luc mice, wherein the expression of the senescent cell marker p16INK4a can be visualized, raised under specific pathogen‐free (SPF) or germ‐free (GF) conditions, indicated that, unlike ileal GC B cells, the accumulation of senescent cells in GC B cells of cervical lymph nodes increases with age regardless of the presence of commensal bacteria. Furthermore, longitudinal studies utilizing the same individual mice throughout their lifespan revealed concurrent age‐related alterations in the composition of the oral microbiota and a decline in salivary IgA secretion. Further investigation involving Rag1−/− mice transplanted with B cells from wild‐type or p16INK4a and p21Waf1/Cip1 ‐double knockout mice unveiled that B cell senescence leads to reduced IgA secretion and alteration of the oral microbiota. These findings advance our understanding of the mechanism of age‐associated changes in the oral microbiota and open up possibilities of their control. [ABSTRACT FROM AUTHOR]

As a hallmark of senescent cells, the derepression of Long Interspersed Elements 1 (LINE1) transcription results in accumulated LINE1 cDNA, which triggers the secretion of the senescence-associated secretory phenotype (SASP) and paracrine senescence in a cGAS-STING pathway-dependent manner. However, transcription factors that govern senescence-associated LINE1 reactivation remain ill-defined. Here, we predict several transcription factors that bind to human LINE1 elements to regulate their transcription by analyzing the conserved binding motifs in the 5'-untranslated regions (UTR) of the commonly upregulated LINE1 elements in different types of senescent cells. Further analysis reveals that PAX5 directly binds to LINE1 5'-UTR and the binding is enhanced in senescent cells. The enrichment of PAX5 at the 5'-UTR promotes cellular senescence and SASP by activating LINE1. We also demonstrate that the longevity gene SIRT6 suppresses PAX5 transcription by directly binding to the PAX5 promoter, and overexpressing PAX5 abrogates the suppressive effect of SIRT6 on stress-dependent cellular senescence. Our work suggests that PAX5 could serve as a potential target for drug development aiming to suppress LINE1 activation and treat senescence-associated diseases. Synopsis: Transcription factor PAX5 can activate human LINE1 retrotransposons, promoting cellular senescence. The longevity gene SIRT6 directly binds to the PAX5 promoter and suppresses its transcription. Several transcription factors that bind to the 5'-UTR of the commonly upregulated LINE1 in different types of human senescent cells are identified. Among these factors, PAX5 potentiates LINE1 transcription and promotes cellular senescence. PAX5-mediated LINE1 activation and cellular senescence may result from the downregulation of SIRT6-mediated inhibition of PAX5. Transcription factor PAX5 can activate human LINE1 retrotransposons, promoting cellular senescence. The longevity gene SIRT6 directly binds to the PAX5 promoter and suppresses its transcription. [ABSTRACT FROM AUTHOR]

Aging leads to an accumulation of cellular mutations and damage, increasing the risk of senescence, apoptosis, and malignant transformation. Cellular senescence, which is pivotal in aging, acts as both a guard against cellular transformation and as a check against cancer progression. It is marked by stable cell cycle arrest, widespread macromolecular changes, a pro‐inflammatory profile, and altered gene expression. However, it remains to be determined whether these differing subsets of senescent cells result from unique intrinsic programs or are influenced by their environmental contexts. Multiple transcription regulators and chromatin modifiers contribute to these alterations. Special AT‐rich sequence‐binding protein 1 (SATB1) stands out as a crucial regulator in this process, orchestrating gene expression by structuring chromatin into loop domains and anchoring DNA elements. This review provides an overview of cellular senescence and delves into the role of SATB1 in senescence‐related diseases. It highlights SATB1's potential in developing antiaging and anticancer strategies, potentially contributing to improved quality of life and addressing aging‐related diseases. [ABSTRACT FROM AUTHOR]

Facial skin redness can be an indicator of skin inflammation, however the physiological connection between facial redness and inflammatory status, as well as its role in age‐related skin changes, remains poorly understood. This study aims to investigate the association between the pattern of facial skin redness and biological inflammatory status, as well as age‐related changes occurring in the skin. Four studies were conducted recruiting healthy Northern Asian females. Disordered spatial patterns of facial skin redness signals were assessed using image analysis, i.e., the a* gradient algorithm, which quantifies the disordered shape and pattern of localized redness signals on facial skin. This redness pattern was compared with (1) inflammatory protein markers (IL‐1Ra/ IL‐1α and IL‐8) measured from stripped corneocyte samples, (2) gene expression profiles obtained through transcriptome analysis using skin biopsy samples, and (3) the distribution pattern of blood vessel measured using a photoacoustic microscope. The association between the skin redness pattern and current and future ageing‐related skin changes was examined through a longitudinal study tracking the same subjects for 10 years. A significant correlation was observed between the a* gradient and the levels of inflammatory cytokines (IL‐1Ra/IL‐1α and IL‐8). Transcriptome analysis revealed upregulation of genes related to acute inflammation, chronic inflammation, cellular senescence, and angiogenesis in subjects with higher a* gradients. The high a* gradient group exhibited an extension of blood vessel diameter and increased blood vessel density, while the medium a* gradient group only exhibited blood vessel extension. Lastly, the 10‐year longitudinal study demonstrated that the a* gradient was associated with current and future skin ageing‐related attributes, such as increased skin texture and wrinkle formation. The spatial pattern of localized redness on the skin reflects the biological inflammatory status, and this inflammatory condition helps predict current and future age‐related skin changes. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is a common pregnancy‐related disorder. Cbl proto‐oncogene like 1 (CBLL1) is an E3 ubiquitin ligase, which has been reported to vary with the menstrual cycle in the endometrium. However, whether CBLL1 is involved in the occurrence and development of RSA remains unclear. This study aimed to investigate the effects of CBLL1 on RSA. We analyzed the expression of CBLL1 in the decidua of RSA patients, as well as its functional effects on cellular senescence, oxidative stress, and proliferation of human endometrial stromal cells (HESCs). RNA sequencing was employed to identify a key downstream target gene regulated by CBLL1. We found that CBLL1 was upregulated in the decidua of RSA patients. Additionally, overexpression of CBLL1 promoted HESC senescence, increased oxidative stress levels, and inhibited proliferation. Phosphatase and tensin homolog located on chromosome 10 (PTEN) was identified as one of the important downstream target genes of CBLL1. In vivo experiments demonstrated that CBLL1 overexpression in the endometrium caused higher embryo absorption rate in mice. Consequently, elevated CBLL1 expression is a potential cause of RSA, representing a novel therapeutic target for RSA. [ABSTRACT FROM AUTHOR]

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age‐related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB‐DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA‐NFκB binding at the transcription start sites of age‐associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics‐dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state. [ABSTRACT FROM AUTHOR]

Objectives: Abnormal mechanical stress is the pivotal risk factor of temporomandibular joint osteoarthritis (TMJOA). This study investigated the pathogenic mechanism by which abnormal mechanical stress induced chondrocyte senescence. Materials and Methods: Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading in vitro. The effects of Yes‐associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase‐like 3 (METTL3) and N6‐methyladenosine (m6A) modification were evaluated. The role of m6A modification in chondrocyte senescence was determined. The therapeutic effects of m6A inhibition in TMJOA were investigated. Results: Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence in vitro. This mechanical stress‐induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3‐dependent m6A modification. Moreover, inhibition of m6A modification rescued chondrocyte senescence in vitro and in vivo, and suppressed TMJOA progression in rats. Conclusions: This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6A inhibition in TMJOA. [ABSTRACT FROM AUTHOR]

In this review, we summarize how an increasingly stressed and aging placenta contributes to the maternal clinical signs of preeclampsia, a potentially lethal pregnancy complication. The pathophysiology of preeclampsia has been conceptualized in the two‐stage model. Originally, highlighting the importance of poor placentation for early‐onset preeclampsia, the revised two‐stage model explains late‐onset preeclampsia as well, which is often preceded by normal placentation. We discuss how cellular senescence in the placenta may fit with the framework of the revised two‐stage model of preeclampsia pathophysiology and summarize potential cellular and molecular mechanisms, including effects on placental and maternal endothelial function. Cellular senescence may occur in response to inflammatory processes and oxidative, mitochondrial, or endoplasmic reticulum stress and chronic stress induce accelerated, premature placental senescence. In preeclampsia, both circulating and tissue‐based senescence markers are present. We suggest that aspirin prophylaxis, commonly recommended from the first trimester onward for women at risk of preeclampsia, may affect placentation and possibly mechanisms of placental senescence, thus attenuating the risk of preeclampsia developing clinically. We propose that biomarkers of placental dysfunction and senescence may contribute to altered preventive strategies, including discontinuation of aspirin at week 24–28 depending on placenta‐associated biomarker risk stratification. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune‐mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B‐lymphoma‐2 (BCL‐2) family and interferon‐induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL‐15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL‐2 family and ISGs. Further, treatment with ABT‐263 (a senolytic BCL‐2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L−PD‐1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T‐bet+ age‐related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL‐2 inhibitor ABT‐263 may be the potential treatment in ameliorating lupus phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the level of cellular senescence in stem cells derived from microfragmented abdominal adipose tissue harvested from patients with knee osteoarthritis (OA). Methods: Stem cells harvested from microfragmented abdominal adipose tissue from 20 patients with knee OA, aged 29–65 years (mean = 49.8, SD = 9.58), were analysed as a function of patient age and compared with control cells exhibiting signs of cellular senescence. Steady‐state mRNA levels of a panel of genes associated with senescence were measured by qPCR. Intracellular senescence‐associated proteins p16 and p21, and senescence‐associated β‐galactosidase activity were measured by flow cytometry. Cellular proliferation was assessed using a 5‐ethynyl‐2′‐deoxyuridine proliferation assay. Stemness was assessed by stem cell surface markers using flow cytometry and the capacity to undergo adipogenic and osteogenic differentiation in vitro. Results: No correlation was found between cellular senescence levels of the microfragmented adipose tissue‐derived stem cells and patient age for any of the standard assays used to quantify senescence. The level of cellular senescence was generally low across all senescence‐associated assays compared to the positive senescence control. Stemness was verified for all samples. An increased capacity to undergo adipogenic differentiation was shown with increasing patient age (p = 0.02). No effect of patient age was found for osteogenic differentiation. Conclusions: Autologous microfragmented adipose tissue‐derived stem cells may be used in clinical trials of knee OA of patients aged 29–65 years, at least until passage 4, as they show stemness potential and negligible senescence in vitro. Level of Evidence: Not applicable. [ABSTRACT FROM AUTHOR]

There is an urgent need to improve conventional cancer‐treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo‐ or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self‐assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy. [ABSTRACT FROM AUTHOR]

Cellular senescence is a significant contributor to intervertebral disc aging and degeneration. However, the application of senotherapies, such as senomorphics targeting senescence markers and the senescence‐associated secretory phenotype (SASP), remains limited due to challenges in precise delivery. Given that the natural killer group 2D (NKG2D) ligands are increased on the surface of senescent nucleus pulposus (NP) cells, the NKG2D‐overexpressing NP cell membranes (NNPm) are constructed, which is expected to achieve a dual targeting effect toward senescent NP cells based on homologous membrane fusion and the NKG2D‐mediated immunosurveillance mechanism. Then, mesoporous silica nanoparticles carrying a peroxisome proliferator‐activated receptor‐ɣ coactivator 1α (PGC1α)inducer (SP) are coated with NNPm (SP@NNPm) and it is found that SP@NNPm selectively targets senescent NP cells, and the SP cores exhibit pH‐responsive drug release. Moreover, SP@NNPm effectively induces PGC1α‐mediated mitochondrial biogenesis and mitigates senescence‐associated markers induced by oxidative stress and the SASP, thereby alleviating puncture‐induced senescence and disc degeneration. This dual‐targeting nanotherapeutic system represents a novel approach to delivery senomorphics for disc degeneration treatment. [ABSTRACT FROM AUTHOR]

Age‐induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular and bone diseases in the elderly, the underlying mechanisms for the vascular‐bone cross‐talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt‐driven‐axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson‐Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long‐term inhibitory effects. microRNA‐transcriptomics of HGPS patient plasma combined with aged‐vascular niche analyses in progeria mice reveal abundant secretion of Wnt‐repressive microRNA‐31‐5p. Moreover, we show that inhibition of microRNA‐31‐5p as well as selective Wnt‐activator CHIR99021 boosts the osteogenic potential of BMSCs through de‐repression and activation of the Wnt‐signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA‐based therapies of bone loss in elderly. [ABSTRACT FROM AUTHOR]

Introduction: Senescent cells contribute to age‐related tissue deterioration, including the skin, which plays important roles in overall health and social interactions. This study aimed to assess the effects of the senotherapeutic peptide, OS‐01 (a.k.a. Pep 14), on skin. Methods: A 12‐week split‐face, double‐blinded, vehicle‐controlled study involving 22 participants was conducted. The OS‐01‐containing formulation was applied to one side of the face, while the other side received an identical control formulation lacking the peptide. Skin characteristics were assessed using instrumental measurements, expert clinical grading, and subjective questionnaires. Results: Results showed that the OS‐01 formulation significantly improved one aspect of skin barrier function, as evidenced by reduced trans‐epidermal water loss compared to both baseline and vehicle control. Expert grading and Antera 3D image analysis revealed a reduction in wrinkle appearance and indentation in the periorbital area, and improved skin texture and radiance on both sides of the face, with the OS‐01‐containing formulation demonstrating superior results. Participants also perceived improvements in skin hydration, smoothness, radiance, and overall appearance. Conclusion: The findings suggest that the OS‐01 formulation promotes skin health by strengthening the skin barrier, protecting against dehydration, reducing the appearance of wrinkles, and improving skin texture and radiance. These effects are likely attributed to the senotherapeutic properties of OS‐01 in reducing cellular senescence and its associated detrimental effects. [ABSTRACT FROM AUTHOR]

Atherosclerosis, characterized by the accumulation of lipid plaques on the inner walls of arteries, is the leading cause of heart attack, stroke and severe ischemic injuries. Senescent cells have been found to accumulate within atherosclerotic lesions and contribute to the progression of atherosclerosis. In our previous study, we discovered that suppressing Larp7 accelerates senescence by inhibiting Sirt1 activity, resulting in increased atherosclerosis in high‐fat diet (HFD) fed and ApoE deficient (ApoEKO) mice. However, there has been no direct evidence demonstrating Larp7 per se could attenuate atherosclerosis. To this end, we generated a tetO‐controlled and Cre‐activated Larp7 gain‐of‐function mouse. Through RT‐PCR and western blotting, we confirmed Larp7 overexpression in the aortas of HFD‐fed ApoEKO; Larp7tetO mice. Larp7 overexpression led to increased Sirt1 activity and decreased cellular senescence signals mediated by p53/p65 in the aortas. Additionally, Larp7 overexpression reduced the presence of p16‐positive senescent cells in the aortic lesions. Furthermore, Larp7 overexpression resulted in a decrease in pro‐inflammatory macrophages and SASP factors. Consequently, Larp7 overexpression led to a reduction in the area of atherosclerotic lesions in HFD‐fed ApoEKO; Larp7tetO mice. In summary, our study provides evidence that Larp7 overexpression holds promise as an approach to inhibit cellular senescence and prevent atherosclerosis. [ABSTRACT FROM AUTHOR]

Mammalian somatic cells undergo terminal proliferation arrest after a limited number of cell divisions, a phenomenon termed cellular senescence. However, cells acquire the ability to proliferate infinitely (cellular immortalization) through multiple genetic alterations. Inactivation of tumor suppressor genes such as p53, RB and p16 is important for cellular immortalization, although additional molecular alterations are required for cellular immortalization to occur. Here, we aimed to gain insights into these molecular alterations. Given that cellular immortalization is the escape of cells from cellular senescence, genes that regulate cellular senescence are likely to be involved in cellular immortalization. Because senescent cells show altered heterochromatin organization, we investigated the implications of lamin A/C, lamin B1 and lamin B receptor (LBR), which regulate heterochromatin organization, in cellular immortalization. We employed human immortalized cell lines, KMST‐6 and SUSM‐1, and found that expression of LBR was upregulated upon cellular immortalization and downregulated upon cellular senescence. In addition, knockdown of LBR induced cellular senescence with altered chromatin configuration. Additionally, enforced expression of LBR increased cell proliferation likely through suppression of genome instability in human primary fibroblasts that expressed the simian virus 40 large T antigen (TAg), which inactivates p53 and RB. Furthermore, expression of TAg or knockdown of p53 led to upregulated LBR expression. These observations suggested that expression of LBR might be upregulated to suppress genome instability in TAg‐expressing cells, and, consequently, its upregulated expression assisted the proliferation of TAg‐expressing cells (i.e. p53/RB‐defective cells). Our findings suggest a crucial role for LBR in the process of cellular immortalization. [ABSTRACT FROM AUTHOR]

Senescence is a heterogenous and dynamic process in which various cell types undergo cell‐cycle arrest due to cellular stressors. While senescence has been implicated in aging and many human pathologies, therapeutic interventions remain inadequate due to the absence of a comprehensive set of biomarkers in a context‐dependent manner. Polyphenols have been investigated as senotherapeutics in both preclinical and clinical settings. However, their use is hindered by limited stability, toxicity, modest bioavailability, and often inadequate concentration at target sites. To address these limitations, nanocarriers such as polymer nanoparticles and lipid vesicles can be utilized to enhance the efficacy of senolytic polyphenols. Focusing on widely studied senolytic agents—specifically fisetin, quercetin, and resveratrol—we provide concise summaries of their physical and chemical properties, along with an overview of preclinical and clinical findings. We also highlight common signaling pathways and potential toxicities associated with these agents. Addressing challenges linked to nanocarriers, we present examples of senotherapeutic delivery to various cell types, both with and without nanocarriers. Finally, continued research and development of senolytic agents and nanocarriers are encouraged to reduce the undesirable effects of senescence on different cell types and organs. This review underscores the need for establishing reliable sets of senescence biomarkers that could assist in evaluating the effectiveness of current and future senotherapeutic candidates and nanocarriers. [ABSTRACT FROM AUTHOR]

The follicular microenvironment is crucial for normal ovarian function, and intra‐ovarian factors, in coordination with gonadotropins, contribute to its regulation. Recent research has revealed that the accumulation of senescent cells worsens the adverse environment of various tissues and plays critical roles in chronological aging and various pathological conditions. Cellular senescence involves cell‐cycle arrest, a senescence‐associated secretory phenotype (SASP), macromolecular damage, and dysmetabolism. In this review, I summarize the latest knowledge regarding the role of cellular senescence in pathological conditions in the ovary, in the context of reproduction. Specifically, cellular senescence is known to impair follicular and oocyte health in cisplatin‐ and cyclophosphamide‐induced primary ovarian insufficiency and to contribute to the pathogenesis of polycystic ovary syndrome (PCOS). In addition, cellular senescence is induced during the decline in ovarian reserve that is associated with chronological aging, endometriosis, psychological stress, and obesity, but it remains unclear whether it plays a causative role in these conditions. Finally, I discuss the potential for use of cellular senescence as a novel therapeutic target. The modification of SASP using a senomorphic and/or the elimination of senescent cells using a senolytic represent promising therapeutic strategies. Further elucidation of the role of cellular senescence in the effects of various insults on ovarian reserve, including chronological aging, as well as in pathogenesis of ovarian pathologies, including PCOS, may facilitate a new era of reproductive medicine. [ABSTRACT FROM AUTHOR]

Background: Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly has not been well defined. This study aims to elucidate the mechanisms of HDFs senescence and how senescent HDFs affect wound healing in aged skin. Methods: The expression and function of sperm equatorial segment protein 1 (SPESP1) in skin ageing were evaluated via in vivo and in vitro experiments. To delve into the potential molecular mechanisms by which SPESP1 influences skin ageing, a combination of techniques was employed, including proteomics, RNA sequencing, immunoprecipitation, chromatin immunoprecipitation and liquid chromatography‐mass spectrometry analyses. Clearance of senescent cells by dasatinib plus quercetin (D+Q) was investigated to explore the role of SPESP1‐induced senescent HDFs in wound healing. Results: Here, we define the critical role of SPESP1 in ameliorating HDFs senescence and retarding the skin ageing process. Mechanistic studies demonstrate that SPESP1 directly binds to methyl‐binding protein, leading to Decorin demethylation and subsequently upregulation of its expression. Moreover, SPESP1 knockdown delays wound healing in young mice and SPESP1 overexpression induces wound healing in old mice. Notably, pharmacogenetic clearance of senescent cells by D+Q improved wound healing in SPESP1 knockdown skin. Conclusions: Taken together, these findings reveal the critical role of SPESP1 in skin ageing and wound healing, expecting to facilitate the development of anti‐ageing strategies and improve wound healing in the elderly. [ABSTRACT FROM AUTHOR]

SRY‐box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell‐cycle‐arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2–Smad2/3–p53–p21WAF1/CIP1–Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4–MAPK (JNK/ERK/p38)–ATF2 and WT1–ATF2 pathways, which is dependent on its high‐mobility group (HMG) domain. In addition, the SOX6‐induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT‐263 (navitoclax) and ABT‐199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6‐induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin‐resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1–ATF2–TGFβ2 axis mediates SOX6‐induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer. [ABSTRACT FROM AUTHOR]

The high mortality rate and postoperative recurrence of hepatocellular carcinoma (HCC) contribute to the burden on society and healthcare. The prognostic value and underlying mechanisms of cellular senescence and tumor microenvironment (TME) in HCC remain unclear. Bulk transcriptomic data were obtained from 368 HCC samples in The Cancer Genome Atlas‐liver hepatocellular carcinoma cohort and 64 samples from the GSE116174 dataset. Single‐cell RNA sequencing (scRNA‐seq) data of HCC were obtained from the GSE149614 dataset, including 18 tumor samples from 10 patients. Prognosis‐related cellular senescence genes and immune cells were identified through univariate analysis. Least absolute shrinkage and selection operator regression analysis was performed to construct the CellAge score and TME score, both of which were identified as independent prognostic factors for HCC based on multivariate Cox analysis. The combined CellAge and TME scores showed improved prognostic stratification for HCC patients, as confirmed by multivariate Cox analysis (p <.001). The gene set enrichment analysis (GSEA) revealed enrichment of the extracellular matrix receptor interaction signaling pathway in the group with high CellAge scores and low TME scores, which exhibited a worse prognosis. Single‐cell sequencing results revealed higher expression activity of the cAMP response element modulator (CREM) extended transcription factor in HCC cells and most immune cells, indicating its involvement in TME remodeling. Finally, the tumor immune dysfunction and exclusion (TIDE) analysis demonstrated that the combined scores could predict the outcomes of immune therapy in patients with HCC. In conclusion, cellular senescence contributes to TME remodeling in HCC, and the developed CellAge and TME scores serve as independent prognostic factors and predictors of immune therapy in HCC. [ABSTRACT FROM AUTHOR]

We previously showed that mice with knockout in the peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PPARGC1A) gene encoding the PGC‐1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age‐related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC‐1α in AMD pathogenesis we used young (3‐month) and old (12‐month) mice with knockout in the PPARGC1A gene and age‐matched wild‐type (WT) animals. An immunohistochemical analysis showed age‐dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3‐month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC‐1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC‐1α in AMD pathogenesis and confirm the utility of mice with PGC‐1α knockout as an animal model to study AMD pathogenesis. [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro‐survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions. [ABSTRACT FROM AUTHOR]

Unlike chronological age, biological age is a strong indicator of health of an individual. However, the molecular fingerprint associated with biological age is ill‐defined. To define a high‐resolution signature of biological age, we analyzed metabolome, circulating senescence‐associated secretome (SASP)/inflammation markers and the interaction between them, from a cohort of healthy and rapid agers. The balance between two fatty acid oxidation mechanisms, β‐oxidation and ω‐oxidation, associated with the extent of functional aging. Furthermore, a panel of 25 metabolites, Healthy Aging Metabolic (HAM) index, predicted healthy agers regardless of gender and race. HAM index was also validated in an independent cohort. Causal inference with machine learning implied three metabolites, β‐cryptoxanthin, prolylhydroxyproline, and eicosenoylcarnitine as putative drivers of biological aging. Multiple SASP markers were also elevated in rapid agers. Together, our findings reveal that a network of metabolic pathways underlie biological aging, and the HAM index could serve as a predictor of phenotypic aging in humans. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the regulatory effect of RUNX2 mutation on dental follicle cells (DFCs) senescence and clarify the underlying mechanism. This study aimed to explore the basis for a novel mechanism of delayed permanent tooth eruption in cleidocranial dysplasia (CCD) patients. Materials and Methods: Dental follicles were collected from a CCD patient and healthy controls. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining, Ki67 staining, cell cycle assays, and senescence‐related gene and protein expression assays were performed to assess DFCs senescence. Western blotting was performed to detect the activation of mitogen‐activated protein kinase (MAPK) signalling pathways, and the molecular mechanism underlying RUNX2 regulating in DFCs senescence was explored. Results: RUNX2 mutation inhibited the cellular senescence of DFCs from the CCD patient compared with healthy controls. Ki67 staining showed that mutant RUNX2 promoted DFCs proliferation, and cell cycle assays revealed that the healthy control‐derived DFCs arrested at G1 phase. RUNX2 mutation significantly downregulated senescence‐associated gene and protein expression. RUNX2 mutation suppressed ERK signalling pathway activation, an ERK inhibitor decreased healthy control‐derived DFCs senescence, and an ERK activator promoted CCD patient‐derived DFCs senescence. Conclusions: RUNX2 mutation delayed DFCs senescence through the ERK signalling pathway, which may be responsible for delayed permanent tooth eruption in CCD patients. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 μM Pazopanib, respectively. Cellular senescence was measured using senescence-associated β-galactosidase (SA-β-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad-Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2. [ABSTRACT FROM AUTHOR]

Cellular senescence serves as a significant tumor suppression mechanism in mammals. Cellular senescence is induced in response to various stressors and acts as a safeguard against the uncontrolled proliferation of damaged cells that could lead to malignant transformation. Senescent cells also exhibit a distinctive feature known as the senescence‐associated secretory phenotype (SASP), wherein they secrete a range of bioactive molecules, including pro‐inflammatory cytokines, growth factors, and proteases. These SASP components have both local and systemic effects, influencing the surrounding microenvironment and distant tissues, and have been implicated in the processes of tissue aging and the development of chronic diseases. Recent studies utilizing senolysis models have shed light on the potential therapeutic implications of targeting senescent cells. The targeting of senescent cell may alleviate the detrimental effects associated with cellular senescence and its SASP components. Senolytics have shown promise in preclinical studies for treating age‐related pathologies and chronic diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Respiratory diseases have emerged as a significant global health concern, responsible for a considerable number of deaths worldwide. Extensive research conducted in both human subjects and animal models has demonstrated the involvement of cellular senescence in the pathogenesis of respiratory diseases. Chronic pulmonary conditions such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis have been linked to the accumulation of senescent cells. This review aims to present the findings from research on respiratory diseases that have utilized systems targeting senescent cells and to identify potential therapeutic strategies for the clinical management of these conditions. Geriatr Gerontol Int 2024; 24: 60–66. [ABSTRACT FROM AUTHOR]

There is strong evidence that most individuals in the elderly population are characterized by inflamm‐aging which refers to a subtle increase in the systemic pro‐inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm‐aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm‐aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro‐inflammatory tissue environment that provides a rationale for immune system‐independent activation of inflamm‐aging and associated diseases. There is also accumulating evidence that inflamm‐aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence‐based molecular etiology of inflamm‐aging as well as the dynamic reciprocal interactions between inflamm‐aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm‐aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm‐aging with cellular senescence both as an underlying cause and therapeutic target for further studies. Significance statement: The present work is aimed at understanding the interactions between cellular senescence and inflamm‐aging that together predispose the elderly to recurring infections and inflammatory disorders. The rationale for viewing these two processes together with their interdependent pathophysiology has been presented. This paper intends to apprise the scientific community of this developing interconnection and underlying disease pathology that may ultimately help identify novel molecular markers and therapeutic targets of inflammatory disorders during aging. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are stromal cells which have multi‐lineage differentiation and self‐renewal potentials. Accurate estimation of total number of senescent cells in MSCs is crucial for clinical applications. Traditional manual cell counting using an optical bright‐field microscope is time‐consuming and needs an expert operator. In this study, the senescence cells were segmented and counted automatically by deep learning algorithms. However, well‐performing deep learning algorithms require large numbers of labeled datasets. The manual labeling is time consuming and needs an expert. This makes deep learning‐based automated counting process impractically expensive. To address this challenge, self‐supervised learning based approach was implemented. The approach incorporates representation level contrastive learning component into the instance segmentation algorithm for efficient senescent cell segmentation with limited labeled data. Test results showed that the proposed model improves mean average precision and mean average recall of downstream segmentation task by 8.3% and 3.4% compared to original segmentation model. [ABSTRACT FROM AUTHOR]

Cellular senescence and the senescence‐associated secretory phenotype (SASP) contribute to age‐related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP‐related inflammation were lower 1 week after the final dose of oral intermittent (1 week on—2 weeks off—1 weeks on dosing) fisetin supplementation. Old fisetin‐supplemented mice had higher endothelial function. Leveraging old p16‐3MR mice, a transgenic model allowing genetic clearance of p16INK4A‐positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle‐ but not fisetin‐treated mice increased endothelium‐dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular‐ and mitochondrial‐related oxidative stress. Arterial stiffness was lower in fisetin‐treated mice. Ex vivo genetic senolysis in aorta rings from p16‐3MR mice did not further reduce mechanical wall stiffness in fisetin‐treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age‐related arterial dysfunction. [ABSTRACT FROM AUTHOR]