Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

A simple cell proliferation assay and the inflammatory protein content show significant differences in human plasmas from young and old subjects.

Some studies showed a "rejuvenating" effect of exposing aging tissues to a young environment. In mouse heterochronic parabiosis experiments, in response to young organisms, old animals lived longer than isochrony old age-matched conjoint animals. Comparable "rejuvenating" effects were obtained by injecting young plasma in old mice. This raised great hopes of slowing down the senescence process in humans by the injection of young plasma, as well as to prevent or cure age-related diseases. Some clinical trials are currently being performed or were recently completed. However, these studies are small and of limited duration, and we still lack convincing evidence to support the effectiveness of young plasma injection. It is urgent to perform additional investigations, including the development of an assay to measure the cell proliferation induction capability of different human plasmas, before one can seriously think of a large-scale treatment of humans. We adopted a simple method to measure the potential of different plasmas in supporting cell line proliferation, regardless of the co-presence of a platelet lysate. By comparing plasmas from young and old subjects, we observed a decreased activity in plasmas from old individuals. The young plasma effect may be attributed to specific proteins and growth factors more abundant in younger individuals that could decrease with age. Alternatively, or at the same time, the reduced cell proliferation support could be due to inhibitors present in the old plasma. Studying the different protein content of young and old plasmas was out of the scope of this article. Such differences should be adequately investigated by proteomics using many samples. However, a preliminary study of the different protein content of young and old plasmas was part of the assay validation using a commercially available cytokine array for parallel determination of the relative levels of 105 selected human proteins. We could show the existence of specific differences between young and old plasmas and that plasmas from old individuals presented a higher concentration of "inflammatory" proteins.

Exploring senescence as a modifier of ß cell extracellular vesicles in type 1 diabetes.

Type 1 Diabetes (T1D) is a chronic metabolic disease resulting from insulin deficiency due to autoimmune loss of pancreatic ß cells. In addition to ß cell destruction, it is now accepted that ß cell stress and dysfunction, such as senescence, plays a crucial role in the development of the disease. Accumulation of senescent ß cells occurs during development of T1D in humans and contributes to the progression of T1D in the nonobese diabetic (NOD) mouse model. Senescent ß cells are thought to exacerbate the inflammatory response within the islets by production and secretion of senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) from ß cells have been shown to carry protein and microRNAs (miRNAs), influencing cellular signaling and may contribute to the development of T1D but it remains to be addressed how senescence impacts ß cell EV cargo. In this minireview, we discuss emerging evidence that EV cargo proteins and miRNAs associated with senescence could contribute to the development of T1D and could suggest potential biomarkers and therapeutic targets for the regulation of SASP and elimination of senescent ß cells in T1D. Future investigation exploring the intricate relationship between ß cell senescence, EVs and miRNAs could pave the way for the development of novel diagnostic techniques and therapeutic interventions.

Obesity-Senescence-Breast Cancer: Clinical Presentation of a Common Unfortunate Cycle.

There are few convincing studies establishing the relationship between endogenous factors that cause obesity, cellular aging, and telomere shortening. Without a functional telomerase, a cell undergoing cell division has progressive telomere shortening. While obesity influences health and longevity as well as telomere dynamics, cellular senescence is one of the major drivers of the aging process and of age-related disorders. Oxidative stress induces telomere shortening, while decreasing telomerase activity. When progressive shortening of telomere length reaches a critical point, it triggers cell cycle arrest leading to senescence or apoptotic cell death. Telomerase activity cannot be detected in normal breast tissue. By contrast, maintenance of telomere length as a function of human telomerase is crucial for the survival of breast cancer cells and invasion. Approximately three-quarters of breast cancers in the general population are hormone-dependent and overexpression of estrogen receptors is crucial for their continued growth. In obesity, increasing leptin levels enhance aromatase messenger ribonucleic acid (mRNA) expression, aromatase content, and its enzymatic activity on breast cancer cells, simultaneously activating telomerase in a dose-dependent manner. Meanwhile, applied anti-estrogen therapy increases serum leptin levels and thus enhances leptin resistance in obese postmenopausal breast cancer patients. Many studies revealed that shorter telomeres of postmenopausal breast cancer have higher local recurrence rates and higher tumor grade. In this review, interlinked molecular mechanisms are looked over between the telomere length, lipotoxicity/glycolipotoxicity, and cellular senescence in the context of estrogen receptor alpha-positive (ERα+) postmenopausal breast cancers in obese women. Furthermore, the effect of the potential drugs, which are used for direct inhibition of telomerase and the inhibition of human telomerase reverse transcriptase (hTERT) or human telomerase RNA promoters as well as approved adjuvant endocrine therapies, the selective estrogen receptor modulator and selective estrogen receptor down-regulators are discussed.

Senescence-associated secretory phenotype regulation by dual drug delivery biomimetic nanoplatform for enhanced tumor chemotherapy.

Many chemotherapies, which are still the main clinical treatment for primary tumors, will induce persistent DNA damage in non-tumor stromal cells, especially cancer-associated fibroblasts (CAFs), and activate them to secrete senescence-associated secretory phenotype (SASP). The transition could further result in the formation of tumor immunosuppressive microenvironment and cause drug resistance of neighboring tumor cells. To solve this dilemma, a multi-functional biomimetic drug delivery system (named mPtP@Lipo) was rationally developed by combining CAFs reshaper ginsenoside 20(S)-protopanaxadiol (PPD) and cisplatin prodrug (PtLA) to inhibit tumor progression and the formation of SASP. To achieve effective delivery of these molecules deep into the desmoplastic tumor, fibroblast membrane was fused with liposomes as a targeting carrier. In vitro and in vivo results showed that mPtP@Lipo could penetrate deep into the tumor, reverse CAFs phenotype and inhibit SASP formation, which then blocked the immunosuppressive progress and thus reinforced anti-tumor immune response. The combination of chemotherapeutics and CAFs regulator could achieve both tumor inhibition and tumor immune microenvironment remodeling. In conclusion, mPtP@Lipo provides a promising strategy for the comprehensive stromal-desmoplastic tumor treatment.

The putative contribution of cellular senescence to driving tauopathies.

During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation.

A nutrigeroscience approach: Dietary macronutrients and cellular senescence.

Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.

Proteostasis disruption and senescence in Alzheimer's disease pathways to neurodegeneration.

Alzheimer's Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.

Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human beta cells.

Type 1 diabetes (T1D) is a chronic metabolic disease resulting from an autoimmune destruction of pancreatic beta cells. Beta cells activate various stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling, and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-ßH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D; therefore, we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2-like protein 1 (BCL2L1). Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses.NEW & NOTEWORTHY Beta cell senescence is an emerging contributor to the pathogenesis of type 1 diabetes, but candidate therapeutic targets have not been identified in human beta cells. In this study, we examined the role of a secreted factor, GDF15, and found that although it is not required to maintain viability during senescence, it is required to fine-tune gene expression programs involved in the senescence response during DNA damage in human beta cells.

Construction and validation of a SASP-related prognostic signature in patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a common and highly aggressive haematological malignancy in adults. Senescence-associated secretory phenotype (SASP) plays important roles in tumorigenesis and progression of tumour. However, the prognostic value of SASP in patients with AML has not been clarified. The present study aims to explore the prognostic value of SASP and develop a prognostic risk signature for AML. The RNA-sequencing data was collected from the TCGA, GTEx and TARGET databases. Subsequently, differentially expressed gene analysis, univariate Cox regression and LASSO regression were applied to identified prognostic SASP-related genes and construct a prognostic risk-scoring model. The risk score of each patient were calculated and patients were divided into high- or low-risk groups by the median risk score. This novel prognostic signature included 11 genes: G6PD, CDK4, RPS6KA1, UBC, H2BC12, KIR2DL4, HSF1, IFIT3, PIM1, RUNX3 and TRIM21. The patients with AML in the high-risk group had shorter OS, demonstrating that the risk score acted as a prognostic predictor, which was validated in the TAGET-AML dataset. Univariate and multivariate analysis revealed the risk score was an independent prognostic factor in patients with AML. Furthermore, the present study revealed that the risk score was associated with immune landscape, immune checkpoint gene expression and chemotherapeutic efficacy. In the present study, we constructed and validated a unique SASP-related prognostic model to assess therapeutic effect and prognosis in patients with AML, which might contribute to understanding the role of SASP in AML and guiding the treatment for AML.

The emerging importance of lymphangiogenesis in aging and aging-associated diseases.

Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.

Research progress on the regulatory mechanism of cell senescence in arsenic toxicity: a systematic review.

As an element with metalloid properties, arsenic is pervasively present in the environment and is recognized as a potent carcinogen. Consequently, the issue of human arsenic exposure has become a significant concern within the global public health sector. Numerous studies have indicated that arsenic induces cellular senescence through various mechanisms, including triggering epigenetic alterations, inducing the senescence-associated secretory phenotype (SASP), promoting telomere shortening, and causing mitochondrial dysfunction. This article collates and summarizes the latest research advancements on the involvement of cellular senescence in arsenic toxicity and explores the mechanisms of arsenic-induced toxicity. This study aims to provide new perspectives and directions for future research on arsenic toxicity and the development of prevention and treatment strategies.

Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis.

Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart.

Cellular senescence in cardiomyocytes, characterized by cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype, occurs during aging and in response to various stresses, such as hypoxia/reoxygenation, ischemia/reperfusion, myocardial infarction (MI), pressure overload, doxorubicin treatment, angiotensin II, diabetes, and thoracic irradiation. Senescence in the heart has both beneficial and detrimental effects. Premature senescence of myofibroblasts has salutary effects during MI and pressure overload. On the other hand, persistent activation of senescence in cardiomyocytes precipitates cardiac dysfunction and adverse remodeling through paracrine mechanisms during MI, myocardial ischemia/reperfusion, aging, and doxorubicin-induced cardiomyopathy. Given the adverse roles of senescence in many conditions, specific removal of senescent cells, i.e., senolysis, is of great interest. Senolysis can be achieved using senolytic drugs (such as Navitoclax, Dasatinib, and Quercetin), pharmacogenetic approaches (including INK-ATTAC and AP20187, p16-3MR and Ganciclovir, p16 ablation, and p16-LOX-ATTAC and Cre), and immunogenetic interventions (CAR T cells or senolytic vaccination). In order to enhance the specificity and decrease the off-target effects of senolytic approaches, investigation into the mechanisms through which cardiomyocytes develop and/or maintain the senescent state is needed.

Mitigation of ultraviolet-induced erythema and inflammation by para-hydroxycinnamic acid in human skin.

OBJECTIVE: To evaluate whether p-hydroxycinnamic acid (pHCA) alone and in combination with niacinamide (Nam) can mitigate UV-induced erythema, barrier disruption, and inflammation. METHODS: Three independent placebo-controlled double-blinded studies were conducted on female panellists who were pretreated on sites on their backs for 2 weeks with skin care formulations which contained 0.3% or 1% pHCA with 5% Nam, 1% pHCA alone, 1.8% octinoxate, or control formula. Treated sites were then exposed to 1.5 minimal erythemal dose (MED) solar simulated radiation (SSR) and had chromameter and expert grading measures for erythema, barrier integrity via TEWL, and the skin surface IL-1RA/IL-1α inflammatory biomarkers isolated from D-Squame tapes. RESULTS: Across the three independent studies, pHCA alone or in combination with Nam showed a significant mitigation of UV-induced erythema, barrier disruption, and levels of the surface inflammatory biomarkers IL-1RA/IL-1α. The cinnamate analogue Octinoxate did not replicate the effects of pHCA. CONCLUSION: The study results show that pHCA alone or in combination with Nam can mitigate UV-induced damage to skin. These include mitigation of UV-induced erythema as measured by instrument and expert grade visualization. Additionally, pHCA with Nam protected damage to the barrier and reduced the induction of the SASP-related surface inflammatory biomarker IL-1RA/IL-1α. The inability of Octinoxate to have any protective effect and the detection of low levels of pHCA on skin surface after 24 h of application supports that these effects are based on a biological response to pHCA. These findings add to the body of evidence that pHCA alone or in combination with Nam can enhance the skin's biological response to UV-induced damage. This supports pHCA can potentially impact aging and senescence, thereby maintain skin's functionality and appearance.

OBJECTIF: Évaluer si l'acide p­hydroxycinnamique (p­hydroxycinnamic acid, pHCA) seul et en association avec le niacinamide (Nam) peut atténuer l'érythème induit par les UV, la rupture de la barrière et l'inflammation. MÉTHODES: Trois études en double aveugle, contrôlées par placebo et indépendantes, ont été menées auprès de femmes panélistes ayant reçu un traitement préalable sur le dos pendant deux semaines avec des formulations de soins cutanés contenant 0.3% ou 1% de pHCA avec 5% de Nam, 1% de pHCA seul, 1.8% d'octinoxate ou une formule témoin. Les sites traités ont ensuite été exposés à une dose érythémateuse minimale (MED) de 1.5 de radiation solaire simulée (SSR) et ont été évalués à l'aide de mesures par chromamètre et de cotations par des experts concernant l'érythème, l'intégrité de la barrière via la perte insensible en eau (TEWL), et les biomarqueurs inflammatoires de la surface cutanée IL­1RA/IL­1 α isolés à partir de bandes D­Squame. RÉSULTATS: Dans les 3 études indépendantes, le pHCA seul ou en association avec le Nam a montré une atténuation significative de l'érythème induit par les UV, de la perturbation de la barrière et des taux des biomarqueurs inflammatoires de surface IL­1RA/IL­1α. L'analogue du cinnamate, l'octinoxate, n'a pas reproduit les effets du pHCA. CONCLUSION: Les résultats des études montrent que le pHCA seul ou en association avec le Nam peut atténuer les dommages cutanés induits par les UV. Ceux­ci comprennent l'atténuation de l'érythème induit par les UV, mesuré par instrument et une visualisation de qualité experte. En outre, le pHCA en association avec le Nam a protégé contre les dommages de la barrière et a réduit l'induction du biomarqueur inflammatoire de surface lié à la SASP IL­1RA/IL­1α. L'incapacité de l'octinoxate à avoir un effet protecteur, ainsi que la détection de faibles niveaux de pHCA à la surface de la peau après 24 heures d'application, confirme que ces effets sont basés sur une réponse biologique au pHCA. Ces résultats viennent s'ajouter à l'ensemble des preuves montrant que le pHCA seul ou en association avec le Nam peut améliorer la réponse biologique de la peau aux dommages induits par les UV. Cela soutient l'hypothèse que le pHCA peut avoir une incidence potentielle sur le vieillissement et la sénescence, maintenant ainsi la fonctionnalité et l'aspect de la peau.

Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?

Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment.

Brief guide to senescence assays using cultured mammalian cells.

Cellular senescence is a crucial biological process associated with organismal aging and many chronic diseases. Here, we present a brief guide to mammalian senescence assays, including the measurement of cell cycle arrest, change in cellular morphology, senescence-associated ß-galactosidase (SA-ß-gal) staining, and the expression of senescence-associated secretory phenotype (SASP). This work will be useful for biologists with minimum expertise in cellular senescence assays.

Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence.

Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H2O2), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.

The up-regulation of PD-L1 during boningmycin-induced senescence in human cancer cells depends on the activation of the JAK/STAT signaling pathway mediated by SASP.

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 ß-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.

FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.

Male ageing is always accompanied by decreased fertility. The forkhead O (FOXO) transcription factor FOXO4 is reported to be highly expressed in senescent cells. Upon activation, it binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ. Leydig cells play key roles in assisting spermatogenesis. Leydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis. In this study, we observed that FOXO4-DRI, a specific FOXO4- p53 binding blocker, induced apoptosis in senescent Leydig cells, reduced the secretion of certain Senescence-Associated Secretory Phenotype and improved the proliferation of cocultured GC-1 SPG cells. In naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality and improved spermatogenesis.