RESUMO
Senescence of skeletal muscle (SkM) has been a primary contributor to senior weakness and disability in recent years. The gradually declining SkM function associated with senescence has recently been connected to an imbalance between damage and repair. Macrophages (Mac) are involved in SkM aging, and different macrophage subgroups hold different biological functions. Through comprehensive single-cell transcriptomic analysis, we first compared the metabolic pathways and biological functions of different types of cells in young (Y) and old (O) mice SkM. Strikingly, the Mac population in mice SkM was also explored, and we identified a unique Mac subgroup in O SkM characterized by highly expressed SPP1 with strong senescence and adipogenesis features. Further work was carried out on the metabolic and biological processes for these Mac subgroups. Besides, we verified that the proportion of the SPP1+ Mac was increased significantly in the quadriceps tissues of O mice, and the senotherapeutic drug combination dasatinib + quercetin (D + Q) could dramatically reduce its proportion. Our study provides novel insight into the potential role of SPP1+ Mac in SkM, which may serve as a senotherapeutic target in SkM aging.
Assuntos
Envelhecimento , Dasatinibe , Macrófagos , Músculo Esquelético , Análise de Célula Única , Transcriptoma , Animais , Envelhecimento/genética , Camundongos , Músculo Esquelético/metabolismo , Macrófagos/metabolismo , Dasatinibe/farmacologia , Perfilação da Expressão Gênica , Quercetina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Senoterapia/farmacologia , Senescência Celular/genética , Adipogenia/genéticaRESUMO
Obesity, a global health crisis, disrupts multiple systemic processes, contributing to a cascade of metabolic dysfunctions by promoting the pathological expansion of visceral adipose tissue (VAT). This expansion is characterized by impaired differentiation of pre-adipocytes and an increase in senescent cells, leading to a pro-inflammatory state and exacerbated oxidative stress. Particularly, the senescence-associated secretory phenotype (SASP) and adipose tissue hypoxia further impair cellular function, promoting chronic disease development. This review delves into the potential of autophagy modulation and the therapeutic application of senolytics and senomorphics as novel strategies to mitigate adipose tissue senescence. By exploring the intricate mechanisms underlying adipocyte dysfunction and the emerging role of natural compounds in senescence modulation, we underscore the promising horizon of senotherapeutics in restoring adipose health. This approach not only offers a pathway to combat the metabolic complications of obesity, but also opens new avenues for enhancing life quality and managing the global burden of obesity-related conditions. Our analysis aims to bridge the gap between current scientific progress and clinical application, offering new perspectives on preventing and treating obesity-induced adipose dysfunction.
Assuntos
Tecido Adiposo , Autofagia , Senescência Celular , Obesidade , Senoterapia , Humanos , Obesidade/tratamento farmacológico , Senescência Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Autofagia/fisiologia , Autofagia/efeitos dos fármacos , Senoterapia/farmacologia , Animais , AdipócitosRESUMO
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood-brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher ß-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction.
Assuntos
Barreira Hematoencefálica , Senescência Celular , Células Endoteliais , Peróxido de Hidrogênio , NF-kappa B , Estresse Oxidativo , Senoterapia , Proteínas Quinases p38 Ativadas por Mitógeno , Estresse Oxidativo/efeitos dos fármacos , Humanos , Senescência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Senoterapia/farmacologia , Peróxido de Hidrogênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Therapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers.
Assuntos
Biomarcadores Tumorais , Senescência Celular , Neoplasias , Fenótipo Secretor Associado à Senescência , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Biomarcadores Tumorais/metabolismo , Animais , Biomarcadores , Senoterapia/farmacologiaRESUMO
Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.
Assuntos
Fertilidade , Flavonóis , Quercetina , Senoterapia , Animais , Masculino , Camundongos , Fertilidade/efeitos dos fármacos , Quercetina/farmacologia , Senoterapia/farmacologia , Flavonóis/farmacologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Senescência Celular/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Dieta Ocidental/efeitos adversos , Progressão da Doença , Deficiência de Colina/complicações , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Idiopathic pulmonary fibrosis (IPF) is an age-related disease with poor prognosis and limited therapeutic options. Activation of lung fibroblasts and differentiation to myofibroblasts are the principal effectors of disease pathology, but damage and senescence of alveolar epithelial cells, specifically type II (ATII) cells, has recently been identified as a potential trigger event for the progressive disease cycle. Targeting ATII senescence and the senescence-associated secretory phenotype (SASP) is an attractive therapeutic strategy; however, translatable primary human cell models that enable mechanistic studies and drug development are lacking. Here, we describe a novel system of conditioned medium (CM) transfer from bleomycin-induced senescent primary alveolar epithelial cells (AEC) onto normal human lung fibroblasts (NHLF) that demonstrates an enhanced fibrotic transcriptional and secretory phenotype compared to non-senescent AEC CM treatment or direct bleomycin damage of the NHLFs. In this system, the bleomycin-treated AECs exhibit classical hallmarks of cellular senescence, including SASP and a gene expression profile that resembles aberrant epithelial cells of the IPF lung. Fibroblast activation by CM transfer is attenuated by pre-treatment of senescent AECs with the senolytic Navitoclax and AD80, but not with the standard of care agent Nintedanib or senomorphic JAK-targeting drugs (e.g., ABT-317, ruxolitinib). This model provides a relevant human system for profiling novel senescence-targeting therapeutics for IPF drug development.
Assuntos
Células Epiteliais Alveolares , Bleomicina , Senescência Celular , Fibroblastos , Fibrose Pulmonar Idiopática , Humanos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Bleomicina/toxicidade , Bleomicina/farmacologia , Senescência Celular/efeitos dos fármacos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Meios de Cultivo Condicionados/farmacologia , Indóis/farmacologia , Fenótipo Secretor Associado à Senescência/efeitos dos fármacos , Pulmão/patologia , Pulmão/citologia , Pulmão/efeitos dos fármacos , Sulfonamidas/farmacologia , Senoterapia/farmacologia , Células Cultivadas , Pirimidinas/farmacologia , Pirazóis/farmacologia , Nitrilas/farmacologia , Compostos de AnilinaRESUMO
The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy of senolytics in idiopathic pulmonary fibrosis, a lung disease associated with the presence of senescent cells. Another approach to senotherapeutics consists of controlling inflammation related to cellular senescence or "inflammaging", which participates, among other processes, in establishing pulmonary fibrosis. We evaluate whether polyphenols such as caffeic acid, chlorogenic acid, epicatechin, gallic acid, quercetin, or resveratrol combined with different senotherapeutics such as metformin or rapamycin, and antifibrotic drugs such as nintedanib or pirfenidone, could present beneficial actions in an in vitro model of senescent MRC-5 lung fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by the measurement of interleukin (IL)-6, IL-8, and IL-1ß. The senescent-associated ß-galactosidase (SA-ß-gal) activity and cellular proliferation were assessed. Fibrosis was evaluated using a Picrosirius red assay and the gene expression of fibrosis-related genes. Epithelial-mesenchymal transition (EMT) was assayed in the A549 cell line exposed to Transforming Growth Factor (TGF)-ß in vitro. The combination that demonstrated the best results was metformin and caffeic acid, by inhibiting IL-6 and IL-8 in senescent MRC-5 cells. Metformin and caffeic acid also restore cellular proliferation and reduce SA-ß-gal activity during senescence induction. The collagen production by senescent MRC-5 cells was inhibited by epicatechin alone or combined with drugs. Epicatechin and nintedanib were able to control EMT in A549 cells. In conclusion, caffeic acid and epicatechin can potentially increase the effectiveness of senotherapeutic drugs in controlling lung diseases whose pathophysiological component is the presence of senescent cells and fibrosis.
Assuntos
Senescência Celular , Fibroblastos , Pulmão , Polifenóis , Humanos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Senescência Celular/efeitos dos fármacos , Polifenóis/farmacologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Células A549 , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Metformina/farmacologia , Ácidos Cafeicos/farmacologia , Indóis/farmacologia , Senoterapia/farmacologia , Linhagem Celular , Fenótipo Secretor Associado à Senescência/efeitos dos fármacos , Sirolimo/farmacologia , Interleucina-8/metabolismo , Interleucina-8/genética , Fator de Crescimento Transformador beta/metabolismo , PiridonasRESUMO
Senolytics are drugs that specifically target senescent cells. Flavonoids such as quercetin and fisetin possess selective senolytic activities. This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC50 values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.
Assuntos
Senescência Celular , Chalconas , Células Endoteliais , Fibroblastos , Humanos , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Chalconas/farmacologia , Fibroblastos/efeitos dos fármacos , Células Cultivadas , Senoterapia/farmacologia , Concentração Inibidora 50 , Aorta/efeitos dos fármacos , Aorta/citologia , Relação Estrutura-Atividade , Linhagem CelularRESUMO
Cellular senescence contributes to ageing and age-related diseases, and multiple therapeutic strategies are being developed to counteract it. Senolytic drugs are being tested in clinical trials to eliminate senescent cells selectively, but their effects and mechanisms are still unclear. Several studies reveal that the upregulation of senescence-associated secretory phenotype (SASP) factors in senescent cells is accompanied by increased autophagic activity to counteract the endoplasmic reticulum (ER) stress. Our study shows that Doxo-induced senescent fibroblasts yield several SASP factors and exhibit increased autophagy. Interestingly, Quercetin, a bioactive flavonoid, reduces autophagy, increases ER stress, and partially triggers senescent fibroblast death. Given the role of senescent cells in cancer progression, we tested the effect of conditioned media from untreated and quercetin-treated senescent fibroblasts on osteosarcoma cells to determine whether senolytic treatment affected tumour cell behaviour. We report that the partial senescent fibroblast clearance, achieved by quercetin, reduced osteosarcoma cell invasiveness, curbing the pro-tumour effects of senescent cells. The reduction of cell autophagic activity and increased ER stress, an undescribed effect of quercetin, emerges as a new vulnerability of Doxo-induced senescent fibroblasts and may provide a potential therapeutic target for cancer treatment, suggesting novel drug combinations as a promising strategy against the tumour.
Assuntos
Autofagia , Senescência Celular , Doxorrubicina , Estresse do Retículo Endoplasmático , Fibroblastos , Osteossarcoma , Quercetina , Quercetina/farmacologia , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Osteossarcoma/tratamento farmacológico , Humanos , Autofagia/efeitos dos fármacos , Doxorrubicina/farmacologia , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Senoterapia/farmacologia , Fenótipo Secretor Associado à Senescência/efeitos dos fármacosRESUMO
Cellular senescence (CS) is recognized as one of the hallmarks of aging, and an important player in a variety of age-related pathologies. Accumulation of senescent cells can promote a pro-inflammatory and pro-cancerogenic microenvironment. Among potential senotherapeutics are extracellular vesicles (EVs) (40-1000â¯nm), including exosomes (40-150â¯nm), that play an important role in cell-cell communications. Here, we review the most recent studies on the impact of EVs derived from stem cells (MSCs, ESCs, iPSCs) as well as non-stem cells of various types on CS and discuss potential mechanisms responsible for the senotherapeutic effects of EVs. The analysis revealed that (i) EVs derived from stem cells, pluripotent (ESCs, iPSCs) or multipotent (MSCs of various origin), can mitigate the cellular senescence phenotype both in vitro and in vivo; (ii) this effect is presumably senomorphic; (iii) EVs display cross-species activity, without apparent immunogenic responses. In summary, stem cell-derived EVs appear to be promising senotherapeutics, with a feasible application in humans.
Assuntos
Senescência Celular , Vesículas Extracelulares , Senoterapia , Humanos , Vesículas Extracelulares/fisiologia , Senescência Celular/fisiologia , Animais , Senoterapia/farmacologia , Células-Tronco/fisiologia , Envelhecimento/fisiologiaRESUMO
We have previously demonstrated that androgen-dependent prostate cancer (PCa) cell lines enter a state of senescence following exposure to androgen deprivation therapies (ADT). ADT-induced senescence was found to be transient, as senescent cells develop castration resistance and re-emerge into a proliferative state even under continuous androgen deprivation in vitro. Moreover, the BCL-XL/BCL-2 inhibitor, ABT-263 (navitoclax), an established senolytic agent, promoted apoptosis of senescent PCa cells, suppressing proliferative recovery and subsequent tumor cell outgrowth. As this strategy has not previously been validated in vivo, we used a clinically relevant, syngeneic murine model of PCa, where mice were either castrated or castrated followed by the administration of ABT-263. Our results largely confirm the outcomes previously reported in vitro; specifically, castration alone results in a transient tumor growth suppression with characteristics of senescence, which is prolonged by exposure to ABT-263. Most critically, mice that underwent castration followed by ABT-263 experienced a statistically significant prolongation in survival, with an increase of 14.5 days in median survival time (56 days castration alone vs. 70.5 days castration + ABT-263). However, as is often the case in studies combining the promotion of senescence with a senolytic (the "one-two" punch approach), the suppression of tumor growth by the inclusion of the senolytic agent was transient, allowing for tumor regrowth once the drug treatment was terminated. Nevertheless, the results of this work suggest that the "one-two" punch senolytic strategy in PCa may effectively interfere with, diminish, or delay the development of the lethal castration-resistant phenotype.
Assuntos
Compostos de Anilina , Senescência Celular , Neoplasias da Próstata , Sulfonamidas , Masculino , Animais , Camundongos , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Sulfonamidas/farmacologia , Humanos , Linhagem Celular Tumoral , Senoterapia/farmacologia , Senoterapia/uso terapêutico , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Androgênios/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
Senescence and epigenetic alterations are two important hallmarks of cellular aging. During aging, cells subjected to stress undergo many cycles of damage and repair before finally entering either apoptosis or senescence, a permanent state of cell cycle arrest. The first biomarkers of senescence to be identified were increased ß-galactosidase activity and induction of p16INK4a. Another feature of senescent cells is the senescence-associated secretory phenotype (SASP), a complex secretome containing more than 80 pro-inflammatory factors including metalloproteinases, growth factors, chemokines and cytokines. The secretome is regulated through a dynamic process involving a self-amplifying autocrine feedback loop and activation of the immune system. Senescent cells play positive and negative roles depending on the composition of their SASP and may participate in various processes including wound healing and tumour suppression, as well as cell regeneration, embryogenesis, tumorigenesis, inflammation and finally aging. The SASP is also a biomarker of age, biological aging and age-related diseases. Recent advances in anti-age research have shown that senescence can be now prevented or delayed by clearing the senescent cells or mitigating the effects of SASP factors, which can be achieved by a healthy lifestyle (exercise and diet), and senolytics and senomorphics, respectively. An alternative is tissue rejuvenation, which can be achieved by stimulating aged stem cells and reprogramming deprogrammed aged cells. These non-clinical findings will open up new avenues of clinical research into the development of treatments capable of preventing or treating age-related pathologies in humans.
Assuntos
Senescência Celular , Envelhecimento da Pele , Humanos , Envelhecimento da Pele/fisiologia , Fenótipo Secretor Associado à Senescência , Rejuvenescimento/fisiologia , Envelhecimento/fisiologia , Biomarcadores/metabolismo , SenoterapiaRESUMO
Long associated with aging, senescent cells can promote health and have physiological roles.
Assuntos
Envelhecimento , Senescência Celular , Animais , Humanos , Envelhecimento/fisiologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Camundongos , Notophthalmus viridescens , Senoterapia/farmacologia , Desenvolvimento de MedicamentosRESUMO
Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.
Assuntos
Envelhecimento , Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/terapia , Humanos , Envelhecimento/patologia , Senoterapia/farmacologia , Senoterapia/uso terapêutico , Animais , Senescência Celular , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dano ao DNARESUMO
In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP factors in the ovary, in addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
Assuntos
Envelhecimento , Senescência Celular , Oócitos , Ovário , Animais , Oócitos/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/citologia , Feminino , Camundongos , Envelhecimento/fisiologia , Ovário/metabolismo , Ovário/citologia , Ovário/fisiologia , Sulfonamidas/farmacologia , Folículo Ovariano/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/citologia , Compostos de Anilina/farmacologia , Fenótipo Secretor Associado à Senescência , Senoterapia/farmacologiaRESUMO
Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated ß-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.
Assuntos
Convulsões , Serina-Treonina Quinases TOR , Animais , Serina-Treonina Quinases TOR/metabolismo , Camundongos , Humanos , Convulsões/tratamento farmacológico , Senoterapia/farmacologia , Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Epilepsia/tratamento farmacológico , Masculino , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , FemininoRESUMO
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.
Assuntos
Linfócitos T CD4-Positivos , Senescência Celular , Lúpus Eritematoso Sistêmico , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Senescência Celular/imunologia , Senescência Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Adulto , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Camundongos Endogâmicos MRL lpr , Pessoa de Meia-Idade , Masculino , Senoterapia/farmacologiaRESUMO
Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.
Assuntos
Senescência Celular , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Senescência Celular/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fenótipo Secretor Associado à Senescência , Senoterapia/farmacologiaRESUMO
The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.
Assuntos
Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21 , Humanos , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células HCT116 , Complexo de Endopeptidases do Proteassoma/metabolismo , Apoptose/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Células MCF-7 , Proteólise/efeitos dos fármacos , Células A549 , Wortmanina/farmacologia , Senoterapia/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Dano ao DNA/efeitos dos fármacos , Pirimidinas , QuinazolinasRESUMO
Cellular senescence has a complex role in lymphocyte carcinogenesis and drug resistance of lymphomas. Senescent lymphoma cells combine with immunocytes to create an ageing environment that can be reprogrammed with a senescenceassociated secretory phenotype, which gradually promotes therapeutic resistance. Certain signalling pathways, such as the NFκB, Wnt and PI3K/AKT/mTOR pathways, regulate the tumour ageing microenvironment and induce the proliferation and progression of lymphoma cells. Therefore, targeting senescencerelated enzymes or their signal transduction pathways may overcome radiotherapy or chemotherapy resistance and enhance the efficacy of relapsed/refractory lymphoma treatments. Mechanisms underlying drug resistance in lymphomas are complex. The ageing microenvironment is a novel factor that contributes to drug resistance in lymphomas. In terms of clinical translation, some senolytics have been used in clinical trials on patients with relapsed or refractory lymphoma. Combining immunotherapy with epigenetic drugs may achieve better therapeutic effects; however, senescent cells exhibit considerable heterogeneity and lymphoma has several subtypes. Extensive research is necessary to achieve the practical application of senolytics in relapsed or refractory lymphomas. This review summarises the mechanisms of senescenceassociated drug resistance in lymphoma, as well as emerging strategies using senolytics, to overcome therapeutic resistance in lymphoma.