Achilles Heels of Senescent Cells: From Transcriptome to Senolytic Drugs
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE66236 | GEO | 2015/03/10
SECONDARY ACCESSION(S): PRJNA276172
REPOSITORIES: GEO
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Project description:The healthspan of mice is enhanced by selectively killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. As senescent cells resist apoptosis, we used microarrays to identify transcripts and pathways that differ between senescent and non-senescent preadipocytes, and might be involved in resistance to apoptosis. Primary human abdominal subcutaneous preadipocytes were isolated from 8 healthy lean kidney donors. All subjects were matched by age,gender and BMI. The protocol was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Preadipocytes were radiated at 10 Gy to induce senescence or were sham-radiated. From senescent cells RNA was isolated 20 days after irradiation.
2015-03-10 | E-GEOD-66236 | biostudies-arrayexpress
Project description:In the course of aging, the long term retention of senescent cells in vivo, a process mainly attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells accelerates aging and contributes to age-related diseases. Indeed, senescent cells can be removed by several strategies, thus preventing occurrence of chronic disorders and prolonging lifespan and healthspan. Senolytics, which eliminate senescent cells by pharmacological intervention, have recently emerged as a new line of therapeutic agents to ameliorate diverse age-related pathologies. Achieving the goal using natural or synthetic agents would have a tremendous impact on the quality of life. We report the potential of procyanidin C1 (PCC1), an epicatechin trimer natural product derived from plant sources including grape, apple, and cocoa, in targeting senescent cells via induction of apoptosis. This study demonstrates the efficacy of PCC1 in minimizing the influence of senescent cells in tissue microenvironment and provides a strong rationale for its future use in aging control and geriatric medicine.
2021-10-04 | GSE164012 | GEO
Project description:Physical function declines in advanced age, portending disability, increased health expenditures, and clinical mortality. Cellular senescence leads to tissue dysfunction and contributes to the consequences of aging, but whether age-related pathologies including cancer can be alleviated by targeting senescent cells remains largely unclear. Long term retention of senescent cells in vivo, a process mainly attributed to high expression of BCL2 family proteins, causes chronical tissue damages mainly through the senescence-associated secretory phenotype (SASP). Indeed, senescent cells can be removed by several strategies, thus preventing appearance of chronic symptoms and prolonging healthspan. Strategies involving senolytics, which eliminate senescent cells by pharmacological actions, are recently emerging as a novel and prominent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents would generate a tremendous impact on the quality of life. We test the potential of procyanidin C1 (PCC1), a B type procyanidin flavonoid derived from plant sources including grape, apple and cocoa, in targeting senescent cells through inducing apoptosis and suppressing the pro-inflammatory phenotype. This study demonstrates the efficacy of PCC1 in restraining the SASP expression and minimizing the influence of senescent stromal cells in tumor microenvironment and provides a strong rationale for its future development in anti-aging industrial pipelines.
2021-10-04 | GSE178376 | GEO
Project description:The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3K?, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/?) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/?) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
| S-EPMC4531078 | biostudies-literature
Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.
2022-09-06 | GSE210020 | GEO
Project description:Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to reaccumulate, senolytics can be administered intermittently - a 'hit-and-run' approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment. As anticipated for agents targeting the fundamental ageing mechanisms that are 'root cause' contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.
| S-EPMC7405395 | biostudies-literature
Project description:Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.
2024-03-23 | GSE245935 | GEO
Project description:BACKGROUND:Senolytic drugs are thought to target senescent cells and might thereby rejuvenate tissues. In fact, such compounds were suggested to increase health and lifespan in various murine aging models. So far, effects of senolytic drugs have not been analysed during replicative senescence of human mesenchymal stromal cells (MSCs). METHODS:In this study, we tested four potentially senolytic drugs: ABT-263 (navitoclax), quercetin, nicotinamide riboside, and danazol. The effects of these compounds were analysed during long-term expansion of MSCs, until replicative senescence. Furthermore, we determined the effect on molecular markers for replicative senescence, such as senescence-associated beta-galactosidase staining (SA-β-gal), telomere attrition, and senescence-associated DNA methylation changes. RESULTS:Co-culture experiments of fluorescently labelled early and late passages revealed that particularly ABT-263 had a significant but moderate senolytic effect. This was in line with reduced SA-β-gal staining in senescent MSCs upon treatment with ABT-263. However, none of the drugs had significant effects on the maximum number of population doublings, telomere length, or epigenetic senescence predictions. CONCLUSIONS:Of the four tested drugs, only ABT-263 revealed a senolytic effect in human MSCs-and even treatment with this compound did not rejuvenate MSCs with regard to telomere length or epigenetic senescence signature. It will be important to identify more potent senolytic drugs to meet the high hopes for regenerative medicine.
| S-EPMC5907463 | biostudies-literature
Project description:Senescent cells drive age-related tissue dysfunction partially via the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria also control apoptosis, a cell fate generally perceived as distinct from cellular senescence, which is apoptosis resistant. Here, we show that mitochondrial outer membrane permeability (MOMP) occurring in a small subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores and results in release of mitochondrial DNA (mtDNA) into the cytosol, which in turn activates the cGAS/STING pathway, a major regulator of the SASP. Importantly, we found that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan parameters in aged mice. Our results propose the novel concept that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms, and that sub-lethal mitochondrial apoptotic stress is a major driver of the SASP. We also provide proof-of-concept that inhibition of miMOMP may be a new therapeutic avenue to improve healthspan.
2023-08-16 | GSE196610 | GEO
Project description:Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.
| S-EPMC7790861 | biostudies-literature