1,530 results on '"Campisi, Judith"'
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2. A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence.
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Kang, Taekyu, Moore, Emily C, Kopania, Emily EK, King, Christina D, Schilling, Birgit, Campisi, Judith, Good, Jeffrey M, and Brem, Rachel B
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Animals ,Mice ,DNA Damage ,Cytokines ,Cell Cycle ,Tumor Suppressor Protein p53 ,Upstream Stimulatory Factors ,Cellular Senescence ,DNA damage ,USF2 ,cellular senescence ,natural variation ,novel screen ,Genetics ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aetiology ,Generic health relevance - Abstract
Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-κB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory Mus musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, upstream stimulatory factor 2 (USF2), for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program-shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.
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- 2023
3. Author Correction: PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy
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Dou, Xuefeng, Fu, Qiang, Long, Qilai, Liu, Shuning, Zou, Yejun, Fu, Da, Xu, Qixia, Jiang, Zhirui, Ren, Xiaohui, Zhang, Guilong, Wei, Xiaoling, Li, Qingfeng, Campisi, Judith, Zhao, Yuzheng, and Sun, Yu
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- 2024
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4. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy
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Dou, Xuefeng, Fu, Qiang, Long, Qilai, Liu, Shuning, Zou, Yejun, Fu, Da, Xu, Qixia, Jiang, Zhirui, Ren, Xiaohui, Zhang, Guilong, Wei, Xiaoling, Li, Qingfeng, Campisi, Judith, Zhao, Yuzheng, and Sun, Yu
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- 2023
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5. Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain
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Gulej, Rafal, Nyúl-Tóth, Ádám, Ahire, Chetan, DelFavero, Jordan, Balasubramanian, Priya, Kiss, Tamas, Tarantini, Stefano, Benyo, Zoltan, Pacher, Pal, Csik, Boglarka, Yabluchanskiy, Andriy, Mukli, Peter, Kuan-Celarier, Anna, Krizbai, István A, Campisi, Judith, Sonntag, William E., Csiszar, Anna, and Ungvari, Zoltan
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- 2023
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6. Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.
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Perez, Kevin, Ciotlos, Serban, McGirr, Julia, Limbad, Chandani, Doi, Ryosuke, Nederveen, Joshua, Nilsson, Mats, Winer, Daniel, Evans, William, Tarnopolsky, Mark, Campisi, Judith, and Melov, Simon
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aging ,muscle ,sarcopenia ,senescence ,transcriptomics ,Aged ,Humans ,Sarcopenia ,Frailty ,Aging ,Muscle ,Skeletal ,Inflammation ,Frail Elderly - Abstract
Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.
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- 2022
7. Does senescence play a role in age-related macular degeneration?
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Malek, Goldis, Campisi, Judith, Kitazawa, Koji, Webster, Corey, Lakkaraju, Aparna, and Skowronska-Krawczyk, Dorota
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Age-related macular degeneration ,Aging ,Retinal pigment epithelium ,Senescence ,Middle Aged ,Humans ,Aged ,Retinal Pigment Epithelium ,Macular Degeneration ,Cellular Senescence - Abstract
Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathologic molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss current thoughts on the potential role of senescence in AMD development and progression, with consideration of the model systems used and their relevance to human disease.
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- 2022
8. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung
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Reyes, Nabora S, Krasilnikov, Maria, Allen, Nancy C, Lee, Jin Young, Hyams, Ben, Zhou, Minqi, Ravishankar, Supriya, Cassandras, Monica, Wang, Chaoqun, Khan, Imran, Matatia, Peri, Johmura, Yoshikazu, Molofsky, Ari, Matthay, Michael, Nakanishi, Makoto, Sheppard, Dean, Campisi, Judith, and Peng, Tien
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Regenerative Medicine ,Stem Cell Research ,Underpinning research ,1.1 Normal biological development and functioning ,Humans ,Basement Membrane ,Biomarkers ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,Fibroblasts ,Inflammation ,Lung ,Genes ,Reporter ,Regeneration ,Epithelial Cells ,Stem Cell Niche ,General Science & Technology - Abstract
We engineered an ultrasensitive reporter of p16INK4a, a biomarker of cellular senescence. Our reporter detected p16INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these p16INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, p16INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.
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- 2022
9. Systemic induction of senescence in young mice after single heterochronic blood exchange
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Jeon, Ok Hee, Mehdipour, Melod, Gil, Tae-Hwan, Kang, Minha, Aguirre, Nicholas W, Robinson, Zachery R, Kato, Cameron, Etienne, Jessy, Lee, Hyo Gyeong, Alimirah, Fatouma, Walavalkar, Vighnesh, Desprez, Pierre-Yves, Conboy, Michael J, Campisi, Judith, and Conboy, Irina M
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Medical Biochemistry and Metabolomics ,Medical Physiology ,Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Aging ,Inflammatory and immune system ,Generic health relevance ,Animals ,Cellular Senescence ,Male ,Mice ,Parabiosis ,Medical biochemistry and metabolomics ,Medical physiology ,Nutrition and dietetics - Abstract
AbstactAgeing is the largest risk factor for many chronic diseases. Studies of heterochronic parabiosis, substantiated by blood exchange and old plasma dilution, show that old-age-related factors are systemically propagated and have pro-geronic effects in young mice. However, the underlying mechanisms how bloodborne factors promote ageing remain largely unknown. Here, using heterochronic blood exchange in male mice, we show that aged mouse blood induces cell and tissue senescence in young animals after one single exchange. This induction of senescence is abrogated if old animals are treated with senolytic drugs before blood exchange, therefore attenuating the pro-geronic influence of old blood on young mice. Hence, cellular senescence is neither simply a response to stress and damage that increases with age, nor a chronological cell-intrinsic phenomenon. Instead, senescence quickly and robustly spreads to young mice from old blood. Clearing senescence cells that accumulate with age rejuvenates old circulating blood and improves the health of multiple tissues.
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- 2022
10. Chromosome instability and aneuploidy in the mammalian brain
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Albert, Olivia, Sun, Shixiang, Huttner, Anita, Zhang, Zhengdong, Suh, Yousin, Campisi, Judith, Vijg, Jan, and Montagna, Cristina
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- 2023
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11. Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling
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Yun, Jina, Hansen, Simon, Morris, Otto, Madden, David T., Libeu, Clare Peters, Kumar, Arjun J., Wehrfritz, Cameron, Nile, Aaron H., Zhang, Yingnan, Zhou, Lijuan, Liang, Yuxin, Modrusan, Zora, Chen, Michelle B., Overall, Christopher C., Garfield, David, Campisi, Judith, Schilling, Birgit, Hannoush, Rami N., and Jasper, Heinrich
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- 2023
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12. Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types
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Limbad, Chandani, Doi, Ryosuke, McGirr, Julia, Ciotlos, Serban, Perez, Kevin, Clayton, Zachary S, Daya, Radha, Seals, Douglas R, Campisi, Judith, and Melov, Simon
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Aging ,Genetics ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Cancer ,Biological sciences ,Cell biology ,Molecular biology ,Transcriptomics - Abstract
Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.
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- 2022
13. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
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Xu, Qixia, Fu, Qiang, Li, Zi, Liu, Hanxin, Wang, Ying, Lin, Xu, He, Ruikun, Zhang, Xuguang, Ju, Zhenyu, Campisi, Judith, Kirkland, James L, and Sun, Yu
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Prevention ,Complementary and Integrative Health ,Aging ,Nutrition ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Cancer ,Animals ,Apoptosis ,Cell Line ,Cellular Senescence ,Computational Biology ,Drug Development ,Energy Metabolism ,Flavonoids ,Gene Expression Profiling ,Gene Expression Regulation ,Humans ,Longevity ,Mice ,Mitochondria ,Oxidative Stress ,Senescence-Associated Secretory Phenotype ,Senotherapeutics - Abstract
Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.
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- 2021
14. Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.
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Prasanna, Pataje G, Citrin, Deborah E, Hildesheim, Jeffrey, Ahmed, Mansoor M, Venkatachalam, Sundar, Riscuta, Gabriela, Xi, Dan, Zheng, Guangrong, Deursen, Jan van, Goronzy, Jorg, Kron, Stephen J, Anscher, Mitchell S, Sharpless, Norman E, Campisi, Judith, Brown, Stephen L, Niedernhofer, Laura J, O'Loghlen, Ana, Georgakilas, Alexandros G, Paris, Francois, Gius, David, Gewirtz, David A, Schmitt, Clemens A, Abazeed, Mohamed E, Kirkland, James L, Richmond, Ann, Romesser, Paul B, Lowe, Scott W, Gil, Jesus, Mendonca, Marc S, Burma, Sandeep, Zhou, Daohong, and Coleman, C Norman
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Cancer ,Prevention ,Oncology & Carcinogenesis ,Oncology and Carcinogenesis - Abstract
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
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- 2021
15. Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy
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Prasanna, Pataje G, Citrin, Deborah E, Hildesheim, Jeffrey, Ahmed, Mansoor M, Venkatachalam, Sundar, Riscuta, Gabriela, Xi, Dan, Zheng, Guangrong, van Deursen, Jan, Goronzy, Jorg, Kron, Stephen J, Anscher, Mitchell S, Sharpless, Norman E, Campisi, Judith, Brown, Stephen L, Niedernhofer, Laura J, O'Loghlen, Ana, Georgakilas, Alexandros G, Paris, Francois, Gius, David, Gewirtz, David A, Schmitt, Clemens A, Abazeed, Mohamed E, Kirkland, James L, Richmond, Ann, Romesser, Paul B, Lowe, Scott W, Gil, Jesus, Mendonca, Marc S, Burma, Sandeep, Zhou, Daohong, and Coleman, C Norman
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Cancer ,Prevention ,Good Health and Well Being ,Biomarkers ,Cellular Senescence ,Humans ,Neoplasms ,Senescence-Associated Secretory Phenotype ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
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- 2021
16. Age‐related telomere attrition causes aberrant gene expression in sub‐telomeric regions
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Dong, Xiao, Sun, Shixiang, Zhang, Lei, Kim, Seungsoo, Tu, Zhidong, Montagna, Cristina, Maslov, Alexander Y, Suh, Yousin, Wang, Tao, Campisi, Judith, and Vijg, Jan
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Aging ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Aged ,Cellular Senescence ,Female ,Gene Expression ,Humans ,Male ,Middle Aged ,Telomere ,Young Adult ,aging ,gene expression ,telomere shortening ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Telomere attrition has been proposed as a biomarker and causal factor in aging. In addition to causing cellular senescence and apoptosis, telomere shortening has been found to affect gene expression in subtelomeric regions. Here, we analyzed the distribution of age-related differentially expressed genes from the GTEx RNA sequencing database of 54 tissue types from 979 human subjects and found significantly more upregulated than downregulated genes in subtelomeric regions as compared to the genome-wide average. Our data demonstrate spatial relationships between telomeres and gene expression in aging.
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- 2021
17. Cdkn1a transcript variant 2 is a marker of aging and cellular senescence
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López-Domínguez, José Alberto, Rodríguez-López, Sandra, Ahumada-Castro, Ulises, Desprez, Pierre-Yves, Konovalenko, Maria, Laberge, Remi-Martin, Cárdenas, César, Villalba, José Manuel, and Campisi, Judith
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Aging ,Genetics ,Aniline Compounds ,Animals ,Biomarkers ,Cellular Senescence ,Circadian Rhythm ,Cyclin-Dependent Kinase Inhibitor p21 ,Doxorubicin ,Female ,Male ,Mice ,Inbred C57BL ,Protein Isoforms ,Protein Stability ,Sulfonamides ,Tumor Suppressor Protein p53 ,Up-Regulation ,doxorubicin ,ionizing radiation ,mouse dermal fibroblast ,p21 ,p53 ,Biochemistry and cell biology ,Clinical sciences - Abstract
Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.
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- 2021
18. Age‐associated expression of p21and p53 during human wound healing
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Chia, Chee W, Sherman‐Baust, Cheryl A, Larson, Sara A, Pandey, Ritu, Withers, Roxanne, Karikkineth, Ajoy C, Zukley, Linda M, Campisi, Judith, Egan, Josephine M, Sen, Ranjan, and Ferrucci, Luigi
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Genetics ,Clinical Research ,Adult ,Aged ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase Inhibitor p21 ,Female ,Humans ,Male ,Pilot Projects ,Skin ,Tumor Suppressor Protein p53 ,Wound Healing ,aging ,human wound healing ,p21 ,p53 ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.
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- 2021
19. The progeria research foundation 10th international scientific workshop; researching possibilities, ExTENding lives – webinar version scientific summary
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Gordon, Leslie B, Tuminelli, Kelsey, Andrés, Vicente, Campisi, Judith, Kieran, Mark W, Doucette, Lynn, and Gordon, Audrey S
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Biomedical and Clinical Sciences ,Clinical Sciences ,Heart Disease ,Pediatric ,Orphan Drug ,Genetics ,Aging ,Pediatric Research Initiative ,Rare Diseases ,Cardiovascular ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Disease Progression ,Education ,Humans ,Progeria ,aging ,atherosclerosis ,lamin A ,laminopathy ,progeria ,Biochemistry and cell biology ,Clinical sciences - Abstract
Progeria is an ultra-rare (prevalence 1 in 20 million), fatal, pediatric autosomal dominant premature aging disease caused by a mutation in the LMNA gene. This mutation results in accumulation of a high level of an aberrant form of the nuclear membrane protein, Lamin A. This aberrant protein, termed progerin, accumulates in many tissues and is responsible for the diverse array of disease phenotypes. Children die predominantly from premature atherosclerotic cardiovascular disease. The Progeria Research Foundation's 10th International Scientific Workshop took place via webinar on November 2 and 3, 2020. Participants from 30 countries joined in this new, virtual meeting format. Patient family presentations led the program, followed by updates on Progeria's first-ever application for FDA drug approval as well as initial results from the only current Progeria clinical trial. This was followed by presentations of unpublished preclinical data on drugs in development targeting the disease-causing DNA mutation, the aberrant mRNA, progerin protein, and its downstream effector proteins. Tying bench to bedside, clinicians presented new discoveries on the natural history of disease to inform future clinical trial development and new Progeria aortic valve replacement procedures. The program engaged the Progeria research community as a single unit with a common goal - to treat and cure children with Progeria worldwide.
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- 2021
20. Quantitative Proteomic Analysis of the Senescence‐Associated Secretory Phenotype by Data‐Independent Acquisition
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Neri, Francesco, Basisty, Nathan, Desprez, Pierre‐Yves, Campisi, Judith, and Schilling, Birgit
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Cells ,Cultured ,Cellular Senescence ,Culture Media ,Conditioned ,Phenotype ,Proteomics ,aging ,data-independent acquisition ,mass spectrometry ,quantitative proteomic analysis ,secretome ,senescence - Abstract
Cellular senescence is a complex stress response that induces an essentially permanent cell cycle arrest and a complex secretory phenotype termed the senescence-associated secretory phenotype (SASP), which drives numerous aging pathologies. Characterization of the SASP can provide insights into aging and disease mechanisms, aging biomarker candidates, and targets for counteracting the deleterious effects of senescent cells. Here we describe a mass spectrometry (MS)-compatible protocol to (1) generate senescent cells using different stimuli, (2) collect conditioned medium containing proteins secreted by senescent cells (i.e., SASP), and (3) prepare the SASP for quantitative proteomic analysis using data-independent acquisition (DIA) MS. © 2021 The Authors. Basic Protocol 1: Generating ionizing radiation-induced senescent and control cells Alternate Protocol 1: Generating doxorubicin-induced senescent and control cells Alternate Protocol 2: Generating oncogenic RAS-induced senescent and control cells Alternate Protocol 3: Generating mitochondrial dysfunction-induced senescent and control cells Alternate Protocol 4: Generating atazanavir/ritonavir-induced senescent and control cells Support Protocol: A multiple-assay approach to confirm the phenotype of senescent cells Basic Protocol 2: Generating conditioned medium from senescent cells cultured in low serum and quiescent control cells Alternate Protocol 5: Generating conditioned medium from senescent cells cultured in complete medium and quiescent control cells Basic Protocol 3: Quantitative proteomic analysis of the SASP.
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- 2021
21. ARDD 2020: from aging mechanisms to interventions
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Mkrtchyan, Garik V, Abdelmohsen, Kotb, Andreux, Pénélope, Bagdonaite, Ieva, Barzilai, Nir, Brunak, Søren, Cabreiro, Filipe, de Cabo, Rafael, Campisi, Judith, Cuervo, Ana Maria, Demaria, Marco, Ewald, Collin Y, Fang, Evandro Fei, Faragher, Richard, Ferrucci, Luigi, Freund, Adam, Silva-García, Carlos G, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David J, Gorbunova, Vera, de Grey, Aubrey, He, Wei-Wu, Hoeijmakers, Jan, Hoffmann, Eva, Horvath, Steve, Houtkooper, Riekelt H, Jensen, Majken K, Jensen, Martin Borch, Kane, Alice, Kassem, Moustapha, de Keizer, Peter, Kennedy, Brian, Karsenty, Gerard, Lamming, Dudley W, Lee, Kai-Fu, MacAulay, Nanna, Mamoshina, Polina, Mellon, Jim, Molenaars, Marte, Moskalev, Alexey, Mund, Andreas, Niedernhofer, Laura, Osborne, Brenna, Pak, Heidi H, Parkhitko, Andrey, Raimundo, Nuno, Rando, Thomas A, Rasmussen, Lene Juel, Reis, Carolina, Riedel, Christian G, Franco-Romero, Anais, Schumacher, Björn, Sinclair, David A, Suh, Yousin, Taub, Pam R, Toiber, Debra, Treebak, Jonas T, Valenzano, Dario Riccardo, Verdin, Eric, Vijg, Jan, Young, Sergey, Zhang, Lei, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Biological Sciences ,Aging ,Prevention ,Good Health and Well Being ,Artificial Intelligence ,Biomedical Research ,Cellular Senescence ,Congresses as Topic ,Drug Discovery ,Humans ,Life Style ,Longevity ,Pharmaceutical Preparations ,aging ,interventions ,drug discovery ,artificial intelligence ,Physiology ,Oncology and Carcinogenesis ,Developmental Biology - Abstract
Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.
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- 2020
22. Role of immune cells in the removal of deleterious senescent cells
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Kale, Abhijit, Sharma, Amit, Stolzing, Alexandra, Desprez, Pierre-Yves, and Campisi, Judith
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Age-related pathology ,Cell-based therapy ,Cellular senescence ,Immune surveillance ,Inflammation ,Macrophages ,Natural killer cells ,Clinical Sciences ,Clinical sciences - Abstract
Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.
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- 2020
23. Withdrawal: Selective cleavage of BLM, the Bloom syndrome protein, during apoptotic cell death.
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Bischof, Oliver, Galande, Sanjeev, Farzaneh, Farzin, Kohwi-Shigematsu, Terumi, and Campisi, Judith
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Biological Sciences ,Biomedical and Clinical Sciences ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
This article has been withdrawn by the authors except Dr. Kohwi- Shigematsu, who could not be reached. Fig. 3B has a duplication of the top band in lanes 1 and 3. Fig. 5D has a duplication between the top bands and a horizontal flip of the bottom bands. Fig. 5E likewise has a duplication of the top bands excluding the probe lanes and a horizontal flip of the bottom bands. Fig. 6A has smaller microscopy images pasted on the background of larger microscopy images.
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- 2020
24. FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.
- Author
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Voisin, Jessica, Farina, Francesca, Naphade, Swati, Fontaine, Morgane, Tshilenge, Kizito-Tshitoko, Galicia Aguirre, Carlos, Lopez-Ramirez, Alejandro, Dancourt, Julia, Ginisty, Aurélie, Sasidharan Nair, Satish, Lakshika Madushani, Kuruwitage, Zhang, Ningzhe, Lejeune, François-Xavier, Verny, Marc, Campisi, Judith, Ellerby, Lisa M, and Neri, Christian
- Subjects
Neurons ,Humans ,Huntington Disease ,Cyclin-Dependent Kinase Inhibitor p16 ,Neural Stem Cells ,Forkhead Box Protein O3 ,neurodegenerative disease ,neuronal differentiation ,neuronal senescence ,response mechanisms ,temporal dynamics ,Stem Cell Research ,Brain Disorders ,Neurosciences ,Neurodegenerative ,Huntington's Disease ,Stem Cell Research - Nonembryonic - Non-Human ,Rare Diseases ,Aging ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Neurological ,Developmental Biology ,Biological Sciences ,Medical and Health Sciences - Abstract
Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a , a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3-ETS2-p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.
- Published
- 2020
25. Non-canonical ATM/MRN activities temporally define the senescence secretory program.
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Malaquin, Nicolas, Olivier, Marc-Alexandre, Martinez, Aurélie, Nadeau, Stéphanie, Sawchyn, Christina, Coppé, Jean-Philippe, Cardin, Guillaume, Mallette, Frédérick, Rodier, Francis, and Campisi, Judith
- Subjects
DNA damage response ,MRN complex ,NF-κB ,chromatin ,senescence secretome ,Cellular Senescence ,Chromatin ,DNA Damage ,NF-kappa B ,Signal Transduction - Abstract
Senescent cells display senescence-associated (SA) phenotypic programs such as stable proliferation arrest (SAPA) and a secretory phenotype (SASP). Senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but the SASP requires days to develop. Here, we show that following the immediate canonical DDR, a delayed chromatin accumulation of the ATM and MRN complexes coincides with the expression of SASP factors. Importantly, histone deacetylase inhibitors (HDACi) trigger SAPA and SASP in the absence of DNA damage. However, HDACi-induced SASP also requires ATM/MRN activities and causes their accumulation on chromatin, revealing a DNA damage-independent, non-canonical DDR activity that underlies SASP maturation. This non-canonical DDR is required for the recruitment of the transcription factor NF-κB on chromatin but not for its nuclear translocation. Non-canonical DDR further does not require ATM kinase activity, suggesting structural ATM functions. We propose that delayed chromatin recruitment of SASP modulators is the result of non-canonical DDR signaling that ensures SASP activation only in the context of senescence and not in response to transient DNA damage-induced proliferation arrest.
- Published
- 2020
26. Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma
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Ladomersky, Erik, Zhai, Lijie, Lauing, Kristen L, Bell, April, Xu, Jiahui, Kocherginsky, Masha, Zhang, Bin, Wu, Jennifer D, Podojil, Joseph R, Platanias, Leonidas C, Mochizuki, Aaron Y, Prins, Robert M, Kumthekar, Priya, Raizer, Jeffrey J, Dixit, Karan, Lukas, Rimas V, Horbinski, Craig, Wei, Min, Zhou, Changyou, Pawelec, Graham, Campisi, Judith, Grohmann, Ursula, Prendergast, George C, Munn, David H, and Wainwright, Derek A
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Brain Cancer ,Neurosciences ,Clinical Research ,Rare Diseases ,Orphan Drug ,Aging ,Cancer ,Brain Disorders ,Immunotherapy ,Adult ,Age Factors ,Aged ,Aged ,80 and over ,Animals ,B7-H1 Antigen ,Brain ,CTLA-4 Antigen ,Cellular Senescence ,Disease Models ,Animal ,Female ,Glioblastoma ,Humans ,Immune Checkpoint Inhibitors ,Immunosuppression Therapy ,Indoleamine-Pyrrole 2 ,3 ,-Dioxygenase ,Isocitrate Dehydrogenase ,Male ,Mice ,Knockout ,Middle Aged ,Progression-Free Survival ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeWild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of
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- 2020
27. Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance
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Wang, Changxu, Long, Qilai, Fu, Qiang, Xu, Qixia, Fu, Da, Li, Yan, Gao, Libin, Guo, Jianming, Zhang, Xiaoling, Lam, Eric W.-F., Campisi, Judith, and Sun, Yu
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- 2022
- Full Text
- View/download PDF
28. Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice.
- Author
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Acklin, Scarlett, Zhang, Manchao, Du, Wuying, Zhao, Xin, Plotkin, Matthew, Chang, Jianhui, Campisi, Judith, Zhou, Daohong, and Xia, Fen
- Abstract
Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological 'senolytic' agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.
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- 2020
29. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity.
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He, Yonghan, Zhang, Xuan, Chang, Jianhui, Kim, Ha-Neui, Zhang, Peiyi, Wang, Yingying, Khan, Sajid, Liu, Xingui, Zhang, Xin, Lv, Dongwen, Song, Lin, Li, Wen, Thummuri, Dinesh, Yuan, Yaxia, Wiegand, Janet S, Ortiz, Yuma T, Budamagunta, Vivekananda, Elisseeff, Jennifer H, Campisi, Judith, Almeida, Maria, Zheng, Guangrong, and Zhou, Daohong
- Subjects
Blood Platelets ,Cell Line ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Sulfonamides ,Aniline Compounds ,Adaptor Proteins ,Signal Transducing ,Models ,Animal ,Aging ,Female ,Male ,bcl-X Protein ,Primary Cell Culture ,Proteolysis ,Cellular Senescence ,Transgenic ,Adaptor Proteins ,Signal Transducing ,Models ,Animal - Abstract
Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
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- 2020
30. Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin
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Kim, Dong Eun, Dollé, Martijn ET, Vermeij, Wilbert P, Gyenis, Akos, Vogel, Katharina, Hoeijmakers, Jan HJ, Wiley, Christopher D, Davalos, Albert R, Hasty, Paul, Desprez, Pierre‐Yves, and Campisi, Judith
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Stem Cell Research ,Aging ,Cancer ,Genetics ,Stem Cell Research - Nonembryonic - Non-Human ,Underpinning research ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Generic health relevance ,Animals ,Apoptosis ,Cells ,Cultured ,Cellular Senescence ,DNA-Binding Proteins ,Endonucleases ,Fibroblasts ,Gene Knockdown Techniques ,Humans ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Phenotype ,Signal Transduction ,Skin ,Stem Cells ,Transfection ,Tumor Necrosis Factor-alpha ,Tumor Suppressor Protein p53 ,DNA damage repair ,aging ,cell death ,senescence-associated secretory phenotype ,tumor necrosis factor α ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
ERCC1 (excision repair cross complementing-group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross-link repair. Ercc1-/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1-/Δ mice display combined features of human progeroid and cancer-prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1-/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1-/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1-/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence-associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor-suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1-deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1-/Δ mouse skin, where the apoptotic cells are localized, compared to age-matched wild-type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1-depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health- or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.
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- 2020
31. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity
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He, Yonghan, Li, Wen, Lv, Dongwen, Zhang, Xin, Zhang, Xuan, Ortiz, Yuma T, Budamagunta, Vivekananda, Campisi, Judith, Zheng, Guangrong, and Zhou, Daohong
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Cell Survival ,Cellular Senescence ,Doxorubicin ,HEK293 Cells ,Human Umbilical Vein Endothelial Cells ,Humans ,Mice ,Proto-Oncogene Proteins c-mdm2 ,RNA Interference ,Signal Transduction ,Thiophenes ,Transfection ,Tumor Suppressor Protein p53 ,Ubiquitin-Specific Peptidase 7 ,Ubiquitination ,MDM2 ,Senescence ,USP7 ,apoptosis ,p53 ,senolytics ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.
- Published
- 2020
32. Astrocyte senescence promotes glutamate toxicity in cortical neurons.
- Author
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Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R, Tracy, Tara E, Gan, Li, Desprez, Pierre-Yves, and Campisi, Judith
- Subjects
Aging ,Dementia ,Genetics ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Neurosciences ,Alzheimer's Disease ,Neurodegenerative ,Acquired Cognitive Impairment ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Neurological ,Alzheimer's Disease including Alzheimer's Disease Related Dementias ,General Science & Technology - Abstract
Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.
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- 2020
33. A proteomic atlas of senescence-associated secretomes for aging biomarker development.
- Author
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Basisty, Nathan, Kale, Abhijit, Jeon, Ok Hee, Kuehnemann, Chisaka, Payne, Therese, Rao, Chirag, Holtz, Anja, Shah, Samah, Sharma, Vagisha, Ferrucci, Luigi, Campisi, Judith, and Schilling, Birgit
- Subjects
Cells ,Cultured ,Humans ,Proteome ,Proteomics ,Aging ,Phenotype ,Databases ,Protein ,Female ,Exosomes ,Secretory Pathway ,Biomarkers ,Cellular Senescence ,Cells ,Cultured ,Databases ,Protein ,Genetics ,Cancer ,Developmental Biology ,Biological Sciences ,Medical and Health Sciences ,Agricultural and Veterinary Sciences - Abstract
The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the "SASP Atlas," a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA). Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus, and tissue of origin of senescent cells in vivo.
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- 2020
34. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression
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Xu, Qixia, Long, Qilai, Zhu, Dexiang, Fu, Da, Zhang, Boyi, Han, Liu, Qian, Min, Guo, Jianming, Xu, Jianmin, Cao, Liu, Chin, Y Eugene, Coppé, Jean‐Philippe, Lam, Eric W‐F, Campisi, Judith, and Sun, Yu
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Cancer ,Aging ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Amphiregulin ,Animals ,Antineoplastic Agents ,B7-H1 Antigen ,Cells ,Cultured ,Cellular Senescence ,Drug Resistance ,Neoplasm ,Humans ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Stromal Cells ,Tumor Microenvironment ,aging ,amphiregulin ,cancer resistance ,clinical biomarker ,combinational treatment ,programmed cell death 1 ligand ,senescence-associated secretory phenotype ,stroma ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence-associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD-L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME-mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging-related morbidity and mortality.
- Published
- 2019
35. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis.
- Author
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Wiley, Christopher D, Brumwell, Alexis N, Davis, Sonnet S, Jackson, Julia R, Valdovinos, Alexis, Calhoun, Cheresa, Alimirah, Fatouma, Castellanos, Carlos A, Ruan, Richard, Wei, Ying, Chapman, Harold A, Ramanathan, Arvind, Campisi, Judith, and Jourdan Le Saux, Claude
- Subjects
Lung ,Cell Line ,Fibroblasts ,Bronchoalveolar Lavage Fluid ,Animals ,Humans ,Mice ,Disease Models ,Animal ,Disease Progression ,Arachidonate 5-Lipoxygenase ,Bleomycin ,Leukotrienes ,Prostaglandins ,Lipoxygenase Inhibitors ,Culture Media ,Conditioned ,Gene Expression Profiling ,Signal Transduction ,Gene Expression Regulation ,Male ,Idiopathic Pulmonary Fibrosis ,Primary Cell Culture ,Cellular Senescence ,Cell Biology ,Cellular senescence ,Eicosanoids ,Fibrosis ,Pulmonology ,Rare Diseases ,Autoimmune Disease ,Aetiology ,2.1 Biological and endogenous factors ,Respiratory - Abstract
Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction. The synthesis of LT was biphasic and followed by antifibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts (IMR-90) induced profibrotic signaling in naive fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl LT in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cell removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+ cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs. This study demonstrates for the first time to our knowledge that senescent cells secrete functional LTs, significantly contributing to the LT pool known to cause or exacerbate IPF.
- Published
- 2019
36. Senescent characteristics of human corneal endothelial cells upon ultraviolet-A exposure
- Author
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Numa, Kohsaku, primary, Patel, Sandip Kumar, additional, Zhang, Zhixin A., additional, Burton, Jordan B., additional, Matsumoto, Akifumi, additional, Hughes, Jun-Wei B., additional, Sotozono, Chie, additional, Schilling, Birgit, additional, Desprez, Pierre-Yves, additional, Campisi, Judith, additional, and Kitazawa, Koji, additional
- Published
- 2024
- Full Text
- View/download PDF
37. SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells
- Author
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Wiley, Christopher D, Liu, Su, Limbad, Chandani, Zawadzka, Anna M, Beck, Jennifer, Demaria, Marco, Artwood, Robert, Alimirah, Fatouma, Lopez-Dominguez, Jose-Alberto, Kuehnemann, Chisaka, Danielson, Steven R, Basisty, Natan, Kasler, Herbert G, Oron, Tal Ronnen, Desprez, Pierre-Yves, Mooney, Sean D, Gibson, Bradford W, Schilling, Birgit, Campisi, Judith, and Kapahi, Pankaj
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Hematology ,Cancer ,Genetics ,Underpinning research ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Cellular Senescence ,Hemostasis ,Humans ,SASP ,aging ,cellular senescence ,chemotherapy ,clotting ,coagulation ,homeostasis ,proteomics ,secretion ,thrombosis ,Medical Physiology ,Biological sciences - Abstract
Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence. We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis.
- Published
- 2019
38. Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging
- Author
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Muñoz, Denise P, Yannone, Steven M, Daemen, Anneleen, Sun, Yu, Vakar-Lopez, Funda, Kawahara, Misako, Freund, Adam M, Rodier, Francis, Wu, Jennifer D, Desprez, Pierre-Yves, Raulet, David H, Nelson, Peter S, van 't Veer, Laura J, Campisi, Judith, and Coppé, Jean-Philippe
- Subjects
Cancer ,Aging ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Animals ,Antineoplastic Agents ,Biopsy ,Breast ,Breast Neoplasms ,Cell Line ,Tumor ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,DNA Damage ,Datasets as Topic ,Drug Resistance ,Neoplasm ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Humans ,Immunologic Surveillance ,Male ,Metalloendopeptidases ,Mice ,NK Cell Lectin-Like Receptor Subfamily K ,Prostate ,Prostatic Neoplasms ,Tissue Array Analysis ,Tumor Escape ,Tumor Microenvironment ,Cellular senescence ,Oncology ,Proteases ,Tumor suppressors - Abstract
Cellular senescence is a tumor suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells (SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals secretome-targeted therapeutic strategies to selectively eliminate -and restore the clearance of- the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.
- Published
- 2019
39. A direct comparison of interphase FISH versus low-coverage single cell sequencing to detect aneuploidy reveals respective strengths and weaknesses.
- Author
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Andriani, Grasiella A, Maggi, Elaine, Piqué, Daniel, Zimmerman, Samuel E, Lee, Moonsook, Quispe-Tintaya, Wilber, Maslov, Alexander, Campisi, Judith, Vijg, Jan, Mar, Jessica C, and Montagna, Cristina
- Subjects
Biochemistry and Cell Biology ,Other Physical Sciences - Abstract
Aneuploidy has been reported to occur at remarkably high levels in normal somatic tissues using Fluorescence In Situ Hybridization (FISH). Recently, these reports were contradicted by single-cell low-coverage whole genome sequencing (scL-WGS) analyses, which showed aneuploidy frequencies at least an order of magnitude lower. To explain these seemingly contradictory findings, we used both techniques to analyze artificially generated mock aneuploid cells and cells with natural random aneuploidy. Our data indicate that while FISH tended to over-report aneuploidies, a modified 2-probe approach can accurately detect low levels of aneuploidy. Further, scL-WGS tends to underestimate aneuploidy levels, especially in a polyploid background.
- Published
- 2019
40. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition.
- Author
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Pereira, Branca I, Devine, Oliver P, Vukmanovic-Stejic, Milica, Chambers, Emma S, Subramanian, Priya, Patel, Neil, Virasami, Alex, Sebire, Neil J, Kinsler, Veronica, Valdovinos, Alexis, LeSaux, Claude Jourdan, Passos, João F, Antoniou, Antony, Rustin, Malcom HA, Campisi, Judith, and Akbar, Arne N
- Subjects
Killer Cells ,Natural ,CD8-Positive T-Lymphocytes ,Fibroblasts ,Skin ,Dermis ,Humans ,Nevus ,Pigmented ,p38 Mitogen-Activated Protein Kinases ,RNA ,Small Interfering ,Histocompatibility Antigens Class I ,Cytokines ,Signal Transduction ,Aging ,Phenotype ,Adult ,Aged ,NK Cell Lectin-Like Receptor Subfamily C ,Young Adult ,In Vitro Techniques ,Cellular Senescence ,Killer Cells ,Natural ,Nevus ,Pigmented ,RNA ,Small Interfering ,MD Multidisciplinary - Abstract
Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.
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- 2019
41. Targeting senescent cells alleviates obesity‐induced metabolic dysfunction
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Palmer, Allyson K, Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M, Hachfeld, Christine M, Prata, Larissa G, van Dijk, Theo H, Verkade, Esther, Casaclang‐Verzosa, Grace, Johnson, Kurt O, Cubro, Hajrunisa, Doornebal, Ewald J, Ogrodnik, Mikolaj, Jurk, Diana, Jensen, Michael D, Chini, Eduardo N, Miller, Jordan D, Matveyenko, Aleksey, Stout, Michael B, Schafer, Marissa J, White, Thomas A, Hickson, LaTonya J, Demaria, Marco, Garovic, Vesna, Grande, Joseph, Arriaga, Edgar A, Kuipers, Folkert, von Zglinicki, Thomas, LeBrasseur, Nathan K, Campisi, Judith, Tchkonia, Tamar, and Kirkland, James L
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Medical Physiology ,Biomedical and Clinical Sciences ,Nutrition ,Obesity ,Prevention ,Diabetes ,2.1 Biological and endogenous factors ,Aetiology ,Cardiovascular ,Metabolic and endocrine ,Adipocytes ,Adipogenesis ,Adipose Tissue ,Aging ,Animals ,Cell Death ,Cell Line ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,Dasatinib ,Female ,Ganciclovir ,Glucose ,Humans ,Inflammation ,Insulin Resistance ,Macrophages ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Quercetin ,adipogenesis ,aging ,cellular senescence ,dasatinib ,quercetin ,senolytics ,type 2 diabetes ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.
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- 2019
42. Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice
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Kim, Ha‐Neui, Chang, Jianhui, Iyer, Srividhya, Han, Li, Campisi, Judith, Manolagas, Stavros C, Zhou, Daohong, and Almeida, Maria
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Biomedical and Clinical Sciences ,Clinical Sciences ,Stem Cell Research ,Aging ,Osteoporosis ,1.1 Normal biological development and functioning ,Underpinning research ,Musculoskeletal ,Animals ,Bone Density ,Cellular Senescence ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Osteoclasts ,Stem Cells ,aging ,osteoblasts ,osteocytes ,osteoporosis ,p16 ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Both an increase in osteoclast and a decrease in osteoblast numbers contribute to skeletal aging. Markers of cellular senescence, including expression of the cyclin inhibitor p16, increase with aging in several bone cell populations. The elimination of p16-expressing cells in old mice, using the INK-ATTAC transgene, increases bone mass indicating that senescent cells contribute to skeletal aging. However, the identity of the senescent cells and the extent to which ablation of p16-expressing cells may prevent skeletal aging remain unknown. Using mice expressing the p16-3MR transgene, we examined whether elimination of p16-expressing cells between 12 and 24 months of age could preserve bone mass; and whether elimination of these cells from 20 to 26 months of age could restore bone mass. The activation of the p16-3MR transgene by ganciclovir (GCV) greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated by GCV. However, GCV did not alter p16 levels in osteocytes-the most abundant cell type in bone-and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitors and senescent cells in other tissues, as described previously. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.
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- 2019
43. Systemic clearance of p16INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration
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Patil, Prashanti, Dong, Qing, Wang, Dong, Chang, Jianhui, Wiley, Christopher, Demaria, Marco, Lee, Joon, Kang, James, Niedernhofer, Laura J, Robbins, Paul D, Sowa, Gwendolyn, Campisi, Judith, Zhou, Daohong, and Vo, Nam
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Biomedical and Clinical Sciences ,Clinical Sciences ,Pain Research ,Aging ,Chronic Pain ,Clinical Research ,ADAMTS4 Protein ,Aggrecans ,Animals ,Cell Death ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,Ganciclovir ,Interleukin-6 ,Intervertebral Disc ,Intervertebral Disc Degeneration ,Matrix Metalloproteinase 13 ,Mice ,Mice ,Transgenic ,Proteoglycans ,Thymidine Kinase ,aggrecanolysis ,aging ,cellular senescence ,intervertebral disc ,p16Ink4a ,proteoglycan ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
RationaleAge-related changes in the intervertebral discs are the predominant contributors to back pain, a common physical and functional impairment experienced by older persons. Cellular senescence, a process wherein cells undergo growth arrest and chronically secrete numerous inflammatory molecules and proteases, has been reported to cause decline in the health and function of multiple tissues with age. Although senescent cells have been reported to increase in intervertebral degeneration (IDD), it is not known whether they are causative in age-related IDD.ObjectiveThe study aimed to elucidate whether a causal relationship exists between cellular senescence and age-related IDD.Methods and resultsTo examine the impact of senescent cells on age-associated IDD, we used p16-3MR transgenic mice, which enables the selective removal of p16Ink4a -positive senescent cells by the drug ganciclovir. Disc cellularity, aggrecan content and fragmentation alongside expression of inflammatory cytokine (IL-6) and matrix proteases (ADAMTS4 and MMP13) in discs of p16-3MR mice treated with GCV and untreated controls were assessed. In aged mice, reducing the per cent of senescent cells decreased disc aggrecan proteolytic degradation and increased overall proteoglycan matrix content along with improved histological disc features. Additionally, reduction of senescent cells lowered the levels of MMP13, which is purported to promote disc degenerative changes during aging.ConclusionsThe findings of this study suggest that systemic reduction in the number of senescent cells ameliorates multiple age-associated changes within the disc tissue. Cellular senescence could therefore serve as a therapeutic target to restore the health of disc tissue that deteriorates with age.
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- 2019
44. Aging and drug discovery
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Bakula, Daniela, Aliper, Alexander M, Mamoshina, Polina, Petr, Michael A, Teklu, Amanuel, Baur, Joseph A, Campisi, Judith, Ewald, Collin Y, Georgievskaya, Anastasia, Gladyshev, Vadim N, Kovalchuk, Olga, Lamming, Dudley W, Luijsterburg, Martijn S, Martín-Montalvo, Alejandro, Maudsley, Stuart, Mkrtchyan, Garik V, Moskalev, Alexey, Olshansky, S Jay, Ozerov, Ivan V, Pickett, Alexander, Ristow, Michael, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Biological Sciences ,Aging ,Good Health and Well Being ,aging ,drug discovery ,Biochemistry and cell biology ,Clinical sciences - Abstract
Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.
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- 2018
45. The metabolic roots of senescence: mechanisms and opportunities for intervention
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Wiley, Christopher D. and Campisi, Judith
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- 2021
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46. Oxidation resistance 1 is a novel senolytic target
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Zhang, Xin, Zhang, Suping, Liu, Xingui, Wang, Yingying, Chang, Jianhui, Zhang, Xuan, Mackintosh, Samuel G, Tackett, Alan J, He, Yonghan, Lv, Dongwen, Laberge, Remi‐Martin, Campisi, Judith, Wang, Jianrong, Zheng, Guangrong, and Zhou, Daohong
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Biochemistry and Cell Biology ,Biological Sciences ,Neurodegenerative ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Apoptosis ,Cell Survival ,Cells ,Cultured ,Chromatography ,Liquid ,Humans ,Mitochondrial Proteins ,Proteins ,RNA ,Small Interfering ,Reactive Oxygen Species ,Recombinant Proteins ,Tandem Mass Spectrometry ,cellular senescence ,OXR1 ,piperlongumine ,reactive oxygen species ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
The selective depletion of senescent cells (SCs) by small molecules, termed senolytic agents, is a promising therapeutic approach for treating age-related diseases and chemotherapy- and radiotherapy-induced side effects. Piperlongumine (PL) was recently identified as a novel senolytic agent. However, its mechanism of action and molecular targets in SCs was unknown and thus was investigated. Specifically, we used a PL-based chemical probe to pull-down PL-binding proteins from live cells and then mass spectrometry-based proteomic analysis to identify potential molecular targets of PL in SCs. One prominent target was oxidation resistance 1 (OXR1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR1 was upregulated in senescent human WI38 fibroblasts. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. The knockdown of OXR1 expression by RNA interference significantly increased the production of reactive oxygen species in SCs in conjunction with the downregulation of antioxidant enzymes such as heme oxygenase 1, glutathione peroxidase 2, and catalase, but these effects were much less significant when OXR1 was knocked down in non-SCs. More importantly, knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SCs are highly resistant to oxidative stress and suggest that OXR1 is a novel senolytic target that can be further exploited for the development of new senolytic agents.
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- 2018
47. Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype.
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Wiley, Christopher D, Schaum, Nicholas, Alimirah, Fatouma, Lopez-Dominguez, Jose Alberto, Orjalo, Arturo V, Scott, Gary, Desprez, Pierre-Yves, Benz, Christopher, Davalos, Albert R, and Campisi, Judith
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Lung ,Cell Line ,Fibroblasts ,Epithelial Cells ,Humans ,Imidazoles ,Piperazines ,Indoles ,Spiro Compounds ,Interleukin-6 ,Enzyme Inhibitors ,Gamma Rays ,Male ,Tumor Suppressor Protein p53 ,Proto-Oncogene Proteins c-mdm2 ,Interleukin-1alpha ,Foreskin ,Cell Cycle Checkpoints ,Cellular Senescence ,Biochemistry and Cell Biology ,Other Physical Sciences - Abstract
Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.
- Published
- 2018
48. Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease.
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Chinta, Shankar J, Woods, Georgia, Demaria, Marco, Rane, Anand, Zou, Ying, McQuade, Amanda, Rajagopalan, Subramanian, Limbad, Chandani, Madden, David T, Campisi, Judith, and Andersen, Julie K
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Animals ,Humans ,Mice ,Parkinson Disease ,Paraquat ,Risk Factors ,Neuropathology ,Cellular Senescence ,aging ,antagonistic pleiotropy ,neurodegeneration ,senescence-associated secretory phenotype ,tumor suppression ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson's disease (PD). Therapies based on PQ's presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor.
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- 2018
49. A novel suicide gene therapy for the treatment of p16Ink4a-overexpressing tumors
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Kohli, Jaskaren, Campisi, Judith, and Demaria, Marco
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Genetics ,Cancer ,Orphan Drug ,Biotechnology ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,cell cycle ,cellular senescence ,p16Ink4a ,p53 ,sarcoma ,Oncology and Carcinogenesis - Abstract
p16Ink4a is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4a is highly expressed but fails to block cell proliferation. p16Ink4a-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a-overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16Ink4a+ senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16Ink4a promoter. Activation of the suicide efficiently killed p16Ink4a-overxpressing sarcoma cells in vitro and in vivo. These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16Ink4a+ cancers.
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- 2018
50. Analysis of individual cells identifies cell‐to‐cell variability following induction of cellular senescence
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Wiley, Christopher D, Flynn, James M, Morrissey, Christapher, Lebofsky, Ronald, Shuga, Joe, Dong, Xiao, Unger, Marc A, Vijg, Jan, Melov, Simon, and Campisi, Judith
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Cancer ,Biotechnology ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Bleomycin ,Cell Cycle Proteins ,Cell Line ,Cellular Senescence ,Cytokines ,Fetus ,Fibroblasts ,Gene Expression Profiling ,Gene Expression Regulation ,Genetic Variation ,Humans ,Lung ,Microfluidics ,Nanotechnology ,Polymerase Chain Reaction ,Protein Interaction Mapping ,Signal Transduction ,Single-Cell Analysis ,Transcriptome ,beta-Galactosidase ,aging ,cellular senescence ,cytokines ,single cell ,transcriptomics ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence-associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo.
- Published
- 2017
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