Featured
-
-
Article
| Open AccessIdentification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease
The LINE-1 retrotransposon is a target for the development of therapies to treat age-associated disease. Here the AUs describes the characterization of small molecule inhibitors of the endonuclease domain of LINE-1.
- Alexandra M. D’Ordine
- , Gerwald Jogl
- & John M. Sedivy
-
Article
| Open AccessSenescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment
Recent evidence suggests that senescence can negatively affect immune cell function. Here the authors show that accumulation of senescent cells in tumor-bearing mice previously exposed to irradiation or chemotherapy is associated with resistance to immune checkpoint inhibitors, associated with an exacerbated immunosuppressive profile of tumor-infiltrating myeloid cells.
- Damien Maggiorani
- , Oanh Le
- & Christian Beauséjour
-
Perspective
| Open AccessThe long and winding road of reprogramming-induced rejuvenation
Rejuvenation and partial reprogramming are two frontier areas in the field of aging. Here, the authors summarize advances in these fields and suggest future directions for research and therapy.
- Ali Doğa Yücel
- & Vadim N. Gladyshev
-
Article
| Open AccessDetection of senescence using machine learning algorithms based on nuclear features
Identifying senescence is complicated by a lack of universal markers. Here, Duran et al. use nuclear morphology features to devise machine-learning classifiers that detect senescence in cell lines and liver sections of patients and mouse models of aging and disease.
- Imanol Duran
- , Joaquim Pombo
- & Jesús Gil
-
Article
| Open AccessMid-old cells are a potential target for anti-aging interventions in the elderly
In this study, the authors introduce the concept of a unique cellular subtype within the organic stroma, which does not conform to a typical young or senescent but is significantly associated with age-related organic dysfunction among the elderly.
- Young Hwa Kim
- , Young-Kyoung Lee
- & Tae Jun Park
-
Article
| Open AccessMYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling
Age is the greatest risk factor for osteoarthritis (OA) and chondrocyte senescence is an important cellular event that contributes to OA development. This study shows that clathrin-mediated endocytosis and activation of Notch signaling promotes articular chondrocyte senescence and OA development, which is negatively regulated by myosin light chain 3 (MYL3).
- He Cao
- , Panpan Yang
- & Kai Li
-
Article
| Open AccessCD44 connects autophagy decline and ageing in the vascular endothelium
Mechanisms underlying the connection between autophagy decline and vascular endothelial cell (VEC) ageing remain unclear. Here, the authors identify a key role for CD44 in controlling autophagy and ageing in VECs, and this function is conserved in nematodes.
- Lu Zhang
- , Peichang Yang
- & Shiwei Ma
-
Article
| Open AccessCircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications
Osteoarthritis is a prevalent age-related disease. Here, the authors show that that CircRREB1 is highly expressed in second generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression.
- Zhe Gong
- , Jinjin Zhu
- & Shuying Shen
-
Article
| Open AccessMultiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton
Technical challenges have previously hindered the detailed study of in vivo senescent cells. Here, the authors deeply characterize senescent skeletal cells across murine aging, establishing CD24 as a marker of osteolineage cells cleared by senolytics.
- Madison L. Doolittle
- , Dominik Saul
- & Sundeep Khosla
-
Article
| Open AccessThe intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal
Senescence and quiescence are considered different cell states but are hard to distinguish. Here, single-cell imaging followed by immunostaining reveals that the intensities of senescence biomarkers are graded rather than binary, reflecting the duration of cell-cycle withdrawal rather than irreversible cell-cycle arrest.
- Humza M. Ashraf
- , Brianna Fernandez
- & Sabrina L. Spencer
-
Article
| Open AccessMulti-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1
Mesenchymal stem cells (MSC) are used for immunosuppressive therapy and a uniform source or heterogeneity characterisation is needed. Here the authors use multi-omics to compare human MSC from different sources and ages of donors and show differences in gene expression and immunosuppressive function.
- Yuchen Gao
- , Ying Chi
- & Xiaomin Zhang
-
Article
| Open AccessClearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1
Muscle stem cells drive muscle regeneration and are affected in myotonic dystrophy type 1. Here, the authors demonstrate that some muscle stem cells show signs of senescence in myotonic dystrophy type 1 and administer senolytics to eliminate these defective cells and restore myogenesis.
- Talita C. Conte
- , Gilberto Duran-Bishop
- & Nicolas A. Dumont
-
Article
| Open AccessSalicylic acid metabolism and signalling coordinate senescence initiation in aspen in nature
Deciduous trees exhibit autumn senescence driven by environmental seasonality. Here, the authors show that senescence timing in aspen tree genotypes depends on environmental changes but also on the ability of each genotype to sustain stress tolerance mediated by the phytohormone salicylic acid.
- Jenna Lihavainen
- , Jan Šimura
- & Stefan Jansson
-
Article
| Open AccessArtificial Hsp104-mediated systems for re-localizing protein aggregates
Protein aggregates are a hallmark of neurodegenerative disease and aging. Here, Fischbach et al. report engineered, artificial systems to re-localise or export protein aggregates from cells, with preliminary data showing that mHtt inclusions in S. cerevisiae may be cytotoxic.
- Arthur Fischbach
- , Angela Johns
- & Thomas Nyström
-
Article
| Open AccessSoluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy
Brain microvascular dysfunction occurs in Alzheimer’s disease and other taupathies. Here the authors show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy, and that it contributes to vascular deficits in these mice.
- Stacy A. Hussong
- , Andy Q. Banh
- & Veronica Galvan
-
Article
| Open AccessA stress-induced cilium-to-PML-NB route drives senescence initiation
Exposure to irreparable stresses induces transient ciliogenesis, enabling communication with PML-NBs via a FBF1 pathway to trigger senescence in mammalian cells. Fbf1 ablation reduces senescence and associated health decline in mice, highlighting cilia as a promising senotherapy target.
- Xiaoyu Ma
- , Yingyi Zhang
- & Jinghua Hu
-
Article
| Open AccessPhosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence
Little is known about the role of glycolysis in cellular senescence. Here, authors report that glycolysis-derived serine biosynthesis activates PKM2 to phosphorylate histone H3T11, prevent cell senescence, and promote healthy aging.
- Yinsheng Wu
- , Lixu Tang
- & Xilan Yu
-
Article
| Open AccessNon-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
-
Article
| Open AccessNicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity
Nicotine, a metabolite of the NAD+ metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here, the authors show that low-dose nicotine promotes SIRT1 deacetylation of NAMPT and enhanced NAMPT activity which boosts NAD generation and improves age related symptoms.
- Liang Yang
- , Junfeng Shen
- & Xiang Li
-
Article
| Open AccessTiming and cell specificity of senescence drives postnatal lung development and injury
Senescence causes age-related diseases and stress-related injury, but it is also physiologically essential during development. Here, Yao et al. show that programmed senescence in mesenchymal cells orchestrates postnatal lung development and that neonatal hyperoxia can induce senescence, particularly in type II, Pdgfra+ mesenchymal and immune cells, during the alveolar stage, resulting in lung injury.
- Hongwei Yao
- , Joselynn Wallace
- & Phyllis A. Dennery
-
Article
| Open AccessThe metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans
Understanding how metabolites modulate longevity is crucial for reducing aging-related disease. Here, the authors demonstrate that α-ketobutyrate exhibits an anti-aging effect by coordinating NAD + -SIRT1 signaling and peroxisome function.
- Nan Wu
- , Yi-Cheng Ma
- & Cheng-Gang Zou
-
Article
| Open AccessSenescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling
Cellular senescence and associated secretory phenotype (SASP) are thought to contribute to aging and tissue dysfunction, though it is unclear how SASP impacts regeneration. Here the authors show that SASP factors impair regeneration, and that Ptk7 is a key secreted protein mediating that dysregulation.
- Jina Yun
- , Simon Hansen
- & Heinrich Jasper
-
Article
| Open AccessUnique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.
- Hirofumi Nagao
- , Ashok Kumar Jayavelu
- & C. Ronald Kahn
-
Article
| Open AccessTargeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression
Cutaneous hyperpigmented lesions, including nevi, are populated by senescent melanocytes. Here the authors provide evidence for a novel strategy based on combining inhibition of the BCL-2 and MCL1 anti-apoptotic pathways that selectively eliminates senescent melanocytes in culture and in vivo.
- Jaskaren Kohli
- , Chen Ge
- & Marco Demaria
-
Article
| Open AccessUSP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity
Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.
- Juan Li
- , Yang Wang
- & Zhi-Xiong Jim Xiao
-
Article
| Open AccessSirt6 attenuates chondrocyte senescence and osteoarthritis progression
Ji and colleagues identify Sirt6 as a regulator of chondrocyte senescence. Mechanistically, Sirt6 physically interacts with STAT5 and deacetylates it at K163, which reduces the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus.
- Ming-liang Ji
- , Hua Jiang
- & Jun Lu
-
Article
| Open AccessA Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice
Monitoring the aging process in vivo is challenging. Here the authors generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter mouse model, where the GAC signal is consistently correlated with established biomarkers of cellular senescence, cardiac hypertrophy and shortened lifespan, which may prove helpful for studies developing anti-aging interventions.
- Jie Sun
- , Ming Wang
- & Baohua Liu
-
Article
| Open AccessA BDNF-TrkB autocrine loop enhances senescent cell viability
Selective elimination of senescent cells is an approach that has shown promise to ameliorate age-associated pathologies in preclinical models. Here the authors report that BDNF enhances senescent cell viability via TrkB in cultured cells, and that TrkB inhibition can reduce the accumulation of senescent cells in aged mouse organs.
- Carlos Anerillas
- , Allison B. Herman
- & Myriam Gorospe
-
Article
| Open AccessRejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.
- Xu Zhang
- , Vesselina M. Pearsall
- & Marissa J. Schafer
-
Article
| Open AccessReversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.
- Moh’d Mohanad Al-Dabet
- , Khurrum Shahzad
- & Berend Isermann
-
Article
| Open AccessHepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells
Ras mutations induce cell competition and cellular senescence to inhibit the proliferation of oncogenic mutated cells. Here the authors demonstrate that cellular senescence inhibits cell competition-induced elimination of oncogenic cells through HGF signalling.
- Nanase Igarashi
- , Kenichi Miyata
- & Akiko Takahashi
-
Article
| Open AccessNestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing
The regulatory mechanisms contributing to male reproductive ageing are unknown. Here, the authors show that Nestin-dependent mito-ER contacts (MERCs) regulate stem Leydig cell (SLC) senescence and provide insights into SLCs-targeting therapies.
- Senyu Yao
- , Xiaoyue Wei
- & Jiancheng Wang
-
Article
| Open AccessSenescent cells limit p53 activity via multiple mechanisms to remain viable
To develop therapeutics that selectively eliminate pathological senescent cells it is important to understand their survival mechanisms. Here, the authors show that senescent cells manage to survive by keeping p53 activity in check through multiple mechanisms, including inhibitory mechanisms that involve p53 binding to ribonucleases.
- Ines Sturmlechner
- , Chance C. Sine
- & Jan M. van Deursen
-
Article
| Open AccessSingle-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.
- Martina Troiani
- , Manuel Colucci
- & Andrea Alimonti
-
Article
| Open AccessZebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis
It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting.
- Yukinari Haraoka
- , Yuki Akieda
- & Tohru Ishitani
-
Article
| Open AccessWTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and Nucleus pulposus cell senescence contributes a lot to its progression. Here, the authors reveal WTAP-mediated m6A modification of lncRNA NORAD promotes IVDD.
- Gaocai Li
- , Liang Ma
- & Cao Yang
-
Article
| Open AccessRestoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing
Age-dependent decline in remyelination in the CNS is associated with declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). Here, the authors show nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing in mouse OPCs. β-nicotinamide mononucleotide (β-NMN) supplement delays myelin aging and enhances remyelination in the aged mice.
- Xiao-Ru Ma
- , Xudong Zhu
- & Jing-Wei Zhao
-
Article
| Open AccessThe flavonoid corylin exhibits lifespan extension properties in mouse
Various traditional Chinese herbs and complex formulas have been suggested to exhibit lifespan extension properties. Here, the authors isolated the flavonoid corylin from Psoralea corylifolia and demonstrated its longevity properties in yeast, human cells and mouse.
- Tong-Hong Wang
- , Wei-Che Tseng
- & Chin-Chuan Chen
-
Article
| Open AccessA putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis
Most eukaryotes maintain telomeres using a specialized reverse transcriptase. Here the authors report that Thc1 (Telomerase Holoenzyme Component 1) and Bmc1 (Bin3/MePCE 1) form a complex with Pof8, a constitutive member of telomerase in fission yeast.
- Diego J. Páez-Moscoso
- , David V. Ho
- & Peter Baumann
-
Article
| Open AccessTRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence
Mitochondrial Ca2+ homeostasis is reported to influence cellular senescence. Here the authors show that TRPC3 limits senescence by inhibiting IP3R-mediated Ca2+ release and ER mitochondria Ca2+ transfer and that the downregulation of TRPC3 in stromal cells affects SASP production and tumour progression.
- Valerio Farfariello
- , Dmitri V. Gordienko
- & Natalia Prevarskaya
-
Article
| Open AccessSelenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis
Osteoarthritis is caused by the gradual accumulation of oxidative stress in cartilage. Here, the authors show that dysregulation of the selenium metabolic pathway underlies a shift in redox homeostasis in chondrocytes, leading to chronic osteoarthritic changes in joints.
- Donghyun Kang
- , Jeeyeon Lee
- & Jin-Hong Kim
-
Article
| Open AccessEnhanced germline stem cell longevity in Drosophila diapause
Drosophila enter adult reproductive diapause in low temperatures and short day, halting ovarian development yet preserving fertility. Here the authors show that ovarian arrest in diapause is distinct from other stress responses and that despite DNA damage and decreased division, germline stem cells recover.
- Sreesankar Easwaran
- , Matthew Van Ligten
- & Denise J. Montell
-
Article
| Open AccessHigh-spatial and colourimetric imaging of histone modifications in single senescent cells using plasmonic nanoprobes
The authors demonstrate a colourimetric imaging method using plasmonic nanoparticles for visualisation of heterochromatin histone markers. Based on the distance-dependent coupling effect, resulting in spectral shifts, they observe reorganisation of histone markers caused by oncogene-induced senescence.
- Hyun Ji An
- , Yun Kim
- & Inhee Choi
-
Article
| Open AccessGut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion
Several bacteria in the gut microbiota have been associated with colorectal cancer (CRC) but it is not completely clear whether they have a role in tumourigenesis. Here, the authors show enrichment of 12 bacterial taxa in two cohorts of CRC patients and that two Porphyromonas species accelerate CRC onset through butyrate secretion.
- Shintaro Okumura
- , Yusuke Konishi
- & Eiji Hara
-
Article
| Open AccessLong-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice
Intervertebral disc degeneration is a leading cause of chronic back pain and disability. Here the authors show that long term treatment with senolytic compounds Dasatinib and Quercetin reduces disc senescence burden and ameliorates age-dependent degeneration in mice.
- Emanuel J. Novais
- , Victoria A. Tran
- & Makarand V. Risbud
-
Article
| Open AccessZNF768 links oncogenic RAS to cellular senescence
RAS-induced senescence is a safeguarding process against tumour development. Here, the authors show that RAS activation destabilises the transcription factor ZNF768, which blocks ZNF768- dependent repression of p53 activity and thus induces senescence.
- Romain Villot
- , Audrey Poirier
- & Mathieu Laplante
-
Article
| Open AccessOncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis
BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.
- Riccardo Biavasco
- , Emanuele Lettera
- & Eugenio Montini
-
Article
| Open AccessGATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage
GATA3 has been considered to be primarily associated with CD4+ Th2 cell function. Using CD4+ effector memory that re-express CD45RA (EMRA) T cells the authors show that in response to DNA damage GATA3 can regulate increase of mitochondrial mass and biogenesis involving AMPK.
- Lauren A. Callender
- , Johannes Schroth
- & Sian M. Henson
-
Article
| Open AccessThe long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.
- Marta Montes
- , Michal Lubas
- & Anders H. Lund