Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular ...senescence, yet a comprehensive understanding of its pathways is still lacking.
We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence.
Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.
•Extracellular vesicles (EVs) are key mediators within the senescence-associated secretory phenotype (SASP).•Increased EV production has been demonstrated following senescence induction.•Changes in ...EVs cargoes including proteins, nucleic acids and lipids have been demonstrated following senescence induction.•EVs have been demonstrated to contribute to both the beneficial (Bright) and detrimental (Dark) sides of the SASP.
Senescence is a state of proliferative arrest which has been described as a protective mechanism against the malignant transformation of cells. However, senescent cells have also been demonstrated to accumulate with age and to contribute to a variety of age-related pathologies. These pathological effects have been attributed to the acquisition of an enhanced secretory profile geared towards inflammatory molecules and tissue remodelling agents – known as the senescence-associated secretory phenotype (SASP). Whilst the SASP has long been considered to be comprised predominantly of soluble mediators, growing evidence has recently emerged for the role of extracellular vesicles (EVs) as key players within the secretome of senescent cells. This review is intended to consolidate recent evidence for the roles of senescent cell-derived EVs to both the beneficial (Bright) and detrimental (Dark) effects of the SASP.
Killing senescent cells to improve health-span holds great promise. However, screening for senescence-regulating genes and molecules is challenging because these cells do not proliferate. In this ...issue, Colville and Liu et al. develop Death-seq, a positive selection screening tool that overcomes this hurdle to offer broad genetic and pharmacological utility.
Killing senescent cells to improve health-span holds great promise. However, screening for senescence-regulating genes and molecules is challenging because these cells do not proliferate. In this issue, Colville and Liu et al. develop Death-seq, a positive selection screening tool that overcomes this hurdle to offer broad genetic and pharmacological utility.
Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils ...adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.
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•Aged mice show high levels of neutrophil reverse transendothelial migration (rTEM)•Mast cells (MC) and MC-derived CXCL1 drive neutrophil rTEM in inflamed aged tissues•Intensified endothelial ACKR1-CXCL1 axis promotes neutrophil CXCR2 internalization•Aged lungs program rTEM neutrophils toward an activated and noxious phenotype
Aging is a critical risk factor for inflammatory disorders. Barkaway, Rolas et al. show that inflamed aged tissues present a high frequency of neutrophil reverse transendothelial migration (rTEM) back into the circulation in a mast cell-dependent manner. rTEM neutrophils are retained in aged lungs and programmed toward an activated phenotype, capable of inducing tissue damage.
Senescence is a widely appreciated tumour suppressive mechanism, which acts as a barrier to cancer development by arresting cell cycle progression in response to harmful stimuli. However, senescent ...cell accumulation becomes deleterious in aging and contributes to a wide range of age-related pathologies. Furthermore, senescence has beneficial roles and is associated with a growing list of normal physiological processes including wound healing and embryonic development. Therefore, the biological role of senescent cells has become increasingly nuanced and complex. The emergence of sophisticated, next-generation profiling technologies, such as single-cell RNA sequencing, has accelerated our understanding of the heterogeneity of senescence, with distinct final cell states emerging within models as well as between cell types and tissues. In order to explore data sets of increasing size and complexity, the senescence field has begun to employ machine learning (ML) methodologies to probe these intricacies. Most notably, ML has been used to aid the classification of cells as senescent, as well as to characterise the final senescence phenotypes. Here, we provide a background to the principles of ML tasks, as well as some of the most commonly used methodologies from both traditional and deep ML. We focus on the application of these within the context of senescence research, by addressing the utility of ML for the analysis of data from different laboratory technologies (microscopy, transcriptomics, proteomics, methylomics), as well as the potential within senolytic drug discovery. Together, we aim to highlight both the progress and potential for the application of ML within senescence research.
Intestinal fibrosis with stricture formation is a complication of CD (Crohn's disease) that may mandate surgical resection. Accurate biomarkers that reflect the relative contribution of fibrosis to ...an individual stricture are an unmet need in managing patients with CD. The miRNA-29 (miR-29) family has been implicated in cardiac, hepatic and pulmonary fibrosis. In the present study, we investigated the expression of miR-29a, miR-29b and miR-29c in mucosa overlying a stricture in CD patients (SCD) paired with mucosa from non-strictured areas (NSCD). There was significant down-regulation of the miR-29 family in mucosa overlying SCD compared with mucosa overlying NSCD. miR-29b showed the largest fold-decrease and was selected for functional analysis. Overexpression of miR-29b in CD fibroblasts led to a down-regulation of collagen I and III transcripts and collagen III protein, but did not alter MMP (matrix metalloproteinase)-3, MMP-12 and TIMP (tissue inhibitor of metalloproteinase)-1 production. TGF (transforming growth factor)-β1 up-regulated collagen I and III transcripts and collagen III protein as a consequence of the down-regulation of miR-29b, and TGF-β1-induced collagen expression was reversed by exogenous overexpression of miR-29b. Furthermore, serum levels of miR-29 were lower in patients with stricturing disease compared with those without. These findings implicate the miR-29 family in the pathogenesis of intestinal fibrosis in CD and provide impetus for the further evaluation of the miR-29 family as biomarkers.
Melanocytes reside within the basal epidermis of human skin, and function to protect the skin from ultraviolet light through the production of melanin. Prolonged exposure of the skin to UV light can ...induce irreparable DNA damage and drive cells into senescence, a sustained cell cycle arrest that prevents the propagation of this damage. Senescent cells can also be detrimental and contribute to skin ageing phenotypes through their senescence-associated secretory phenotype. Senescent cells can act in both an autocrine and paracrine manner to produce widespread tissue inflammation and skin ageing. Recently, melanocytes have been identified as the main senescent cell population within the epidermis and have been linked to a variety of skin ageing phenotypes, such as epidermal thinning and the presence of wrinkles. However, the literature surrounding melanocyte senescence is limited and tends to focus on the role of senescence in the prevention of melanoma. Therefore, this review aims to explore the current understanding of the contribution of senescent melanocytes to human skin ageing.
Upon cellular entry retroviruses must avoid innate restriction factors produced by the host cell. For human immunodeficiency virus (HIV) human restriction factors, APOBEC3 ...(apolipoprotein-B-mRNA-editing-enzyme), p21 and tetherin are well characterised.
To identify intrinsic resistance factors to HIV-1 replication we screened 19,121 human genes and identified 114 factors with significant inhibition of infection. Those with a known function are involved in a broad spectrum of cellular processes including receptor signalling, vesicle trafficking, transcription, apoptosis, cross-nuclear membrane transport, meiosis, DNA damage repair, ubiquitination and RNA processing. We focused on the PAF1 complex which has been previously implicated in gene transcription, cell cycle control and mRNA surveillance. Knockdown of all members of the PAF1 family of proteins enhanced HIV-1 reverse transcription and integration of provirus. Over-expression of PAF1 in host cells renders them refractory to HIV-1. Simian Immunodeficiency Viruses and HIV-2 are also restricted in PAF1 expressing cells. PAF1 is expressed in primary monocytes, macrophages and T-lymphocytes and we demonstrate strong activity in MonoMac1, a monocyte cell line.
We propose that the PAF1c establishes an anti-viral state to prevent infection by incoming retroviruses. This previously unrecognised mechanism of restriction could have implications for invasion of cells by any pathogen.
The recent advent of ‘organs in a dish’ has revolutionised the research landscape. These 3D culture systems have paved the way for translational, post genomics research by enabling scientists to ...model diseases in the laboratory, grow patient-derived organoids, and unite this technology with other cutting-edge methodologies such as drug discovery. Fields such as dermatology and neuroscience have revolutionised the development of robust 3D models, which faithfully recapitulate native physiology in vivo to provide important functional and mechanistic insights. These models have underpinned a rapid growth in the number of organs and myriad of human diseases that can be modelled in 3D, which currently includes breast, cerebral cortex, heart, intestine, kidney, liver, lung, neural tube, pancreas, prostate, skin and stomach, as well as patient derived tumours. However, so far, they have not yet been employed extensively in the study of fundamental cellular programmes such as senescence. Thus, tissue engineering and 3D culture offer an exciting opportunity to further understand the bright and dark sides of senescence in a more complex and physiologically relevant environment. Below, we will discuss previous approaches to investigating senescence and ageing using organotypic models, and some potential opportunities for future research.
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