scholarly journals Nuclear morphology is a deep learning biomarker of senescence across tissues and species

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Garik Mkrtchyan ◽  
Michael Ben Ezra ◽  
Daniela Bakula ◽  
Jakob Madsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Positive Association ◽  
Protective Role ◽  
Premature Aging ◽  
Malignant Neoplasms ◽  
Nuclear Morphology ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Abstract Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes, murine neurons, and fibroblasts derived from premature aging diseases in culture. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies, suggesting that alterations in nuclear morphology is a universal feature of senescence. Evaluating corresponding medical records reveals that individuals with a higher rate of senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. Additionally, we find a positive association with lower significance for other conditions, including osteoporosis, osteoarthritis, hypertension, cerebral infarction, hyperlipidemia, and hypercholesteremia. In sum, we introduce a predictor of cellular senescence based on nuclear morphology that is applicable across tissues and species and is associated with health outcomes in humans.

scholarly journals Deep Learning Shows Cellular Senescence Is a Barrier to Cancer Development

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Michael Ben Ezra ◽  
Garik V Mkrtchyan ◽  
Jakob Sture Madsen ◽  
Malte Hasle Nielsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Protective Role ◽  
Premature Aging ◽  
Cancer Development ◽  
Malignant Neoplasms ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes and fibroblasts derived from premature aging diseases in vitro. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating corresponding medical records reveals that individuals with increased senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. In sum, we introduce a novel predictor of cellular senescence and apply it to diagnostic medical images, indicating cancer occurs more frequently for those with a lower rate of senescence.

scholarly journals p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions

2019 ◽  
Vol 20 (23) ◽  
pp. 6023 ◽  
Author(s):  
Kaori Fujita
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Full Length ◽  
Protein Isoforms ◽  
Specific Cell ◽  
Gene Expressions ◽  
Related Disorder ◽  
Immune System Activation ◽  
Age Related ◽  
P53 Isoforms

Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

scholarly journals Cellular Senescence in Adrenocortical Biology and Its Disorders

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3474
Author(s):  
Xin Gao ◽  
Faping Li ◽  
Bin Liu ◽  
Yuxiong Wang ◽  
Yishu Wang ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Zona Glomerulosa ◽  
Adrenal Androgen ◽  
Senescent Phenotype ◽  
Age Related ◽  
Endocrine Organs ◽  
Age Dependent ◽  
Sexual Characteristics

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

scholarly journals LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity

2021 ◽  
Author(s):  
Bing Zhang ◽  
Pengyi Yan ◽  
Zixuan Li ◽  
Junhao Xiong ◽  
Zilong Geng ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Transcriptional Activity ◽  
Rna Binding ◽  
Senescent Cell ◽  
Premature Aging ◽  
Vascular Aging ◽  
Ataxia Telangiectasia Mutated ◽  
Age Related ◽  
Cell Accumulation ◽  
Damage Response

Abstract Cellular senescence is associated with pleiotropic essential physiopathological processes including aging and age-related diseases. The persistent DNA damage response (DDR) is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identified La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as a novel aging antagonist. DDR-mediated Ataxia Telangiectasia Mutated (ATM) activation triggered the extracellular shuttling and down regulation of LARP7, which dampened SIRT1 deacetylase activity, enhanced p53 and NF-κB transcriptional activity by augmenting their acetylation, and thereby accelerated cellular senescence. Deletion of LARP7 led to senescent cell accumulation and premature aging in rodent model. Furthermore, we show that this ATM-LARP7-SIRT1-p53/NF-κB senescence axis was active in vascular aging and atherogenesis, and preventing its activation substantially alleviated aging and atherogenesis. Together, this study identifies LARP7 as a gatekeeper for senescence, and the altered ATM-LARP7-SIRT1-p53/NF-κB pathway plays an important role in DDR-mediated cellular senescence and aging-related atherosclerosis.

scholarly journals Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

2020 ◽  
Vol 11 ◽  
Author(s):  
Jie Xu ◽  
Lili Zhou ◽  
Youhua Liu
Keyword(s):  
Cellular Senescence ◽  
Premature Aging ◽  
Fine Tuning ◽  
Ckd Progression ◽  
Kidney Fibrosis ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype ◽  
Characteristic Features ◽  
Aging Kidney

Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed as a state of accelerated and premature aging. Aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. While developmental senescence and acute senescence may positively contribute to the fine-tuning of embryogenesis and injury repair, chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. In this review, we discuss current understanding of the role and mechanism of cellular senescence in kidney fibrosis. We also highlight potential options of targeting senescent cells for the treatment of CKD.

scholarly journals Melatonin in Retinal Physiology and Pathology: The Case of Age-Related Macular Degeneration

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Janusz Blasiak ◽  
Russel J. Reiter ◽  
Kai Kaarniranta
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Protective Role ◽  
Premature Aging ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Established Role

Melatonin, an indoleamine, is synthesized mainly in the pineal gland in a circadian fashion, but it is produced in many other organs, including the retina, which seems to be especially important as the eye is a primary recipient of circadian signals. Melatonin displays strong antioxidative properties, which predispose it to play a protective role in many human pathologies associated with oxidative stress, including premature aging and degenerative disease. Therefore, melatonin may play a role in age-related macular degeneration (AMD), a disease affecting photoreceptors, and retinal pigment epithelium (RPE) with an established role of oxidative stress in its pathogenesis. Several studies have shown that melatonin could exert the protective effect against damage to RPE cells evoked by reactive oxygen species (ROS), but it has also been reported to increase ROS-induced damage to photoreceptors and RPE. Melatonin behaves like synthetic mitochondria-targeted antioxidants, which concentrate in mitochondria at relatively high levels; thus, melatonin may prevent mitochondrial damage in AMD. The retina contains telomerase, an enzyme implicated in maintaining the length of telomeres, and oxidative stress inhibits telomere synthesis, while melatonin overcomes this effect. These features support considering melatonin as a preventive and therapeutic agent in the treatment of AMD.

The Role of Cellular Senescence in Werner Syndrome: Toward Therapeutic Intervention in Human Premature Aging

2007 ◽  
Vol 1100 (1) ◽  
pp. 455-469 ◽  
Author(s):  
T. DAVIS ◽  
F. S. WYLLIE ◽  
M. J. ROKICKI ◽  
M. C. BAGLEY ◽  
D. KIPLING
Keyword(s):  
Cellular Senescence ◽  
Therapeutic Intervention ◽  
Werner Syndrome ◽  
Premature Aging

scholarly journals Cellular Senescence in Lung Fibrosis

2021 ◽  
Vol 22 (13) ◽  
pp. 7012
Author(s):  
Fernanda Hernandez-Gonzalez ◽  
Rosa Faner ◽  
Mauricio Rojas ◽  
Alvar Agustí ◽  
Manuel Serrano ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Lung Fibrosis ◽  
Lung Diseases ◽  
Physiological Mechanism ◽  
Lung Parenchyma ◽  
Scar Tissue ◽  
Interstitial Lung Diseases ◽  
Cellular Damage ◽  
Age Related

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

scholarly journals Cellular Senescence and Mammalian Healthspan

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 742-742
Author(s):  
Judith Campisi
Keyword(s):  
Growth Factors ◽  
Cell Fate ◽  
Cellular Senescence ◽  
Complex Cell ◽  
Transgenic Mouse Models ◽  
Bioactive Lipids ◽  
Age Related ◽  
Mammalian Tissues ◽  
Secretory Phenotype ◽  
Near Future

Abstract Cellular senescence is a complex cell fate, often induced by stress or damage, that can be beneficial or deleterious, depending on the physiological context and age of the organism. A prominent feature of senescent cells is a multi-faceted senescence-associated secretory phenotype (SASP), which includes growth factors, cytokine and chemokines, growth factors, proteases, bioactive lipids and metabolites. Senescent cells increase with age in most, if not all, mammalian tissues. Through the use of transgenic mouse models, senescent cells are now known to causally drive numerous age-related pathologies, largely through the SASP. Eliminating senescent cells, genetically or through the use of senolytic/senomorphic agents, can improve the health span, at least in mice, and hold promise for extension to humans in the near future.

scholarly journals Dendranthema zawadskii var. lucidum (Nakai) J.H. Park Extract Inhibits Cellular Senescence in Human Dermal Fibroblasts and Aging-Related Inflammation in Rats

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 801
Author(s):  
Jehun Choi ◽  
Gwi-Yeong Jang ◽  
Jeonghoon Lee ◽  
Hae-Young Chung ◽  
Hyung-Jun Noh ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Dermal Fibroblast ◽  
Dermal Fibroblasts ◽  
Dependent Manner ◽  
Aged Rats ◽  
Age Related ◽  
Dendranthema Zawadskii ◽  
Beta Galactosidase

Senescence is the phenomenon by which physiological functions of organisms degenerate with time. Cellular senescence is marked by an inhibition of cell cycle progression. Beta-galactosidase accumulates in the lysosomes of aged cells. In this study, human dermal fibroblast cells (HDFs) were treated with 0.5 μM doxorubicin for 4 h to induce cellular senescence. Senescence-associated beta-galactosidase (SA-β-gal) activity was then measured 72 h after treatment with aerial parts of Dendranthema zawadskii var. lucidum (Nakai) J.H. Park (DZ) extract. Treatment with DZ extract significantly decreased SA-β-gal activity in a dose-dependent manner in HDFs. Additionally, DZ extract treatment reduced age-related oxidative stress and inflammation in the aortas of aged rats. The reactive oxygen species (ROS) levels in aortas of aged control rats were higher than those in young rats. However, DZ extract-fed aged rats showed significantly lower ROS levels than the aged control rats. When the aged rats were treated with DZ extract at either 0.2 or 1.0 mg∙kg−1∙day−1, NF-κB levels in aorta tissue decreased significantly compared to those in aorta tissue of the aged control rats without DZ treatment. In addition, DZ extract-fed aged rat aortas showed significant reductions in expression of iNOS and COX-2 induced by NF-κB translocation. Therefore, these results suggest that DZ effectively inhibited senescence-related NF-κB activation and inflammation. DZ extract may have a role in the prevention of the vascular inflammatory responses that occur during vascular aging.

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