scholarly journals Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Shrestha Ghosh ◽  
Sheung Kin Wong ◽  
Zhixin Jiang ◽  
Baohua Liu ◽  
Yi Wang ◽  
...  
Keyword(s):  
Accelerated Aging ◽  
Premature Death ◽  
Heterozygous Deletion ◽  
Reduced Body ◽  
Age Related ◽  
Damage Repair ◽  
Cell Decline ◽  
The Stability ◽  
Marrow Stem Cell ◽  
Deficient Mice

Mammalian sirtuin 6 (Sirt6) is a conserved NAD+-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging.

scholarly journals Extramedullary Erythropoiesis in Spleen of HIF Prolyl 4-Hydroxylase-2 Deficient Mice Is Mediated By Notch Signaling Downregulation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2656-2656
Author(s):  
Mikko Myllymäki ◽  
Jenni Määttä ◽  
Elitsa Dimova ◽  
Valerio Izzi ◽  
Timo Väisänen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Mass ◽  
Hypoxia Inducible Factor ◽  
Premature Death ◽  
Hematopoietic Stem ◽  
Extramedullary Erythropoiesis ◽  
Equity Ownership ◽  
The Stability ◽  
Deficient Mice ◽  
Notch Ligands

Abstract Erythrocytosis, an increase in absolute red cell mass, is mainly driven by erythropoietin, while hypoxia-inducible factor (HIF) regulates the expression of a number of genes involved in it, including erythropoietin. Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2/PHD2/EGLN1), the major regulator of the stability of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis and premature death. Although bone marrow is the primary site for erythropoiesis, spleen retains a capability for extramedullary erythropoiesis. We studied HIF-P4H-2 hypomorphic mice (Hif-p4h-2gt/gt) which show slightly induced erythropoiesis only upon aging despite no increased erythropoietin levels. Spleen was identified as the site of extramedullary erythropoiesis in these mice. Hematopoietic stem cells (HSCs) from spleens of the Hif-p4h-2gt/gt mice showed increased growth of BFU-Es and the mice were protected against anemia by induced extramedullary erythropoiesis. HIF-1α and HIF-2α were stabilized in the spleens, while the Notch ligands and target Jag1, Jag2, Dll1 and Hes1 became downregulated upon aging dependent on HIF-2α. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased growth of BFU-Es in the Hif-p4h-2gt/gt mice. We conclude that HIFα stabilization can mediate non-erythropoietin-driven extramedullary erythropoiesis in the spleen via altered Notch signaling. Disclosures Myllyharju: FibroGen Inc.: Equity Ownership, Research Funding.

scholarly journals Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1776
Author(s):  
Elham Pishavar ◽  
Hongrong Luo ◽  
Johanna Bolander ◽  
Antony Atala ◽  
Seeram Ramakrishna
Keyword(s):  
Drug Delivery ◽  
Progenitor Cells ◽  
Transfection Efficiency ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Nanofibrous Scaffolds ◽  
The Stability

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

scholarly journals Implication of ferroptosis in aging

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maryam Mazhar ◽  
Ahmad Ud Din ◽  
Hamid Ali ◽  
Guoqiang Yang ◽  
Wei Ren ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Accelerated Aging ◽  
Underlying Mechanism ◽  
Toxic Chemicals ◽  
Whole Body ◽  
Regulated Cell Death ◽  
Age Related ◽  
The Subject ◽  
Conventional Cell

AbstractLife is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

scholarly journals Accelerated aging in normal breast tissue of women with breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Shoghag Panjarian ◽  
Jozef Madzo ◽  
Kelsey Keith ◽  
Carolyn M. Slater ◽  
Carmen Sapienza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Anomaly Detection ◽  
Breast Tissue ◽  
Preventive Intervention ◽  
Normal Breast Tissue ◽  
Accelerated Aging ◽  
Normal Breast ◽  
Age Related ◽  
Unsupervised Anomaly Detection

Abstract Background DNA methylation alterations have similar patterns in normal aging tissue and in cancer. In this study, we investigated breast tissue-specific age-related DNA methylation alterations and used those methylation sites to identify individuals with outlier phenotypes. Outlier phenotype is identified by unsupervised anomaly detection algorithms and is defined by individuals who have normal tissue age-dependent DNA methylation levels that vary dramatically from the population mean. Methods We generated whole-genome DNA methylation profiles (GSE160233) on purified epithelial cells and used publicly available Infinium HumanMethylation 450K array datasets (TCGA, GSE88883, GSE69914, GSE101961, and GSE74214) for discovery and validation. Results We found that hypermethylation in normal breast tissue is the best predictor of hypermethylation in cancer. Using unsupervised anomaly detection approaches, we found that about 10% of the individuals (39/427) were outliers for DNA methylation from 6 DNA methylation datasets. We also found that there were significantly more outlier samples in normal-adjacent to cancer (24/139, 17.3%) than in normal samples (15/228, 5.2%). Additionally, we found significant differences between the predicted ages based on DNA methylation and the chronological ages among outliers and not-outliers. Additionally, we found that accelerated outliers (older predicted age) were more frequent in normal-adjacent to cancer (14/17, 82%) compared to normal samples from individuals without cancer (3/17, 18%). Furthermore, in matched samples, we found that the epigenome of the outliers in the pre-malignant tissue was as severely altered as in cancer. Conclusions A subset of patients with breast cancer has severely altered epigenomes which are characterized by accelerated aging in their normal-appearing tissue. In the future, these DNA methylation sites should be studied further such as in cell-free DNA to determine their potential use as biomarkers for early detection of malignant transformation and preventive intervention in breast cancer.

scholarly journals Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation

2017 ◽  
Vol 28 (6) ◽  
pp. 834-842 ◽  
Author(s):  
Amol Chaudhari ◽  
Richa Gupta ◽  
Sonal Patel ◽  
Nikkhil Velingkaar ◽  
Roman Kondratov
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Skeletal Muscles ◽  
Cancer Metabolism ◽  
Reduced Body ◽  
Circadian Control ◽  
Cell Growth And Proliferation ◽  
Deficient Mice ◽  
Igf Signaling

Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)—transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone–induced, JAK2 kinase–mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.

scholarly journals NAD+Metabolism in Aging and Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Tyler G. Demarest ◽  
Mansi Babbar ◽  
Mustafa N. Okur ◽  
Xiuli Dan ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Accelerated Aging ◽  
Cancer Therapies ◽  
Nad Metabolism ◽  
Cellular Processes ◽  
Cancer Pathogenesis ◽  
Nicotinamide Mononucleotide ◽  
Age Related

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

scholarly journals Epidemic Characteristics of Histomonosis in Geese Flocks in the Orenburg Region

2021 ◽  
Author(s):  
Pavel I. Khristianovsky ◽  
Stanislav A. Platonov ◽  
Vladislav V. Belimenko
Keyword(s):  
High Load ◽  
Parasitic Diseases ◽  
Orenburg Region ◽  
Reduced Body ◽  
Age Related ◽  
Body Resistance ◽  
The Village

In May-June 2019, there was a mortality surge among adult geese on the IP Samodurov farm (in the village of Krasnokholm, Orenburg Region). The deaths stopped as soon as the geese were out of lay. Pathological and microbiological studies established three parasitic diseases in the flock: heterakidosis, histomonosis, and eimeriosis. A one-off seasonal and age-related manifestation of these diseases is due to a reduced body resistance in the winter, huddling behaviour, and a high load in female geese during the laying season. Keywords: histomonosis, epidemic characteristics, eimeriosis

scholarly journals Age-related decrements in cycling and running performance

2004 ◽  
Vol 16 (2) ◽  
pp. 8 ◽  
Author(s):  
A St Clair Gibson ◽  
Ni Lambert ◽  
TD Noakes
Keyword(s):  
Athletic Performance ◽  
Sports Medicine ◽  
Weight Bearing ◽  
Accelerated Aging ◽  
Age Related ◽  
Endurance Cycling ◽  
Order Polynomial ◽  
Bearing Stress ◽  
Rate Of Decline ◽  
The Relationship

Objective. This study examined age-related decrements in athletic performance during running and cycling activities. Design. The age group winning times for males aged between 18 and 70 years competing in the 1999 Argus cycle tour (103 km) and 1999 Comrades running marathon (90 km), South Africa's premier endurance cycling and running events respectively, were examined. Main outcome measures. The relationship between speed (cycling and running respectively) and age was calculated using a 4th order polynomial function. The derivative of each of these functions was determined and then the slope of the function corresponding to each age was calculated. Results. The rate of decline in running speed occurred at an earlier age (~ 32 years) during the running race compared with the cycling tour (~ 55 years). Conclusions. These findings establish a trend that there is ‘accelerated' aging during running which can perhaps be attributed to the increased weight-bearing stress on the muscles during running compared with cycling. SA Sports Medicine Vol.16(2) 2004: 8-11

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