scholarly journals Dexamethasone treatment supports age‐related maturation of the stress response in altricial nestling birds

2019 ◽  
Vol 50 (10) ◽  
Author(s):  
Fernando Torres‐Medina ◽  
Sonia Cabezas ◽  
Tracy A. Marchant ◽  
Julio Blas
Keyword(s):  
Stress Response ◽  
Dexamethasone Treatment ◽  
Age Related

scholarly journals DNA damage responses in ageing

Open Biology ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 190168 ◽  
Author(s):  
Paulo F. L. da Silva ◽  
Björn Schumacher
Keyword(s):  
Dna Damage ◽  
Stress Response ◽  
Cellular Senescence ◽  
Damage Accumulation ◽  
Genome Instability ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Dna Damage Responses ◽  
Universal Feature

Ageing appears to be a nearly universal feature of life, ranging from unicellular microorganisms to humans. Longevity depends on the maintenance of cellular functionality, and an organism's ability to respond to stress has been linked to functional maintenance and longevity. Stress response pathways might indeed become therapeutic targets of therapies aimed at extending the healthy lifespan. Various progeroid syndromes have been linked to genome instability, indicating an important causal role of DNA damage accumulation in the ageing process and the development of age-related pathologies. Recently, non-cell-autonomous mechanisms including the systemic consequences of cellular senescence have been implicated in regulating organismal ageing. We discuss here the role of cellular and systemic mechanisms of ageing and their role in ageing-associated diseases.

scholarly journals NIPA As a Novel Regulator of Aging and Stress Response of the Primitive HSC Pool

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1155-1155
Author(s):  
Stefanie Kreutmair ◽  
Rouzanna Istvanffy ◽  
Cathrin Klingeberg ◽  
Christine Dierks ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Stress Response ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Age Related

Abstract Accumulation of DNA damage in hematopoietic stem cells (HSCs) is associated with aging, bone marrow failure and development of hematological malignancies. Although HSCs numerically expand with age, their functional activity declines over time and the protection mechanism from DNA damage accumulation remains to be elucidated. NIPA (Nuclear Interaction Partner of ALK) is highly expressed in hematopoietic stem and progenitor cells, especially in the most primitive long-term repopulating HSCs (CD34-Flt3-Lin-Sca1+cKit+). Loss of NIPA leads to a significant exhaustion of primitive hematopoietic cells, where Lin-Sca1+cKit+ (LSK) cells were reduced to 40% of wildtype (wt) littermates (p<0.001). All LSK-subgroups, LT-HSCs (p<0.001), ST-HSCs (CD34+Flt3-LSK; p<0.01) and MPPs (CD34+Flt3+LSK; p<0.05) of NIPA deficient animals are affected and failed to age-related increase, whereas the lineage differentiation of Nipako/ko progenitor cells showed no gross differences. Myeloid depression by 5-FU treatment led to severely reduced HSC self renewal in Nipako/ko mice independent of age (p<0.001). Moreover, weekly 5-FU activation showed reduced survival of Nipako/ko vs. wt animals (11 vs. 14.5 days). To further examine the role of NIPA in HSC maintenance and exhaustion, we performed in vivo repopulationexperiments, where Nipa deletion causes bone marrow failure in case of competition, as Nipako/ko cells contributed to less than 10% of transplanted BM cells 6 month after transplantation (TX). According to this, colony formation assays and limiting dilution transplantation showed a dramatic reduction of competitive repopulation units (p<0.0001) in Nipako/ko animals. Serial LSK transplantation assays revealed loss of Nipa-deficient LSKs shortly after TX, whereas long-term repopulation capacity seemed to be maintained, suggesting a role of NIPA in critical stress response. To further investigate the stress response in Nipa-deficient HSCs, we irradiated LSKs with 3 Gy and stained for DNA-Damage foci by pH2ax. Remarkably, loss of NIPA led to significant higher numbers of pH2ax foci in irradiated HSCs (46% > 6 foci vs. 17% > 6 foci in wt cells) and highly increased the rates of apoptotic cells especially in the primitive CD34-LSK population. Taken together our results highlight the importance of the DNA damage response at HSC level for lifelong hematopoiesis and establish NIPA as a novel regulator of aging and stress response of the primitive HSC pool. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Aging Stress Response and Its Implication for AMD Pathogenesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8840
Author(s):  
Janusz Blasiak ◽  
Elzbieta Pawlowska ◽  
Anna Sobczuk ◽  
Joanna Szczepanska ◽  
Kai Kaarniranta
Keyword(s):  
Stress Response ◽  
Vision Loss ◽  
The Elderly ◽  
Cellular Level ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Nutrient Signaling ◽  
Amp Activated Protein Kinase

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

scholarly journals 4-PHENYLBUTYRATE: MOLECULAR MECHANISMS AND AGING INTERVENTION POTENTIAL

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S101-S101
Author(s):  
Michael R Bene ◽  
Kevin Thyne ◽  
Jonathan Dorigatti ◽  
Adam B Salmon
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Molecular Mechanisms ◽  
Oxidative Stress Response ◽  
Chemical Chaperone ◽  
Mouse Muscle ◽  
Age Related ◽  
Primary Mouse ◽  
Wide Range

Abstract 4-Phenylbutyrate (PBA) is a FDA approved drug for treating patients with urea cycle disorders. Additionally, PBA acts upon several pathways thought of as important modifiers of aging including: histone deacetylation, proteostasis as a chemical chaperone, and stress resistance by regulating expression of oxidative stress response proteins. PBA has also been shown to extend lifespan and improve markers of age-related health in Drosophila. Due to its wide range of effects PBA has been investigated for use in numerous age-related disorders including neurodegenerative and cardiovascular diseases. To better understand the effects of PBA on the molecular level, we used both in cellulo and in vivo studies. Treatment of primary mouse fibroblasts, C2C12 mouse muscle cells, and NCTC 1469 mouse liver cells with PBA demonstrated differential responses among cell lines to upregulation of oxidative stress response and histone acetylation. Specifically, upregulation of the oxidative stress response protein DJ-1 by PBA was found to have a corresponding dose response curve to histone H3 acetylation in primary fibroblasts. To study effects of PBA in vivo, four cohorts of HET3 mice were treated with PBA at different doses in drinking water for 4 weeks. PBA was well tolerated and led to different effects on body composition dependent on the sex of mice. We are currently investigating the molecular effects of PBA treatment in multiple tissues samples from these mice. The potential of PBA to alter many fundamental pathways, and specifically those related to stress responses, make it an attractive prospect for treatment of many age-related disorders.

scholarly journals Multifactorial Attenuation of the Murine Heat Shock Response With Age

2019 ◽  
Vol 75 (10) ◽  
pp. 1846-1852 ◽  
Author(s):  
Donald A Jurivich ◽  
Gunjan D Manocha ◽  
Rachana Trivedi ◽  
Mary Lizakowski ◽  
Sharlene Rakoczy ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Protein Interactions ◽  
Messenger Rna ◽  
Physiological Stress ◽  
Cellular Stress Response ◽  
Heat Shock Factor 1 ◽  
Protein Levels ◽  
Age Related ◽  
Age Dependent

Abstract Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 (HSF1)–DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of HSF1 activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in HSF1 phosphorylation and acetylation. HSF1 protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of HSF1 protein levels that are low in neurodegeneration and elevated in cancer.

Effects of Neonatal Dexamethasone Treatment on the Cardiovascular Stress Response of Children at School Age

PEDIATRICS ◽  
2008 ◽  
Vol 122 (5) ◽  
pp. 978-987 ◽  
Author(s):  
R. Karemaker ◽  
J. M. Karemaker ◽  
A. Kavelaars ◽  
M. Tersteeg-Kamperman ◽  
W. Baerts ◽  
...  
Keyword(s):  
Stress Response ◽  
School Age ◽  
Dexamethasone Treatment ◽  
Cardiovascular Stress

scholarly journals TNFα, Interferon, and Stress Response Induction as a Function of Age-Related Susceptibility to Fatal Sindbis Virus Infection of Mice

Virology ◽  
1999 ◽  
Vol 263 (2) ◽  
pp. 339-348 ◽  
Author(s):  
Joanne Trgovcich ◽  
Judith F. Aronson ◽  
J.Charles Eldridge ◽  
Robert E. Johnston
Keyword(s):  
Stress Response ◽  
Virus Infection ◽  
Sindbis Virus ◽  
Age Related

scholarly journals Mitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans

2017 ◽  
Author(s):  
Sarah M. Chang ◽  
Melanie R. McReynolds ◽  
Wendy Hanna-Rose
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Drug Targets ◽  
Physiological Role ◽  
Oxidative Stress Response ◽  
Altered Expression ◽  
C Elegans ◽  
Mitochondrial Superoxide ◽  
Age Related ◽  
Extended Lifespan

ABSTRACTMitochondrial sirtuins regulate biochemical pathways and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, their functions remain unclear. Here, we uncover a novel physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using a genetic approach, we demonstrate that sir-2.2 and sir-2.3 mutants live 28-30% longer than controls when fed the normal lab diet of E. coli OP50. Interestingly, this effect is diet specific and is not observed when animals are fed the strain HT115, which is typically used for RNAi experiments. While decreased consumption of food is a known mechanism for lifespan extension, this does not account for the increased lifespan in the mitochondrial sirtuin mutants. sir-2.2 and sir-2.3 mutants display altered expression of genes involved in oxidative stress response, including increased expression of the mitochondrial superoxide dismutase sod-3 and decreased levels of catalases ctl-1 and ctl-2. Like their extended lifespan phenotype, these alterations in oxidative stress gene expression are diet dependent. The mitochondrial sirtuin mutants are more resistant to the lifespan extending effects of low levels of superoxide, suggesting that their increased lifespan involves a hormetic response. Our data suggest that sir-2.2 and sir-2.3 are not completely redundant in function and may possess overlapping yet distinct mechanisms for regulating oxidative stress response and lifespan.

scholarly journals In vitro modeling of the complex retinal condition age-related macular degeneration

2022 ◽  
Author(s):  
Karolina Plössl ◽  
Emily Webster ◽  
Christina Kiel ◽  
Felix Grassmann ◽  
Caroline Brandl ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Macular Degeneration ◽  
Cell Lines ◽  
Genetic Risk ◽  
Oxidative Stress Response ◽  
Age Related Macular Degeneration ◽  
Nrf2 Pathway ◽  
Age Related

Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions. Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression. Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway. Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document