scholarly journals Antagonistic pleiotropy and mutation accumulation contribute to age‐related decline in stress response

Evolution ◽  
2018 ◽  
Vol 72 (2) ◽  
pp. 303-317 ◽  
Author(s):  
Elizabeth R. Everman ◽  
Theodore J. Morgan
Keyword(s):  
Stress Response ◽  
Mutation Accumulation ◽  
Antagonistic Pleiotropy ◽  
Age Related

scholarly journals Evolution of age-specific decline in stress phenotypes is driven by both antagonistic pleiotropy and mutation accumulation

2017 ◽  
Author(s):  
Elizabeth R. Everman ◽  
Theodore J. Morgan
Keyword(s):  
Stress Response ◽  
Cold Stress ◽  
Association Mapping ◽  
Genetic Architecture ◽  
Mutation Accumulation ◽  
Antagonistic Pleiotropy ◽  
Starvation Resistance ◽  
Theories Of Aging ◽  
Age Related ◽  
Stress Survival

AbstractEfforts to more fully understand and test evolutionary theories of aging have produced distinct predictions for mutation accumulation (MA) and antagonistic pleiotropy (AP) mechanisms. We build on these predictions through the use of association mapping and investigation of the change in additive effects of polymorphisms across age and among traits for multiple stress response phenotypes. We found that cold stress survival with acclimation, cold stress survival without acclimation, and starvation resistance declined with age and that changes in the genetic architecture of each phenotype were consistent with MA predictions. We used a novel test for MA and AP by calculating the additive effect of polymorphisms across ages and found support for both MA and AP mechanisms in the age-related decline in stress tolerance. These patterns suggest both MA and AP contribute to age-related change in stress response and highlight the utility of association mapping to identify genetic shifts across age.

scholarly journals Intra-Organ Variation in Age-Related Mutation Accumulation in the Mouse

PLoS ONE ◽  
2007 ◽  
Vol 2 (9) ◽  
pp. e876 ◽  
Author(s):  
Rita A. Busuttil ◽  
Ana Maria Garcia ◽  
Robert L. Reddick ◽  
Martijn E. T. Dollé ◽  
Robert B. Calder ◽  
...  
Keyword(s):  
Mutation Accumulation ◽  
Age Related

Antagonistic pleiotropy and mutation accumulation influence human senescence and disease

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Juan Antonio Rodríguez ◽  
Urko M. Marigorta ◽  
David A. Hughes ◽  
Nino Spataro ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Mutation Accumulation ◽  
Antagonistic Pleiotropy

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 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 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.

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