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1. Accelerated senescence as a cost of reproduction: Testing associations between oxidative stress and reproductive effort in rural and urban women

   https://doi.org/10.1002/ajhb.23537  

   Sancilio, Amelia ; Jasienska, Grazyna ; Panter‐Brick, Catherine ; Ziomkiewicz, Anna ; Nenko, Ilona ; Bribiescas, Richard G. ( November 2020 , American Journal of Human Biology)

   Oxidative stress is hypothesized to contribute to age‐related somatic deterioration. Both reproductive and ecological context may necessitate tradeoffs that influence this outcome. We examined whether measures of lifetime reproductive effort were related to levels of oxidative stress biomarkers in peri‐ and post‐menopausal women and whether associations were moderated by rural or urban residence.

   We surveyed 263 healthy women (age 62.1 ± 10.0 SD) from rural (N = 161) and urban Poland (N = 102), collecting sociodemographic data and urine samples to analyze biomarkers of oxidative stress (8‐oxo‐2′‐deoxyguanosine, 8‐OHdG) and antioxidative defense (copper‐zinc superoxide dismutase, Cu‐Zn SOD). Linear regression models, adjusted for residence, were used to test for associations between reproductive effort and 8‐OHdG and Cu‐Zn SOD.

   Univariate models demonstrated significant associations between gravidity and the biomarkers of oxidative stress (8‐OHdG:R² = 0.042,P ≤ .001; Cu‐Zn SOD:R² = 0.123,P ≤ .001). Multivariate models incorporating potential confounding variables, as well as cross‐product interaction terms, indicated that gravidity was associated with 8‐OHdG (P < .01,R²_adj = 0.067) and Cu‐Zn SOD (P = .01,R²_adj = 0.159). Residence (ie, urban vs rural) did not significantly moderate the associations between the biomarkers and reproductive effort.

   Higher lifetime reproductive effort contributes to increases in oxidative stress and antioxidative defenses. Our results provide evidence of potential mechanisms underlying the physiological tradeoffs influencing senescence for women with high reproductive effort. We illustrate the value of applying an evolutionary perspective to elucidate variation in human health and senescence.

    

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2. Chronic cold exposure induces mitochondrial plasticity in deer mice native to high altitudes

   https://doi.org/10.1113/JP280298  

   Mahalingam, Sajeni ; Cheviron, Zachary A. ; Storz, Jay F. ; McClelland, Grant B. ; Scott, Graham R. ( September 2020 , The Journal of Physiology)

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in cold hypoxic environments remains unresolved.

   We examined high‐altitude deer mice, which have evolved a high capacity for aerobic thermogenesis, to determine the mechanisms of mitochondrial plasticity during chronic exposure to cold and hypoxia, alone and in combination.

   Cold exposure in normoxia or hypoxia increased mitochondrial leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency, which may serve to augment non‐shivering thermogenesis. Cold also increased muscle oxidative capacity, but reduced the capacity for mitochondrial respiration via complex II relative to complexes I and II combined.

   High‐altitude mice had a more oxidative muscle phenotype than low‐altitude mice.

   Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitude.

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold and hypoxic environments. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in small mammals at high altitude remains unresolved. High‐altitude deer mice (Peromyscus maniculatus) and low‐altitude white‐footed mice (P. leucopus) were born and raised in captivity, and chronically exposed as adults to warm (25°C) normoxia, warm hypoxia (12 kPa O₂), cold (5°C) normoxia, or cold hypoxia. We then measured oxidative enzyme activities, oxidative fibre density and capillarity in the gastrocnemius, and used a comprehensive substrate titration protocol to examine the function of muscle mitochondria by high‐resolution respirometry. Exposure to cold in both normoxia or hypoxia increased the activities of citrate synthase and cytochrome oxidase. In lowlanders, this was associated with increases in capillary density and the proportional abundance of oxidative muscle fibres, but in highlanders, these traits were unchanged at high levels across environments. Environment had some distinct effects on mitochondrial OXPHOS capacity between species, but the capacity of complex II relative to the combined capacity of complexes I and II was consistently reduced in both cold environments. Both cold environments also increased leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency in both species, which may serve to augment non‐shivering thermogenesis. These cold‐induced changes in mitochondrial function were overlaid upon the generally more oxidative phenotype of highlanders. Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitudes.

    

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3. Water availability and temperature induce changes in oxidative status during pregnancy in a viviparous lizard

   https://doi.org/10.1111/1365-2435.13481  

   Dupoué, Andréaz ; Blaimont, Pauline ; Rozen‐Rechels, David ; Richard, Murielle ; Meylan, Sandrine ; Clobert, Jean ; Miles, Donald B. ; Martin, Rémi ; Decencière, Beatriz ; Agostini, Simon ; et al ( December 2019 , Functional Ecology)

   Reproduction involves considerable reorganization in an organism's physiology that incurs potential toxicity for cells (e.g., oxidative stress) and decrease in fitness. This framework has been the cornerstone of the so‐called ‘oxidative cost of reproduction’, a theory that remains controversial and relatively overlooked in non‐model ectotherms.

   Here, we used two complementary approaches in natural and controlled conditions to test whether altered access to climate conditions (water and temperature resources) alters oxidative status and mediates reproductive trade‐offs in viviparous populations of the common lizard (Zootoca vivipara).

   First, we examined whether access to free‐standing water and differences in ambient temperature across 12 natural populations could be related to variation in oxidative status, reproductive effort and reproductive success. Second, we determined whether an experimental restriction to water triggers higher oxidative cost of reproduction and correlates with fitness measures (reproductive success, future survival rate and probability of future reproduction).

   Pregnant females exhibited higher sensitivity than males to natural or experimental limitations in temperature and water access. That is, in restricted environments, pregnant females with higher reproductive effort exhibited stronger oxidative damage despite enhanced non‐enzymatic antioxidant capacity.

   Enhanced antioxidant defensive capacity in pregnant females was positively correlated with higher reproductive success, whereas elevated oxidative damage negatively correlated with offspring annual survival.

   Altogether, our results revealed a context‐dependent oxidative cost of reproduction that was concomitant with a conflict in water demand from offspring. These new insights should be critical for understanding ectotherm responses to heat waves and summer droughts that are increasing in frequency and duration.

   A freePlain Language Summarycan be found within the Supporting Information of this article.

    

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4. A network of transcription factors in complex with a regulating cell cycle cyclin orchestrates fungal oxidative stress responses

   https://doi.org/10.1186/s12915-024-01884-3  

   Kan, Yanze ; He, Zhangjiang ; Keyhani, Nemat O. ; Li, Ning ; Huang, Shuaishuai ; Zhao, Xin ; Liu, Pengfei ; Zeng, Fanqin ; Li, Min ; Luo, Zhibing ; et al ( April 2024 , BMC Biology)

   Response to oxidative stress is universal in almost all organisms and the mitochondrial membrane protein, BbOhmm, negatively affects oxidative stress responses and virulence in the insect fungal pathogen,Beauveria bassiana. Nothing further, however, is known concerning howBbOhmmand this phenomenon is regulated.

   Threeoxidativestressresponse regulating Zn₂Cys₆transcription factors (BbOsrR1, 2, and 3) were identified and verified via chromatin immunoprecipitation (ChIP)-qPCR analysis as binding to theBbOhmmpromoter region, with BbOsrR2 showing the strongest binding. Targeted gene knockout ofBbOsrR1orBbOsrR3led to decreasedBbOhmmexpression and consequently increased tolerances to free radical generating compounds (H₂O₂and menadione), whereas the ΔBbOsrR2strain showed increasedBbOhmmexpression with concomitant decreased tolerances to these compounds. RNA and ChIP sequencing analysis revealed that BbOsrR1 directly regulated a wide range of antioxidation and transcription-associated genes, negatively affecting the expression of theBbClp1cyclin andBbOsrR2. BbClp1 was shown to localize to the cell nucleus and negatively mediate oxidative stress responses. BbOsrR2 and BbOsrR3 were shown to feed into the Fus3-MAPK pathway in addition to regulating antioxidation and detoxification genes. Binding motifs for the three transcription factors were found to partially overlap in the promoter region ofBbOhmmand other target genes. Whereas BbOsrR1 appeared to function independently, co-immunoprecipitation revealed complex formation between BbClp1, BbOsrR2, and BbOsrR3, with BbClp1 partially regulating BbOsrR2 phosphorylation.

   These findings reveal a regulatory network mediated by BbOsrR1 and the formation of a BbClp1-BbOsrR2-BbOsrR3 complex that orchestrates fungal oxidative stress responses.

    

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5. Advanced age protects resistance arteries of mouse skeletal muscle from oxidative stress through attenuating apoptosis induced by hydrogen peroxide

   https://doi.org/10.1113/JP278255  

   Norton, Charles E. ; Sinkler, Shenghua Y. ; Jacobsen, Nicole L. ; Segal, Steven S. ( July 2019 , The Journal of Physiology)

   Vascular oxidative stress increases with advancing age.

   We hypothesized that resistance vessels develop resilience to oxidative stress to protect functional integrity and tested this hypothesis by exposing isolated pressurized superior epigastric arteries (SEAs) of old and young mice to H₂O₂.

   H₂O₂‐induced death was greater in smooth muscle cells (SMCs) than endothelial cells (ECs) and lower in SEAs from oldvs. young mice; the rise in vessel wall [Ca²⁺]_iinduced by H₂O₂was attenuated with ageing, as was the decline in noradrenergic vasoconstriction; genetic deletion of IL‐10 mimicked the effects of advanced age on cell survival.

   Inhibiting NO synthase or scavenging peroxynitrite reduced SMC death; endothelial denudation or inhibiting gap junctions increased SMC death; delocalization of cytochrome C activated caspases 9 and 3 to induce apoptosis.

   Vascular cells develop resilience to H₂O₂during ageing by preventing Ca²⁺overload and endothelial integrity promotes SMC survival.

   Advanced age is associated with elevated oxidative stress and can protect the endothelium from cell death induced by H₂O₂. Whether such protection occurs for intact vessels or differs between smooth muscle cell (SMC) and endothelial cell (EC) layers is unknown. We tested the hypothesis that ageing protects SMCs and ECs during acute exposure to H₂O₂(200 µm, 50 min). Mouse superior epigastric arteries (SEAs; diameter, ∼150 µm) were isolated and pressurized to 100 cmH₂O at 37˚C. For SEAs from young (4 months) mice, H₂O₂killed 57% of SMCs and 11% of ECs in malesvs. 8% and 2%, respectively, in females. Therefore, SEAs from males were studied to resolve the effect of ageing and experimental interventions. For old (24 months) mice, SMC death was reduced to 10% with diminished accumulation of [Ca²⁺]_iin the vessel wall during H₂O₂exposure. In young mice, genetic deletion of IL‐10 mimicked the protective effect of ageing on cell death and [Ca²⁺]_iaccumulation. Whereas endothelial denudation or gap junction inhibition (carbenoxolone; 100 µm) increased SMC death, inhibiting NO synthase (l‐NAME, 100 µm) or scavenging peroxynitrite (FeTPPS, 5 µm) reduced SMC death along with [Ca²⁺]_i. Despite NO toxicity via peroxynitrite formation, endothelial integrity protects SMCs. Caspase inhibition (Z‐VAD‐FMK, 50 µm) attenuated cell death with immunostaining for annexin V, cytochrome C, and caspases 3 and 9 pointing to induction of intrinsic apoptosis during H₂O₂exposure. We conclude that advanced age reduces Ca²⁺influx that triggers apoptosis, thereby promoting resilience of the vascular wall during oxidative stress.

    

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