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1. ASCORBATE PEROXIDASE6 delays the onset of age-dependent leaf senescence

   https://doi.org/10.1093/plphys/kiaa031  

   Chen, Changming ; Galon, Yael ; Rahmati Ishka, Maryam ; Malihi, Shimrit ; Shimanovsky, Vladislava ; Twito, Shir ; Rath, Abhishek ; Vatamaniuk, Olena K ; Miller, Gad ( November 2020 , Plant Physiology)

   null (Ed.)

   Abstract Age-dependent changes in reactive oxygen species (ROS) levels are critical in leaf senescence. While H2O2-reducing enzymes such as catalases and cytosolic ASCORBATE PEROXIDASE1 (APX1) tightly control the oxidative load during senescence, their regulation and function are not specific to senescence. Previously, we identified the role of ASCORBATE PEROXIDASE6 (APX6) during seed maturation in Arabidopsis (Arabidopsis thaliana). Here, we show that APX6 is a bona fide senescence-associated gene. APX6 expression is specifically induced in aging leaves and in response to senescence-promoting stimuli such as abscisic acid (ABA), extended darkness, and osmotic stress. apx6 mutants showed early developmental senescence and increased sensitivity to dark stress. Reduced APX activity, increased H2O2 level, and altered redox state of the ascorbate pool in mature pre-senescing green leaves of the apx6 mutants correlated with the early onset of senescence. Using transient expression assays in Nicotiana benthamiana leaves, we unraveled the age-dependent post-transcriptional regulation of APX6. We then identified the coding sequence of APX6 as a potential target of miR398, which is a key regulator of copper redistribution. Furthermore, we showed that mutants of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7), the master regulator of copper homeostasis and miR398 expression, have a higher APX6 level compared with the wild type, which further increased under copper deficiency. Our study suggests that APX6 is a modulator of ROS/redox homeostasis and signaling in aging leaves that plays an important role in developmental- and stress-induced senescence programs. 

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2. Stress-Free Evolution: The Nrf-Coordinated Oxidative Stress Response in Early Diverging Metazoans

   https://doi.org/10.1093/icb/icz055  

   Doonan, Liam B ; Hartigan, Ashlie ; Okamura, Beth ; Long, Paul F ( May 2019 , Integrative and Comparative Biology)

   Abstract Environmental stress from ultraviolet radiation, elevated temperatures or metal toxicity can lead to reactive oxygen species in cells, leading to oxidative DNA damage, premature aging, neurodegenerative diseases, and cancer. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activates many cytoprotective proteins within the nucleus to maintain homeostasis during oxidative stress. In vertebrates, Nrf2 levels are regulated by the Kelch-family protein Keap1 (Kelch-like ECH-associated protein 1) in the absence of stress according to a canonical redox control pathway. Little, however, is known about the redox control pathway used in early diverging metazoans. Our study examines the presence of known oxidative stress regulatory elements within non-bilaterian metazoans including free living and parasitic cnidarians, ctenophores, placozoans, and sponges. Cnidarians, with their pivotal position as the sister phylum to bilaterians, play an important role in understanding the evolutionary history of response to oxidative stress. Through comparative genomic and transcriptomic analysis our results show that Nrf homologs evolved early in metazoans, whereas Keap1 appeared later in the last common ancestor of cnidarians and bilaterians. However, key Nrf–Keap1 interacting domains are not conserved within the cnidarian lineage, suggesting this important pathway evolved with the radiation of bilaterians. Several known downstream Nrf targets are present in cnidarians suggesting that cnidarian Nrf plays an important role in oxidative stress response even in the absence of Keap1. Comparative analyses of key oxidative stress sensing and response proteins in early diverging metazoans thus provide important insights into the molecular basis of how these lineages interact with their environment and suggest a shared evolutionary history of regulatory pathways. Exploration of these pathways may prove important for the study of cancer therapeutics and broader research in oxidative stress, senescence, and the functional responses of early diverging metazoans to environmental change. 

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3. Developmental stress and telomere dynamics in a genetically polymorphic species

   https://doi.org/10.1111/jeb.13400  

   Grunst, Andrea S. ; Grunst, Melissa L. ; Gonser, Rusty A. ; Tuttle, Elaina M. ( December 2018 , Journal of Evolutionary Biology)

   A central objective of evolutionary biology is understanding variation in life‐history trajectories and the rate of aging, or senescence. Senescence can be affected by trade‐offs and behavioural strategies in adults but may also be affected by developmental stress. Developmental stress can accelerate telomere degradation, with long‐term longevity and fitness consequences. Little is known regarding whether variation in developmental stress and telomere dynamics contributes to patterns of senescence during adulthood. We investigated this question in the dimorphic white‐throated sparrow (Zonotrichia albicollis), a species in which adults of the two morphs exhibit established differences in behavioural strategy and patterns of senescence, and also evaluated the relationship between oxidative stress and telomere length. Tan morph females, which exhibit high levels of unassisted parental care, display faster reproductive senescence than white females, and faster actuarial senescence than all of the other morph–sex classes. We hypothesized that high oxidative stress and telomere attrition in tan female nestlings could contribute to this pattern, since tan females are small and potentially at a competitive disadvantage even as nestlings. Nestlings that were smaller than nest mates had higher oxidative stress, and nestlings with high oxidative stress and fast growth rates displayed shorter telomeres. However, we found no consistent morph–sex differences in oxidative stress or telomere length. Results suggest that oxidative stress and fast growth contribute to developmental telomere attrition, with potential ramifications for adults, but that developmental oxidative stress and telomere dynamics do not account for morph–sex differences in senescence during adulthood.

    

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4. Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection

   https://doi.org/10.1038/s41467-024-47279-4  

   Giron, Leila B ; Liu, Qin ; Adeniji, Opeyemi S ; Yin, Xiangfan ; Kannan, Toshitha ; Ding, Jianyi ; Lu, David Y ; Langan, Susan ; Zhang, Jinbing ; Azevedo, Joao_L_L C ; et al ( December 2024 , Nature Communications)

   People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in theN-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgGN-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

    

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5. Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection

   https://doi.org/10.1038/s41598-023-29119-5  

   Aryal, Baikuntha ; Tillotson, Joseph ; Ok, Kiwon ; Stoltzfus, Andrew T. ; Michel, Sarah L. J. ; Rao, V. Ashutosh ( February 2023 , Scientific Reports)

   Pathogenesis of COVID-19 by SARS-CoV-2 resulted in a global pandemic and public health emergency in 2020. Viral infection can induce oxidative stress through reactive oxygen species (ROS). Inflammation and environmental stress are major sources of oxidative stress after infection. Micronutrients such as iron, copper, zinc, and manganese play various roles in human tissues and their imbalance in blood can impact immune responses against pathogens including SARS CoV-2. We hypothesized that alteration of free metal ions during infection and metal-catalyzed oxidation plays a critical role towards pathogenesis after infection. We analyzed convalescent and hospitalized COVID-19 patient plasma using orthogonal analytical techniques to determine redox active metal concentrations, overall protein oxidation, oxidative modifications, and protein levels via proteomics to understand the consequences of metal-induced oxidative stress in COVID-19 plasma proteins. Metal analysis using ICP-MS showed significantly greater concentrations of copper in COVID-19 plasma compared to healthy controls. We demonstrate significantly greater total protein carbonylation, other oxidative modifications, and deamidation of plasma proteins in COVID-19 plasma compared to healthy controls. Proteomics analysis showed that levels of redox active proteins including hemoglobulin were elevated in COVID-19 plasma. Molecular modeling concurred with potential interactions between iron binding proteins and SARS CoV-2 surface proteins. Overall, increased levels of redox active metals and protein oxidation indicate that oxidative stress-induced protein oxidation in COVID-19 may be a consequence of the interactions of SARS-CoV-2 proteins with host cell metal binding proteins resulting in altered cellular homeostasis.

    

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