Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments

Gureev, Artem P.; Khorolskaya, Victoria G.; Sadovnikova, Irina S.; Shaforostova, Ekaterina A.; Cherednichenko, Vadim R.; Burakova, Inna; Plotnikov, Egor Y.; Popov, Vasily N.

doi:10.3390/ijms232315197

Cited by 14 publications

(10 citation statements)

References 57 publications

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“…This was accompanied by the decreased expression of three known targets of the NRF2 pathway, NQO1, GCLC, and GCLM. Similary, an age-dependent decrease in the mRNA levels of NRF2 was shown in the cortex of wild-type mice [90]. The high KEAP1 and low GCLC, HO-1, NRF2, and NQO1 gene and protein expression levels in the H 2 O 2 group in our study are similar to those reported by Kanninen et al [89] and Gureev et al [90] in aged mice.…”

Section: Discussionsupporting

confidence: 91%

Lactic Acid Bacteria-Derived Exopolysaccharides Mitigate the Oxidative Response via the NRF2-KEAP1 Pathway in PC12 Cells

Şirin

2023

CIMB

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Parabiotics, including L-EPSs, have been administered to patients with neurodegenerative disorders. However, the antioxidant properties of L-EPSs against H2O2-induced oxidative stress in PC12 cells have not been studied. Herein, we aimed to investigate the antioxidant properties of the L-EPSs, their plausible targets, and their mechanism of action. We first determined the amount of L-EPSs in Lactobacillus delbrueckii ssp. bulgaricus B3 and Lactiplantibacillus plantarum GD2 using spectrophotometry. Afterwards, we studied their effects on TDH, TOS/TAS, antioxidant enzyme activities, and intracellular ROS level. Finally, we used qRT-PCR and ELISA to determine the effects of L-EPSs on the NRF2-KEAP1 pathway. According to our results, the L-EPS groups exhibited significantly higher total thiol activity, native thiol activity, disulfide activity, TAS levels, antioxidant enzyme levels, and gene expression levels (GCLC, HO-1, NRF2, and NQO1) than did the H2O2 group. Additionally, the L-EPS groups caused significant reductions in TOS levels and KEAP1 gene expression levels compared with those in the H2O2 group. Our results indicate that H2O2-induced oxidative stress was modified by L-EPSs. Thus, we revealed that L-EPSs, which regulate H2O2-induced oxidative stress, could have applications in the field of neurochemistry.

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Section: Discussionsupporting

confidence: 91%

Lactic Acid Bacteria-Derived Exopolysaccharides Mitigate the Oxidative Response via the NRF2-KEAP1 Pathway in PC12 Cells

Şirin

2023

CIMB

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“…It is interesting to note in this respect that BRCA1 and ATM have both been shown to be crucially involved in GIT2-associated DDR processes [22]. As we have previously discussed, there is a near-inevitable link in aging between metabolic dysfunction and DNA damage [6,71,[137][138][139]. With this knowledge, we assessed whether the DDR-based stress response component of the GPR19 molecular signature was also linked to energy metabolic processes.…”

Section: Discussionmentioning

confidence: 94%

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Maudsley

Schrauwen

Harputluoğlu

et al. 2023

IJMS

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G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

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“…Nrf2 translocates to the nucleus under oxidative stress, promoting antioxidant gene expression, such as GCS, HO1, and SOD1 [ 86 , 87 ]. There is a general consensus that Nrf2 signaling is reduced during aging [ 88 , 89 ]; however, several reports show controversial results of unchanged or increased Nrf2 in the hippocampus of aged male animals [ 90 ]. A study on the cerebellum of 21m male mice showed increased transcript and protein levels of Nrf2 with an increase in its antioxidant target genes [ 91 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice

Torres

Jara

Llanquinao

et al. 2023

IJMS

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Aging is a physiological process that generates progressive decline in many cellular functions. There are many theories of aging, and one of great importance in recent years is the mitochondrial theory of aging, in which mitochondrial dysfunction that occurs at advanced age could be responsible for the aged phenotype. In this context, there is diverse information about mitochondrial dysfunction in aging, in different models and different organs. Specifically, in the brain, different studies have shown mitochondrial dysfunction mainly in the cortex; however, until now, no study has shown all the defects in hippocampal mitochondria in aged female C57BL/6J mice. We performed a complete analysis of mitochondrial function in 3-month-old and 20-month-old (mo) female C57BL/6J mice, specifically in the hippocampus of these animals. We observed an impairment in bioenergetic function, indicated by a decrease in mitochondrial membrane potential, O2 consumption, and mitochondrial ATP production. Additionally, there was an increase in ROS production in the aged hippocampus, leading to the activation of antioxidant signaling, specifically the Nrf2 pathway. It was also observed that aged animals had deregulation of calcium homeostasis, with more sensitive mitochondria to calcium overload and deregulation of proteins related to mitochondrial dynamics and quality control processes. Finally, we observed a decrease in mitochondrial biogenesis with a decrease in mitochondrial mass and deregulation of mitophagy. These results show that during the aging process, damaged mitochondria accumulate, which could contribute to or be responsible for the aging phenotype and age-related disabilities.

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Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments

Cited by 14 publications

References 57 publications

Lactic Acid Bacteria-Derived Exopolysaccharides Mitigate the Oxidative Response via the NRF2-KEAP1 Pathway in PC12 Cells

Lactic Acid Bacteria-Derived Exopolysaccharides Mitigate the Oxidative Response via the NRF2-KEAP1 Pathway in PC12 Cells

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice

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