Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: Modulation by every-other-day fasting

Bayliak, Maria M.; Sorochynska, Oksana M.; Kuzniak, Oksana V.; Gospodaryov, Dmytro V.; Demianchuk, Oleh I.; Vasylyk, Yulia V.; Mosiichuk, Nadia M.; Storey, Kenneth B.; Garaschuk, Olga; Lushchak, Volodymyr I.

doi:10.1016/j.exger.2020.111182

Cited by 28 publications

(27 citation statements)

References 70 publications

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“…Epidemiological data on neurodegenerative diseases suggest that middle age is a critical period for disease onset and progression, as well as for the identification of promising treatment options able to stop or reverse pathology [58,59]. Interestingly, a recent study showed that middle age (e.g.,~12 months of age in mice) is also characterized by high intensity of oxidative stress and first aging-related changes in the brain's energy metabolism [60]. Consistently, accumulating evidence suggests that the first aging-related switch in microglial function occurs with 9-12 months of age when animals are not even considered old.…”

Section: Unexpected Alertness Of Middle-age Microgliamentioning

confidence: 89%

“…In different mouse strains, CR delayed the onset of age-related pathology, e.g., the appearance of lymphoma, without necessarily prolonging the lifespan of the animals [146]. The beneficial effects of CR on lifespan and cognition are at least in part mediated by attenuation of oxidative stress, inflammation, and metabolic alterations associated with aging [60,144,147]. Indeed, CR decreased transcription of genes associ-ated with inflammatory and stress response during the aging process in the cortex and cerebellum of mice [148].…”

Section: Effect Of Caloric Restrictionmentioning

confidence: 99%

“…Indeed, CR decreased transcription of genes associ-ated with inflammatory and stress response during the aging process in the cortex and cerebellum of mice [148]. Studies investigating different CR regimen in mice of different strains or genders show that some, but not all, of the CR-mediated effects depend on the sex, strain, and degree of restriction [60,146]. As an example, CR-mediated effects on hippocampal gene expression and improvement in learning and memory were larger in female mice [149].…”

Section: Effect Of Caloric Restrictionmentioning

confidence: 99%

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Changing Functional Signatures of Microglia along the Axis of Brain Aging

Brawek

Skok

Garaschuk

2021

IJMS

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Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages. Indeed, microglia adapt exceptionally well to their microenvironment, becoming a legitimate member of the cellular brain architecture. The ramified or surveillant microglia in the young adult brain are characterized by specific morphology (small cell body and long, thin motile processes) and physiology (a unique pattern of Ca2+ signaling, responsiveness to various neurotransmitters and hormones, in addition to classic “immune” stimuli). Their numerous physiological functions far exceed and complement their immune capabilities. As the brain ages, the respective changes in the microglial microenvironment impact the functional properties of microglia, triggering further rounds of adaptation. In this review, we discuss the recent data showing how functional properties of microglia adapt to age-related changes in brain parenchyma in a sex-specific manner, with a specific focus on early changes occurring at middle age as well as some strategies counteracting the aging of microglia.

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Section: Unexpected Alertness Of Middle-age Microgliamentioning

confidence: 89%

Section: Effect Of Caloric Restrictionmentioning

confidence: 99%

Section: Effect Of Caloric Restrictionmentioning

confidence: 99%

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Changing Functional Signatures of Microglia along the Axis of Brain Aging

Brawek

Skok

Garaschuk

2021

IJMS

Self Cite

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“…science and leads to translational failure. A classic example of this is the case of NXY-059, which had positive preclinical studies and meta-analysis but the expensive and large clinical translational program (SAINT-1 and -2 trials) was a complete failure (Bath et al, 2009). Similar methodological pitfalls also exist in other fields of science, such as multiple sclerosis and cardiovascular research (see sections below).…”

Section: Lack Of Validation Replication and Confirmatory Studiesmentioning

confidence: 98%

“…Rats may eventually not be the optimal rodent species for drug translation in stroke; mice may be more "translational." Comparative data from preclinical and clinical studies for the Natalizumab, NXY-059, Magnesium, and especially mesenchymal stem cells treatment in stroke imply that mice either reflect the negative human results or the effect size better than rats (Shuaib et al, 2007;Bath et al, 2009;Vu et al, 2014;Llovera et al, 2015;Saver et al, 2015;Elkind et al, 2020). Recent studies indicate that preclinical inbred and SPF rodents fail to recapitulate a normal "dirty" human environment due to their poor and altered microbiome, mycobiome, and virome.…”

Section: Seeking "Out-of-the-box" Solutions For the Current Common Stroke Practice And Translation Pipelinementioning

confidence: 99%

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

et al. 2021

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Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

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Epicatechin‐mediated modulation of the Nrf2/HO‐1 pathway alleviates senile cerebral ischemic/reperfusion injury

Jiang,

Zhuge,

et al. 2024

Food Science & Nutrition

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Excessive reactive oxygen species (ROS) generated during cerebral ischemic reperfusion (CIRI) are crucial for subsequent tissue damage. However, despite the potential benefits of antioxidants reported in clinical applications, few have proven effective in treating CIRI, particularly in the elderly. Epicatechin (EC) is a catechol flavonoid monomer derived from natural tea plants. Multiple phenolic hydroxyl groups give it strong antioxidant properties, which can not only degrade ROS through chemical reactions between hydroxyl and ROS but also enhance the activity of antioxidant enzymes in cells, and it is easy to penetrate the blood–brain barrier. But its antagonistic effect on age‐related CIRI and potential medicinal value are still unknown. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is the most important transcription factor regulating the expression of antioxidant proteins in the body. This study first compared the pathological differences of the Nrf2 system in CIRI between 2‐month‐old and 12‐month‐old Sprague–Dawley (SD) rats. Subsequently, EC was administered to 12‐month‐old rat models of middle cerebral artery occlusion and reperfusion (MCAO/R) and senescent SH‐SY5Y cell models subjected to oxygen glucose deprivation/reoxygenation (OGD/R). EC treatment improved cerebral morphology and function; increased p‐Nrf2, heme oxygenase‐1 (HO‐1), superoxide dismutase (SOD), and glutathione (GSH) expression; reduced infarct volume; and neuronal apoptosis in senescent rats. Moreover, EC enhanced cellular activity and the expression of p‐Nrf2, HO‐1, and quinone oxidoreductase‐1 (NQO‐1) while decreasing ROS and malondialdehyde (MDA) levels and mitigating apoptosis in senescent SH‐SY5Y cells. These effects were reversed upon si‐Nrf2. In sum, we confirm that EC exerts neuroprotective effects by upregulating Nrf2/ARE and reducing oxidative stress, suggesting that EC may be a promising drug for the treatment of senile cerebral apoplexy. This study also provides a scientific basis for the development and selection of new drugs for ischemic stroke in elderly patients.

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Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: Modulation by every-other-day fasting

Cited by 28 publications

References 70 publications

Changing Functional Signatures of Microglia along the Axis of Brain Aging

Changing Functional Signatures of Microglia along the Axis of Brain Aging

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

Epicatechin‐mediated modulation of the Nrf2/HO‐1 pathway alleviates senile cerebral ischemic/reperfusion injury

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