Microglia in brain aging:An overview of recent basic science and clinical research developments

Aging is characterized by progressive degeneration of tissues and organs,and it is positively associated with an increased mortality rate.The brain,as one of the most significantly affected organs,experiences age-related changes,including abnormal neuronal activity,dysfunctional calcium homeostasis,dysregulated mitochondrial function,and increased levels of reactive oxygen species.These changes collectively contribute to cognitive deterioration.Aging is also a key risk factor for neurodegenerative diseases,such as Alzheimer's disease and Parkinson's disease.For many years,neurodegenerative disease investigations have primarily focused on neurons,with less attention given to microglial cells.However,recently,microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis.Here,we provide an overview of brain aging from the perspective of the microglia.In doing so,we present the current knowledge on the correlation between brain aging and the microglia,summarize recent progress of investigations about the microglia in normal aging,Alzheimer's disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis,and then discuss the correlation between the senescent microglia and the brain,which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.

Two-dimensional horizontal visibility graph analysis of human brain aging on gray matter

Characterizing the trajectory of the healthy aging brain and exploring age-related structural changes in the brain can help deepen our understanding of the mechanism of brain aging.Currently,most structural magnetic resonance imaging literature explores brain aging merely from the perspective of morphological features,which cannot fully utilize the grayscale values containing important intrinsic information about brain structure.In this study,we propose the construction of two-dimensional horizontal visibility graphs based on the pixel intensity values of the gray matter slices directly.Normalized network structure entropy(NNSE)is then introduced to quantify the overall heterogeneities of these graphs.The results demonstrate a decrease in the NNSEs of gray matter with age.Compared with the middle-aged and the elderly,the larger values of the NNSE in the younger group may indicate more homogeneous network structures,smaller differences in importance between nodes and thus a more powerful ability to tolerate intrusion.In addition,the hub nodes of different adult age groups are primarily located in the precuneus,cingulate gyrus,superior temporal gyrus,inferior temporal gyrus,parahippocampal gyrus,insula,precentral gyrus and postcentral gyrus.Our study can provide a new perspective for understanding and exploring the structural mechanism of brain aging.

Astaxanthin alleviates pathological brain aging through the upregulation of hippocampal synaptic proteins

Oxidative stress is currently considered to be the main cause of brain aging.Astaxanthin can improve oxidative stress under multiple pathological conditions.It is therefore hypothesized that astaxanthin might have therapeutic effects on brain aging.To validate this hypothesis and investigate the underlying mechanisms,a mouse model of brain aging was established by injecting amyloid beta(Aβ)25-35(5μM,3μL/injection,six injections given every other day)into the right lateral ventricle.After 3 days of Aβ25-35 injections,the mouse models were intragastrically administered astaxanthin(0.1 mL/d,10 mg/kg)for 30 successive days.Astaxanthin greatly reduced the latency to find the platform in the Morris water maze,increased the number of crossings of the target platform,and increased the expression of brain-derived neurotrophic factor,synaptophysin,sirtuin 1,and peroxisome proliferator-activated receptor-γ coactivator 1α.Intraperitoneal injection of the sirtuin 1 inhibitor nicotinamide(500μM/d)for 7 successive days after astaxanthin intervention inhibited these phenomena.These findings suggest that astaxanthin can regulate the expression of synaptic proteins in mouse hippocampus through the sirtuin 1/peroxisome proliferator-activated receptor-γcoactivator 1αsignaling pathway,which leads to improvements in the learning,cognitive,and memory abilities of mice.The study was approved by the Animal Ethics Committee,China Medical University,China(approval No.CMU2019294)on January 15,2019.

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.

Editor's Choice—Chinese medicine and brain aging

Brain aging is the main manifestation of nervous system senescence, and is clinically represented by reduced learning and memory capacities and slowed reactions. Several studies have shown that Chinese medicines can effectively slow these processes. For example, polysaccharides from Schisandra chinensis have anti-aging effects, while Buyang Huanwu decoction can effectively improve cerebral blood flow and hemorheology,

Effect of Schisandra chinensis polysaccharide on intracerebral acetylcholinesterase and monoamine neurotransmitters in a D-galactose-induced aging brain mouse model

BACKGROUND： The most prominent characteristic of brain aging is decreased learning and memory ability. The functions of learning and memory are closely related to intracerebral acetylcholinesterase （ACHE） and monoamine neurotransmitter activity. Previous studies have shown that Schisandra chinensis polysaccharide has an anti-aging effect. OBJECTIVE： To explore the effects of Schisandra chinensis polysaccharide on AChE activity and monoamine neurotransmitter content, as well as learning and memory ability in a D-galactose-induced aging mouse brain model compared with the positive control drug Kangnaoling. DESIGN, TIME AND SETTING： Completely randomized, controlled experiment based on neurobiochemistry was performed at the Pharmacological Laboratory, Henan University of Traditional Chinese Medicine from September to December 2003. MATERIALS： Schisandra chinensis was purchased from Henan Provincial Medicinal Company. Schisandra chinensis polysaccharide was obtained by water extraction and alcohol precipitation. Kangnaoling pellets were provided by Liaoning Tianlong Pharmaceutical （batch No. 20030804; state drug permit No. H21023095）. A total of 50 six-week-old Kunming mice were randomly divided into five groups： blank control, model, Kangnaoling, high and low dosage Schisandra chinensis polysaccharide groups, with 10 mice per group. METHODS： Mice in the blank control group were subcutaneously injected with 0.5 mL/20 g normal saline into the nape of the neck each day, while the remaining mice were subcutaneously injected with 5% D-galactose saline solution （0.5 mL/20 g） in the nape for 40 days to induce a brain aging model. On day 11, mice in the high and low dosage Schisandra chinensis polysaccharide groups were intragastrically infused with 20 mg/mL and 10 mg/mL Schisandra chinensis polysaccharide solution （0.2 mL/10 g）, respectively. Mice from the Kangnaoling group were intragastrically infused with 35 mg/mL Kangnaoling suspension （0.2 mL/10 g）, and the mice in the model group were intragastrically infused with the same volume of normal saline （0.2 mL/10 g） once per day for 30 consecutive days. MAIN OUTCOME MEASURES： Two hours after the final administration, pathohistological changes in the cerebral cortex and hippocampus were observed using hematoxylin ＆ eosin staining. AChE activity was detected using chromatometry. Monoamine neurotransmitter content was measured using fluorimetry. Learning and memory was measured using the step down test and darkness avoidance test. RESULTS： Both Schisandra chinensis polysaccharide and Kangnaoling improved pathological injury to the cerebral cortex and hippocampus in a mouse model of brain aging. Compared with the blank control group, AChE activity and content of norepinephrine （NA）, dopamine （DA）, and 5-hydroxytryptamine （5-HT） were significantly decreased in the model group （P 〈 0.01 ）. In contrast, AChE activity and NA, DA, and 5-HT levels significantly increased in the Kangnaoling and high dosage Schisandra chinensis polysaccharide groups （P 〈 0.01）, while NA levels significantly increased in the low dosage Schisandra chinensis polysaccharide group （P 〈 0.01）. Drug treatment improved learning and memory abilities （P 〈 0.01 or P 〈 0.05）. CONCLUSION： Schisandra chinensis polysaccharide significantly increased levels of central neurotransmitters and improved learning and memory in a mouse model of brain aging. The effects of Schisandra chinensis polysaccharide were equal to that of Kangnaoling pellets.

Insilico Identification of Genes and Molecular Pathways during Aging in <i>Drosophila</i>Brain

The regulation of gene expression in brain vicissitudes during aging is still not much known and explored. Differential gene expression and regulation is a key factor involved to identify the important landmarks within the brain transcriptome to study neuronal aging. Recently, transcriptomic studies are highly explored to understand and depict diseased versus normal as next generation sequencing enables to capture the complete biological context to the entire genome. Study of gene expression during aging compared to young flies provides a signature and scenario of gene expression and regulation during aging. In this study, we took advantage of NGS raw data of young and old flies head from SRA database of NCBI and decrypted the gene expression regulation during normal aging in drosophila model. We identified 350 genes with significant differential expression between young and old flies having 0.01% FDR. Various pathways in context to identified genes which are involved in aging include autophagy i.e. cell death and apoptosis, proteolysis, oxidative stress, declination grey and white matter and neurotransmitter levels, mitochondrial discrepancy, electron transport chain, sugar degradation pathways, activation of transcription factors involved in epigenetic changes, regulators involved in negative and positive regulation WNT signaling pathways, G protein coupled receptor etc. as all these factors contribute to neurodegeneration and possibly dementia in normal aging. So, to find the specific genes and regulators which are differentially expressed in normal aging, we investigate brain transcriptome of normal aging flies compared to young flies which offer a repertoire of genes, regulators and factors involved in network of neurodegeneration to establish direct correlation between aging and dementia. We also identified the pathways which are involved in aging and corresponding gene regulation in these pathways in aging flies brain. It is found that there are some common pathways whose genes and regulators are highly differentially regulated in both aging and dementia.

Dynamic changes in DNA demethylation in the tree shrew (Tupaia belangeri chinensis) brain during postnatal development and aging

Brain development and aging are associated with alterations in multiple epigenetic systems, including DNA methylation and demethylation patterns. Here, we observed that the levels of the 5- hydroxymethylcytosine （5hmC） ten-eleven transtocation （TET） enzyme-mediated active DNA demethylation products were dynamically changed and involved in postnatal brain development and aging in tree shrews （Tupaia belangeri chinensis）. The levels of 5hmC in multiple anatomic structures showed a gradual increase throughout postnatal development, whereas a significant decrease in 5hmC was found in several brain regions in aged tree shrews, including in the prefrontal cortex and hippocampus, but not the cerebellum. Active changes in Tet mRNA levels indicated that TET2 and TET3 predominantly contributed to the changes in 5hmC levels. Our findings provide new insight into the dynamic changes in 5hmC levels in tree shrew brains during postnatal development and aging processes.

Protein Kinase Activity Changes in the Aging Brain

The aging process in mammals is correlated with changes in psychomotor performance, cognitive function, and ability to adapt to stress (Montgomery et al., 1982; Lorens et al., 1990). These changes may be related to alterations in neuronal tissue that occur during the aging process. The normal aging process may be conceived of as the neuronal cell’s increasing inability to maintain normal cellular function which ultimately results in a number of morphological and biochemical changes. Morphologically, there is a loss of neuronal cells with increasing age (Brizzee and

Long-Term Animal Feeding Trial of the Refined Konjac Meal Ⅱ. Effects of the Refined Konjac Meal on the Aging of the Brain, Liver, and Cardiovascular Tissue Cells in Rats

Rats of both sexes were fed on a basal feed containing 1% refined konjac meal (RKM) for 18 months and the effects of RKM on the cell aging were observed. A comparable group fed on the basic feed was used as the control. Results obtained demonstrate that the long-term feeding of RKM to rats can delay the course of cell aging of the gliocyte, cadiomyocyte, and the endothelial cell of the large and medium arteriases, hence it is likely to delay the occurrence of arteriosclerosis and improve the functions of the brain, heart and vascular system.

Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

Dual-Tasking as Diagnostic and Rehabilitation Tool in Traumatic Brain Injury Patients

Objective: Purpose of this study was to investigate the behavioral and brain activity impairments in patients after moderate traumatic brain injury (mTBI) in comparison with the normal ranges while dual-tasks performing. We would like to evaluate dual-tasking as diagnostic and rehabilitation tool and to test hypothesis of brain aging after mTBI. Material and Methods: Electroencephalographic (EEG), stabilographic and clinical study was performed in 11 patients (mean age 28.8 ± 8.4 years) for up to 1 - 12 months after a mTBI in comparison with 17 healthy subjects (26.7 ± 5.1 years). All the participants performed two motor and two cognitive tasks presented separately, and simultaneously (dual-tasking). Results: Clinical examination revealed predominantly cognitive deficit in mTBI patients with intact postural control. EEG data demonstrated coherence decrease for slow (delta-theta) rhythms in frontal-temporal areas predominantly for left hemisphere during cognitive tasks performance. In contrast, EEG coherence for slow spectral bands increased in the same areas in healthy volunteers. EEG coherence increased for fast spectral bands—alpha2 and beta, predominantly in right hemisphere while both healthy adults and patients performed motor components of dual tasks. Rehabilitation course with dual tasks, led to a predominant reduction in cognitive deficits, and EEG coherence increases at the frontal-temporal areas of the left hemisphere. Conclusions: Dual-tasks may be used as diagnostic tool in patients after mTBI. This approach demonstrates predominant cognitive deficit, and left hemispheric dysfunction in patients similar to elderly persons and support the hypothesis of brain aging after TBI. Pilot studies also suggested rehabilitation effect of dual-tasking in mTBI patients.

Dietary restriction to accompany the aging process in mice Can it be neuroprotective?

BACKGROUND： Prophylactic dietary restriction （DR）, whether lifelong or started in adulthood,retards the aging process and attenuates cognitive decline in rodents. However, whether the anti-aging and neuroprotective efficacy of DR initiate late in life or accompany the aging process remains unclear.OBJECTIVE： The present study sought to： （1） determine if DR could protect against behavioral decline in mice when implemented during the aging process induced by D-galactose and （2） examine neuronal apoptosis in these aged brains and whether DR could block apoptosis.DESIGN, TIME AND SETTING： The randomized controlled animal study. The experiment was performed at the Experimental Animal Center of Capital Medical University and the Laboratory Center of School of Public Health of Captial Medical University of China from April 2006 to October 2007.MATERIALS： D-galactose （D-gal） was purchased from Beijing Chemical-Regent Company （Beijing, China）. Terminal transferase dUTP nick end labeling （TUNEL） detection kit was obtained from Roche, Germany. Assay kits for antioxidant enzyme activities and malondialdehyde contents were purchased from Jiancheng Institute of Biotechnology （Nanjing, China）. Morris water maze （Friends Honesty Life Sciences Co. Ltd., Hong Kong, China） and Flow Cytometry （Coulter, USA） were used in this study.METHODS： A total of 40 male Institute of Cancer Research （lCR） mice, 3 months old, were equally and randomly divided into D-gal treatment, DR treatment, D-gal ＋ DR treatment and normal control groups, and were then randomly assigned to one of two feeding regimens： ad libitum access to food or DR which received a 70% amount of daily food intake as that by ad libitum fed mice. There were two replicates per feeding regimen and mice were fed for 10 weeks,with or without a daily subcutaneous injection of D-gal at 100 mg/kg.MAIN OUTCOME MEASURES： Animals＇ spatial learning and memory performance were tested in the Morris water maze. Neuronal apoptosis rates were evaluated by Annexin V/flow cytometry assay and TUNEL assay. Lipid peroxidation levels and antioxidant defense capacity of the brain were measured using testing kits.RESULTS： DR markedly reduced the prolonged escape latency of D-gal mice in the water maze test （P〈0.01）. Annexin V and TUNEL assays showed that the D-gal mice had a significant higher percentage of neuronal apoptosis compared with normal control mice （P〈0.05）, and that DR treatment markedly decreased this apoptotic cell death （P〈0.05）. DR also reversed the decline of total superoxide dismutase and glutathione peroxidase activities and the increase of malondialdehyde levels in the brain of D-gal mice （P〈0.05, respectively）.CONCLUSION： DR reduces the impact of D-gal-induced brain aging in mice and can reverse performance decline and neurobiochemical impairments. These results demonstrate that implementation of DR in conditions of chronic oxidative stress can be neuroprotective, and that senium DR can be beneficial for healthy aging.

Cross-sectional associations between cortical thiclmess and physical activity in older adults with spontaneous memory complaints:The MAPT Study

Background:Age-related changes in brain structure may constitute the starting point for cerebral function alteration.Physical activity(PA)demonstrated favorable associations with total brain volume,but its relationship with cortical thickness(CT)remains unclear.We investigated the cross-sectional associations between PA level and CT in community-dwelling people aged 70 years and older.Methods:A total of 403 older adults aged 74.8±4.0 years(mean±SD)who underwent a baseline magnetic resonance imaging examination and who had data on PA and confounders were included.PA was assessed with a questionnaire.Participants were categorized according to PA levels.Multiple linear regressions were used to compare the brain CT(mm)of the inactive group(no PA at all)with 6 active groups(growing PA levels)in 34 regions of interest.Results:Compared with inactive persons,people who achieved PA at a level of 1500-1999 metabolic equivalent task-min/week(i.e.,about6-7 h of brisk walking for exercise) and those who achieved it at 2000-2999 metabolic equivalent task-min/week(i.e.,8-11 h of brisk walking for exercise)had higher CT in the fusiform gyrus and the temporal pole.Additionally,dose-response associations between PA and CT were found in the fusiform gyrus(B=0.011,SE=0.004,adj.p=0.035),the temporal pole(B=0.026,SE=0.009,adj.p=0.048),and the caudal middle frontal gyrus,the entorhinal,medial orbitofrontal,lateral occipital,and insular cortices.Conclusion:This study demonstrates a positive association between PA level and CT in temporal areas such as the fusiform gyrus,a brain region often associated to Alzheimer’s disease in people aged 70 years and older.Future investigations focusing on PA type may help to fulfil remaining knowledge gaps in this field.

The influence of gut microbiota alteration on age-related neuroinflammation and cognitive decline

Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attra cted significant attention.Age-related intestinal microbiota changes initiate brain aging and age-related neurodegenerative disorders.Aging is one of the critical predisposing risk factors for the development of neurodegenerative diseases.Maintaining a healthy gut microbiota is essential for a healthy body and aging,but dys biosis could initiate many chro nic diseases.Understanding the underlying mechanisms of gut microbiota alterations/dys biosis will help identify biomarkers for aging-related chro nic conditions.This review summarizes recent advances in micro biota-neurodegenerative disease research and will enhance our unde rstanding of gut microbiota dys biosis and its effects on brain aging.

The choroid plexus-cerebrospinal fluid interface in Alzheimer's disease:more than just a barrier

The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form an anatomical barrier,called the blood-cerebrospinal fluid barrier（BCSFB）,but also present an active interface between blood and cerebrospinal fluid（CSF）.CPE cells perform indispensable functions for the development,maintenance and functioning of the brain.Indeed,the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules,such as nutrients,neurotrophins,and growth factors,as well as by clearing toxic and undesirable molecules from CSF.The choroid plexus also acts as a selective entry gate for leukocytes into the brain.Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer＇s disease.In this review,we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer＇s disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.

Lipid metabolism in Alzheimer's disease

Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer＇s disease （AD）, and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis.