Mechanisms Of Brain Aging Research Articles

Exploring molecular signatures related to the mechanism of aging in different brain regions by integrated bioinformatics.

The mechanism of brain aging is not fully understood. Few studies have attempted to identify molecular changes using bioinformatics at the subregional level in the aging brain. This study aimed to identify the molecular signatures and key genes involved in aging, depending on the brain region. Differentially expressed genes (DEGs) associated with aging of the cerebral cortex (CX), hippocampus (HC), and cerebellum (CB) were identified based on five datasets from the Gene Expression Omnibus (GEO). The molecular signatures of aging were explored using functional and pathway analyses. Hub genes of each brain region were determined by protein-protein interaction network analysis, and commonly expressed DEGs (co-DEGs) were also found. Gene-microRNAs (miRNAs) and gene-disease interactions were constructed using online databases. The expression levels and regional specificity of the hub genes and co-DEGs were validated using animal experiments. In total, 32, 293, and 141 DEGs were identified in aging CX, HC, and CB, respectively. Enrichment analysis indicated molecular changes related to leukocyte invasion, abnormal neurotransmission, and impaired neurogenesis due to inflammation as the major signatures of the CX, HC, and CB. Itgax is a hub gene of cortical aging. Zfp51 and Zfp62 were identified as hub genes involved in hippocampal aging. Itgax and Cxcl10 were identified as hub genes involved in cerebellar aging. S100a8 was the only co-DEG in all three regions. In addition, a series of molecular changes associated with inflammation was observed in all three brain regions. Several miRNAs interact with hub genes and S100a8. The change in gene levels was further validated in an animal experiment. Only the upregulation of Zfp51 and Zfp62 was restricted to the HC. The molecular signatures of aging exhibit regional differences in the brain and seem to be closely related to neuroinflammation. Itgax, Zfp51, Zfp62, Cxcl10, and S100a8 may be key genes and potential targets for the prevention of brain aging.

Reduced frontal white matter microstructure in healthy older adults with low tactile recognition performance

The aging of the nervous system is a heterogeneous process. It remains a significant challenge to identify relevant markers of pathological and healthy brain aging. A central aspect of aging are decreased sensory acuities, especially because they correlate with the decline in higher cognitive functioning. Sensory and higher cognitive processing relies on information flow between distant brain areas. Aging leads to disintegration of the underlying white matter tracts. While this disintegration is assumed to contribute to higher cognitive decline, data linking structural integrity and sensory function are sparse. The investigation of their interrelation may provide valuable insight into the mechanisms of brain aging. We used a combined behavioral and neuroimaging approach and investigated to what extent changes in microstructural white matter integrity reflect performance declines in tactile pattern recognition with aging. Poor performance in older participants was related to decreased integrity in the anterior corpus callosum. Probabilistic tractography showed that this structure is connected to the prefrontal cortices. Our data point to decreased integrity in the anterior corpus callosum as a marker for advanced brain aging. The correlation between impaired tactile recognition and disintegration in frontal brain networks could provide an explanation why the decrease of sensory function predicts cognitive decline.

Alcohol consumption and cognitive aging: can it be beneficial?

We present a literature review which summarizes the data supporting one of the alternative perspectives on the effect of alcohol consumption on cognitive aging – the possible positive effect of low to moderate drinking. Some of the main theories about aging, the mechanisms of brain aging, and the pathogenesis of cognitive decline and dementia are briefly described. In this context, the putative mechanisms of the protective action of non-alcoholic components in alcoholic beverages or low doses of ethanol against oxidative stress, inflammation, mitochondrial dysfunction, brain insulin resistance, and production of amyloid-β peptides are presented. The review article does not favor the data selected and highlighted, but it aims at inspiring more interest and further research on the topic.

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein (GFAP) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and GFAP which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.

МЕХАНІЗМИ СТАРІННЯ МОЗКУ ЯК ОСНОВА ВІКОВОЇ ДИСФУНКЦІЇ ЦЕНТРАЛЬНОЇ НЕРВОВОЇ СИСТЕМИ

Modern views on the mechanisms of brain aging and their connection with age dysfunction of the central nervous system has been analyzed.

Diffeomorphic registration with self-adaptive spatial regularization for the segmentation of non-human primate brains.

Cerebral aging has been linked to structural and functional changes in the brain throughout life. Here, we study the marmoset, a small non-human primate, in order to get insights into the mechanisms of brain aging in normal and pathological conditions. Imaging the brain of small animals with techniques such as MRI, quickly becomes a challenging task when compared with human brain imaging. Very often, a simple pre-processing step such as brain extraction cannot be achieved with classical tools. In this paper, we propose a diffeomorphic registration algorithm, which makes use of learned constraints to propagate the manual segmentation of a marmoset brain template to other MR images of marmoset brains. The main methological contribution of our paper is to explore a new strategy to automatically tune the spatial regularization of the deformations. Results show that we obtain a robust segmentation of the brain, even for images with a low contrast.

The Relationship between Cerebral Glucose Metabolism and Age: Report of a Large Brain PET Data Set

Cerebral glucose metabolism is a reliable index of neural activity and may provide evidence for brain function in healthy adults. We studied the correlation between cerebral glucose metabolism and age under the resting-state in both sexes with position emission tomography. Statistical test of age effect on cerebral glucose metabolism was performed using the statistical parametric mapping software with a voxel-by-voxel approach ( family wise error corrected, -voxel threshold). The subjects consisted of 108 females (mean S.D. = 4510 years) and 126 males (mean S.D. = 4911 years). We showed here that brain activity in the frontal and temporal lobes in both sexes decreased significantly with normal aging. The glucose metabolism in the caudate bilaterally showed a negative correlation with age in males, but not in females. Few regions in males were shown with an increased glucose metabolism with age. Although the mechanisms of brain aging are still unknown, a map of brain areas susceptible to age was described in this report.

Comparative proteomic analysis of brains of naturally aging mice

We used comparative proteomic techniques to identify aging-related brain proteins in normal mice from neonate to old age. By 2-dimensional electrophoresis (2-DE), matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and peptide mass fingerprint (PMF) analysis, 39 proteins were identified, among which 6 stayed unchanged since 3 months, 6 increased and 27 decreased in various manners during aging. They are mainly involved in processes usually with destructive changes during aging, such as metabolism, transport, signaling, stress response and apoptosis. The 27 proteins' decrease may be responsible for brain aging. In particular, decrease of proteasome alpha subunits 3/6, ubiquitin carboxyl-terminal esterase L3, valosin-containing protein and calreticulin may be responsible for the declination of protein quality control; glutamate dehydrogenase 1, isocitrate dehydrogenase 1 and ubiquinol cytochrome c reductase core protein 2 for the shortage of energy and reducing agent; ubiquitin-conjugating enzyme E2N and heterogeneous nuclear ribonucleoprotein A2/B1 for the increase of DNA damage and transcription detuning; calbindin 1 and amphiphysin for the disturbance of synaptic transport and ion signals. The six proteins' increase may be involved in anti-aging processes. In particular, transketolase, mitochondrial creatine kinase 1 and ribosomal protein L37 may help to enhance energy metabolism; triosephosphate isomerase 1 may help to resist oxidative stress. Moreover, most of these proteins were found for the first time to be involved in the natural senescence of brain, which would provide new clues about the mechanism of brain aging.

Biological Markers of Age-Related Memory Deficits

In humans, age-related memory impairments begin in mid-life and cognitive weakening continues with advancing age. An important aspect of defining memory decline is the distinction between dementia as a result of neurological diseases, such as Alzheimer's disease, and memory loss not specifically associated with disease. Within the population of elderly without dementia, there is considerable variability in memory. This variability is likely to be a result of the interaction of genetic make-up and environment, which influences several processes for cell maintenance and repair including oxidative damage and cholesterol metabolism, leading to disruption of Ca(2+) homeostasis, and ultimately Ca(2+)-dependent processes that underlie memory. In humans, several methods have been employed to distinguish biological markers of aging that may predict cognitive decline. Memory deficits associated with normal aging and Alzheimer's disease have been linked to a decrease in the volume of brain structures, such as the hippocampus and to genetic markers, such as apolipoprotein E. In this regard, examination of CSF for biomarkers of disease can help in differentiating normal aging from Alzheimer's disease. Measures of oxidative stress and cholesterol in plasma correlate with memory deficits; research suggests that treatments that reduce oxidative stress or cholesterol through exercise, diet or the use of antioxidant vitamins may delay cognitive decline.Nevertheless, to date, very little treatment is available to reverse memory deficits in later life. In this regard it is important to identify individuals at risk for memory deficits in order to discriminate different mechanisms of brain aging and develop treatments. Considerable effort is driving research to develop accurate biological markers of brain aging. In turn, these markers will provide information on mechanisms of aging and cognitive decline and point to potential treatments. Accordingly, the effectiveness of treatment needs to be verified for both cognitive changes and biological markers that are specific for age-related memory deficits.

The successful aging of Carl Cotman: from proteins of the synapse, through sprouting, regeneration, and spinal cord injury to the mechanisms of brain aging.

I have a flash-bulb memory of the first time I spoketo Carl Cotman in May, 1970. I had applied to the gradu-ate program of the Department of Psychobiology at UCIrvine (my first choice for graduate school) and had notbeen accepted in the first round. I had resigned myself toattending graduate school elsewhere, but received a callfrom Carl one evening. Carl spoke with his characteris-tic candor, which can be either charming or intimidating(in this case, it was intimidating). He said that my cre-dentials weren’t all that great, but he liked the fact thatI had completed my undergraduate studies at the Uni-versity of Colorado in 3 years while supporting myselfthrough part-time jobs—hence the phone interview. Isweated bullets through the interview, and in the end, heoffered me a position in his lab. His decision to give mea chance highlights two features of his personality—hiswillingness to take risks and his personal ethic for hardwork. I don’t think that he had too many occasions toregret his decision, although he probably had some sec-ond thoughts during the early part of my graduate career.I joined Carl’s lab in the fall of 1970 at the start ofCarl’s third year at UCI. By that time, four other studentswere in the lab, included Gary Banker, William (Chip)Levy, Dee Ann Matthews, and Lynn Churchill. The cal-dron of Carl’s lab and the wonderfully intense graduateprogram in the department forged friendships and fos-tered collaborations that have lasted a lifetime. In fact,the University of Virginia later became an outpost ofCarl’s former trainees when I recruited Chip Levy to theDepartment of Neurosurgery and Gary Banker to thenewly established Department of Neuroscience.When I joined Carl’s lab, the main focus of researchwas on the chemistry of the synaptic junction. EachMonday morning started with the collection of rat brains(40 or so) for subcellular fractionation experiments.Everyone participated in this Monday morning “brainsand donuts” collection process. This was really nuts andbolts neurochemistry and led to fundamental, indeedlandmark, discoveries about the structure and proteincomposition of the synaptic junctional complex (1,2).The subcellular fractionation techniques he developed forisolating postsynaptic densities (psds) are still in usetoday, and the psd, which he identified as a definableand isolatable structure, has come to be recognized asa highly organized collection of interrelated signalingmolecules (3).At about the time that I joined the lab, Carl wastrying different approaches to begin to address broaderquestions of synaptic function, especially synaptic plas-ticity. It is remarkable how many important scientificthreads can be traced from his work during that period.My first project in the lab was to try to determinewhether synaptic activation altered protein synthesis inpostsynaptic cells (what we would now call synapticregulation of gene expression). Carl’s idea was to usethe abdominal ganglion of aplysia as a model for stud-ies of synaptic biochemistry. The experiment was toactivate connectives that contained nerves that synapsedon the large R60 neuron in the ganglion in the presenceof labeled amino acids, then dissect out the large R60neuron and assess incorporation into protein usingmicrobiochemical techniques. At that time, we collectedthe experimental animals ourselves in outings to the tidepools off Crystal Cove near Irvine. Fortunately, Carl didnot go on these outings and did not seem to be awareof the tide tables that limited collection times. Thus thecollection party (the graduate students in the lab)planned the day so as to collect the necessary specimens

Emotional state and one-trial learning in OXYS rats with hereditarily elevated production of oxygen radicals.

Comparative analysis of unconditioned and conditioned behavior of Wistar and prematurely aging OXYS rats revealed that the latter have significantly reduced locomotor and exploratory activities, increased anxiety in the elevated plus-maze test, spatial disorientation, and abnormal associative learning. OXYS rats can be used as a biological model for studying molecular, neurobiological, and neurochemical mechanisms of brain aging.

Aging and Alzheimer's disease: Protease inhibitors in cerebrospinal fluid

Recent advances suggested that proteases and their inhibitors could be implicated in the genesis and/or maturation of insoluble deposits associated with Alzheimer's disease (AD). This study was designed to measure the level of α1-antichymotrypsin (ACT) and α1-antitrypsin (AT) in cerebrospinal fluid (CSF) of patients with AD and nondemented humans at various ages. Our analysis failed to demonstrate a significant relationship between inhibitor content and disease. However, a positive correlation was observed between age and the ACT level for the normal control group. Such observation suggests a specific association of ACT with the mechanisms of brain aging.