How Old is Our Brain and Why Does it Age?

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (11 November 2021) | Viewed by 16317

Special Issue Editors


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Guest Editor
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany

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Guest Editor
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
Interests: normal and pathological cognitive aging; neuro-cognitive biomarkers of Alzheimer’s disease; neuro-cognitive enhancement; parameterization of visual attention functions

E-Mail Website
Guest Editor
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
Interests: adult neurogenesis; neural stem cells; hippocampal plasticity; learning and memory; aging; development; spreading depolarization

Special Issue Information

Dear Colleagues,

When ageing people are asked what they fear most, they usually mention impaired cognitive abilities. The ageing brain is characterized by functional and structural alterations which are the basis for these age-dependent changes. If ageing research wants to increase the quality of life of old people it needs to develop reliable methods to measure these age-related changes (e.g. neuropsychological tests, structural and functional brain imaging). In addition it will strive to understand what are the main driving processes on a molecular level and how one might interfere with these processes. Mens sana in corpore sano (a healthy brain in a healthy body) said Juvenal: general body processes (immunosenescence, gut-brain interactions, metabolic disorders, to name a few) might have an impact on brain ageing. In addition there are ageing processes specific for the brain or in the brain (e.g. stem cell exhaustion, amitosenescence, protein aggregation). The current collection of papers addresses these topics, concentrating on those aging processes which are not due to specific degenerative disorders, i.e. with aging as the only physiological process, or disorder.

Prof. Dr. Otto Witte
Prof. Dr. Kathrin Finke
Dr. Anja Urbach
Guest Editors

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Published Papers (5 papers)

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Research

16 pages, 4061 KiB  
Article
Brain Macro-Structural Alterations in Aging Rats: A Longitudinal Lifetime Approach
by Sidra Gull, Christian Gaser, Karl-Heinz Herrmann, Anja Urbach, Marcus Boehme, Samia Afzal, Jürgen R. Reichenbach, Otto W. Witte and Silvio Schmidt
Cells 2023, 12(3), 432; https://doi.org/10.3390/cells12030432 - 28 Jan 2023
Cited by 1 | Viewed by 1840
Abstract
Aging is accompanied by macro-structural alterations in the brain that may relate to age-associated cognitive decline. Animal studies could allow us to study this relationship, but so far it remains unclear whether their structural aging patterns correspond to those in humans. Therefore, by [...] Read more.
Aging is accompanied by macro-structural alterations in the brain that may relate to age-associated cognitive decline. Animal studies could allow us to study this relationship, but so far it remains unclear whether their structural aging patterns correspond to those in humans. Therefore, by applying magnetic resonance imaging (MRI) and deformation-based morphometry (DBM), we longitudinally screened the brains of male RccHan:WIST rats for structural changes across their average lifespan. By combining dedicated region of interest (ROI) and voxel-wise approaches, we observed an increase in their global brain volume that was superimposed by divergent local morphologic alterations, with the largest aging effects in early and middle life. We detected a modality-dependent vulnerability to shrinkage across the visual, auditory, and somato-sensory cortical areas, whereas the piriform cortex showed partial resistance. Furthermore, shrinkage emerged in the amygdala, subiculum, and flocculus as well as in frontal, parietal, and motor cortical areas. Strikingly, we noticed the preservation of ectorhinal, entorhinal, retrosplenial, and cingulate cortical regions, which all represent higher-order brain areas and extraordinarily grew with increasing age. We think that the findings of this study will further advance aging research and may contribute to the establishment of interventional approaches to preserve cognitive health in advanced age. Full article
(This article belongs to the Special Issue How Old is Our Brain and Why Does it Age?)
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20 pages, 872 KiB  
Article
Restoring Age-Related Cognitive Decline through Environmental Enrichment: A Transcriptomic Approach
by Silvio Schmidt, Madlen Haase, Lena Best, Marco Groth, Julia Lindner, Otto W. Witte, Christoph Kaleta and Christiane Frahm
Cells 2022, 11(23), 3864; https://doi.org/10.3390/cells11233864 - 30 Nov 2022
Cited by 2 | Viewed by 1726
Abstract
Cognitive decline is one of the greatest health threats of old age and the maintenance of optimal brain function across a lifespan remains a big challenge. The hippocampus is considered particularly vulnerable but there is cross-species consensus that its functional integrity benefits from [...] Read more.
Cognitive decline is one of the greatest health threats of old age and the maintenance of optimal brain function across a lifespan remains a big challenge. The hippocampus is considered particularly vulnerable but there is cross-species consensus that its functional integrity benefits from the early and continuous exercise of demanding physical, social and mental activities, also referred to as environmental enrichment (EE). Here, we investigated the extent to which late-onset EE can improve the already-impaired cognitive abilities of lifelong deprived C57BL/6 mice and how it affects gene expression in the hippocampus. To this end, 5- and 24-month-old mice housed in standard cages (5mSC and 24mSC) and 24-month-old mice exposed to EE in the last 2 months of their life (24mEE) were subjected to a Barnes maze task followed by next-generation RNA sequencing of the hippocampal tissue. Our analyses showed that late-onset EE was able to restore deficits in spatial learning and short-term memory in 24-month-old mice. These positive cognitive effects were reflected by specific changes in the hippocampal transcriptome, where late-onset EE affected transcription much more than age (24mSC vs. 24mEE: 1311 DEGs, 24mSC vs. 5mSC: 860 DEGs). Remarkably, a small intersection of 72 age-related DEGs was counter-regulated by late-onset EE. Of these, Bcl3, Cttnbp2, Diexf, Esr2, Grb10, Il4ra, Inhba, Rras2, Rps6ka1 and Socs3 appear to be particularly relevant as key regulators involved in dendritic spine plasticity and in age-relevant molecular signaling cascades mediating senescence, insulin resistance, apoptosis and tissue regeneration. In summary, our observations suggest that the brains of aged mice in standard cage housing preserve a considerable degree of plasticity. Switching them to EE proved to be a promising and non-pharmacological intervention against cognitive decline. Full article
(This article belongs to the Special Issue How Old is Our Brain and Why Does it Age?)
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14 pages, 12581 KiB  
Article
Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation
by Diana M. Morales-Prieto, José M. Murrieta-Coxca, Milan Stojiljkovic, Celia Diezel, Priska E. Streicher, Julian A. Henao-Restrepo, Franziska Röstel, Julia Lindner, Otto W. Witte, Sebastian Weis, Christian Schmeer and Manja Marz
Cells 2022, 11(4), 625; https://doi.org/10.3390/cells11040625 - 11 Feb 2022
Cited by 16 | Viewed by 3518
Abstract
Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes [...] Read more.
Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation. Full article
(This article belongs to the Special Issue How Old is Our Brain and Why Does it Age?)
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19 pages, 6351 KiB  
Article
Voluntary Wheel Running in Old C57BL/6 Mice Reduces Age-Related Inflammation in the Colon but Not in the Brain
by Marie-Luise Ederer, Madlen Günther, Lena Best, Julia Lindner, Christoph Kaleta, Otto W. Witte, Rowena Simon and Christiane Frahm
Cells 2022, 11(3), 566; https://doi.org/10.3390/cells11030566 - 06 Feb 2022
Cited by 4 | Viewed by 2905
Abstract
Inflammation is considered a possible cause of cognitive decline during aging. This study investigates the influence of physical activity and social isolation in old mice on their cognitive functions and inflammation. The Barnes maze task was performed to assess spatial learning and memory [...] Read more.
Inflammation is considered a possible cause of cognitive decline during aging. This study investigates the influence of physical activity and social isolation in old mice on their cognitive functions and inflammation. The Barnes maze task was performed to assess spatial learning and memory in 3, 9, 15, 24, and 28 months old male C57BL/6 mice as well as following voluntary wheel running (VWR) and social isolation (SI) in 20 months old mice. Inflammatory gene expression was analyzed in hippocampal and colonic samples by qPCR. Cognitive decline occurs in mice between 15 and 24 months of age. VWR improved cognitive functions while SI had negative effects. Expression of inflammatory markers changed during aging in the hippocampus (Il1a/Il6/S100b/Iba1/Adgre1/Cd68/Itgam) and colon (Tnf/Il6/Il1ra/P2rx7). VWR attenuates inflammaging specifically in the colon (Ifng/Il10/Ccl2/S100b/Iba1), while SI regulates intestinal Il1b and Gfap. Inflammatory markers in the hippocampus were not altered following VWR and SI. The main finding of our study is that both the hippocampus and colon exhibit an increase in inflammatory markers during aging, and that voluntary wheel running in old age exclusively attenuates intestinal inflammation. Based on the existence of the gut-brain axis, our results extend therapeutic approaches preserving cognitive functions in the elderly to the colon. Full article
(This article belongs to the Special Issue How Old is Our Brain and Why Does it Age?)
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29 pages, 23146 KiB  
Article
Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer’s Disease Neuroimaging Initiative
by Emanuele R. G. Plini, Erik O’Hanlon, Rory Boyle, Francesca Sibilia, Gaia Rikhye, Joanne Kenney, Robert Whelan, Michael C. Melnychuk, Ian H. Robertson and Paul M. Dockree
Cells 2021, 10(7), 1829; https://doi.org/10.3390/cells10071829 - 20 Jul 2021
Cited by 19 | Viewed by 5251
Abstract
The noradrenergic theory of Cognitive Reserve (Robertson, 2013–2014) postulates that the upregulation of the locus coeruleus—noradrenergic system (LC–NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing [...] Read more.
The noradrenergic theory of Cognitive Reserve (Robertson, 2013–2014) postulates that the upregulation of the locus coeruleus—noradrenergic system (LC–NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer’s disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD—an objective measure, which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease. Full article
(This article belongs to the Special Issue How Old is Our Brain and Why Does it Age?)
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