RESUMO
Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.
Assuntos
Encéfalo , Indígenas Sul-Americanos , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Idoso de 80 Anos ou mais , Bolívia/epidemiologia , Feminino , Estudos Transversais , Tamanho do Órgão , Tomografia Computadorizada por Raios X , Envelhecimento/fisiologia , Estilo de Vida , AtrofiaRESUMO
Cerebral small vessel disease is a major contributor to both brain aging and cognitive decline. This study aimed to determine the prevalence of cerebral small vessel disease in a Colombian population over 40 years of age who attended a Radiology and Diagnostic Imaging service for brain MRI between October 2018 and March 2019. This was an observational, cross-sectional and analytical study of 710 adult patients over 40 years of age who attended the Radiology and Diagnostic Imaging service for a brain MRI. The analysed data were obtained from an anonymized database of the service. We studied 710 MRI scans of patients aged between 40 and 104 years. The most frequent risk factor was hypertension (36.2%). Brain abnormalities associated with cerebral small vessel disease, such as white matter hyperintensities, were seen in 56.20% of the population, and brain atrophy was observed in 12.96%. Brain disease prevalence increased with age (23.18% for those aged 55 years, 54.49% for those aged 55-64 years, 69.8% for those aged 65-74 years and 90.53% for those older than 75 years). The prevalence of cerebral small vessel disease in our population was similar to that reported in the world literature, as were the prevalence of the evaluated cardiovascular risk factors. Additionally, we identified an association between hypertension and advanced age with cerebral small vessel disease, with white matter hyperintensities being the most characteristic finding.
RESUMO
The theory that aging is driven by the damage produced by reactive oxygen species (ROS) derived from oxidative metabolism dominated geroscience studies during the second half of the 20th century. However, increasing evidence that ROS also plays a key role in the physiological regulation of numerous processes through the reversible oxidation of cysteine residues in proteins, has challenged this notion. Currently, the scope of redox signaling has reached proteomic dimensions through mass spectrometry techniques. Here, we perform a comprehensive bioinformatics analysis of cysteine oxidation changes during mouse brain aging, using the quantitative data provided in the Oximouse dataset. Interestingly, our unbiased analysis identified hundreds of putative cysteine redox switches covering several pathways previously associated with aging. These include the ubiquitin-proteasome pathway and one-carbon metabolism (folate cycle, methionine cycle, transsulfuration and polyamine pathways). Surprisingly, cysteine oxidation changes are enriched in synaptic proteins in a highly asymmetric distribution: while postsynaptic proteins tend to increase cysteine oxidation with age, the opposite occurs for presynaptic proteins. Additionally, cysteine oxidation changes during aging are associated with proteins involved in the regulation of the mitochondrial transition pore opening and synaptic calcium homeostasis. Our analysis reinforces the concept that brain aging is associated with selective changes in the oxidation state of key proteins, rather than an overall trend toward increased oxidation. Also, we provide a prioritized list of specific cysteine residues with putative impact in aging processes for future experimental validation.
Assuntos
Disfunção Cognitiva , Estresse Oxidativo , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Cisteína/metabolismo , Proteômica/métodos , Envelhecimento/metabolismo , Proteínas/metabolismo , Oxirredução , Encéfalo/metabolismoRESUMO
Dysregulated central-energy metabolism is a hallmark of brain aging. Supplying enough energy for neurotransmission relies on the neuron-astrocyte metabolic network. To identify genes contributing to age-associated brain functional decline, we formulated an approach to analyze the metabolic network by integrating flux, network structure and transcriptomic databases of neurotransmission and aging. Our findings support that during brain aging: (1) The astrocyte undergoes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, decreasing lactate supply to the neuron, while the neuron suffers intrinsic energetic deficit by downregulation of Krebs cycle genes, including mdh1 and mdh2 (Malate-Aspartate Shuttle); (2) Branched-chain amino acid degradation genes were downregulated, identifying dld as a central regulator; (3) Ketone body synthesis increases in the neuron, while the astrocyte increases their utilization, in line with neuronal energy deficit in favor of astrocytes. We identified candidates for preclinical studies targeting energy metabolism to prevent age-associated cognitive decline.
Assuntos
Astrócitos , Metabolismo Energético , Astrócitos/metabolismo , Metabolismo Energético/genética , Transmissão Sináptica , Perfilação da Expressão Gênica , Glucose/metabolismoRESUMO
A decrease in brain volume (ie, brain atrophy) is a marker of cognitive health in older adults. Insufficient weekly accumulation of moderate and vigorous physical activity (MVPA) has been associated with lower brain volume. As this association has been established for a small number of brain areas and structures and atrophy rates seem to be nonuniform between them, more comprehensive analyses are warranted. We compared the volume of 71 brain areas and structures in 45 older adults who met and did not meet objectively measured MVPA recommendations. In addition, we used multiple regression models to determine whether cardiorespiratory fitness (VO2PEAK), MVPA, and health-related risk factors could affect the atrophy of brain areas and structures. An accelerometer (GT9-X ActiGraph) was worn for 7 days. Participants were then classified into 2 groups: <150 minutes MVPA (<150'MVPA; n = 20) and ≥150 minutes MVPA (≥150'MVPA; n = 25) per week. Older adults who accumulated ≥150'MVPA per week had significantly higher absolute and relative (% of intracranial volume) volumes of 39 and 9 brain areas and structures, respectively, than those who accumulated <150'MVPA per week. Higher VO2PEAK seems to be a key predictor of the atrophy of brain areas and structures. In conclusion, meeting weekly physical activity recommendations seems to have a widespread effect on preserving the volume of more than 30 brain areas and structures in older adults. VO2PEAK seems to be the most frequent and important predictor of brain volume preservation.
Assuntos
Encéfalo , Exercício Físico , Humanos , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , Atrofia , AcelerometriaRESUMO
Brain atrophy is correlated with risk of cognitive impairment, functional decline, and dementia. Despite a high infectious disease burden, Tsimane forager-horticulturists of Bolivia have the lowest prevalence of coronary atherosclerosis of any studied population and present few cardiovascular disease (CVD) risk factors despite a high burden of infections and therefore inflammation. This study (a) examines the statistical association between brain volume (BV) and age for Tsimane and (b) compares this association to that of 3 industrialized populations in the United States and Europe. This cohort-based panel study enrolled 746 participants aged 40-94 (396 males), from whom computed tomography (CT) head scans were acquired. BV and intracranial volume (ICV) were calculated from automatic head CT segmentations. The linear regression coefficient estimate ß^T of the Tsimane (T), describing the relationship between age (predictor) and BV (response, as a percentage of ICV), was calculated for the pooled sample (including both sexes) and for each sex. ß^T was compared to the corresponding regression coefficient estimate ß^R of samples from the industrialized reference (R) countries. For all comparisons, the null hypothesis ßâT = ßâR was rejected both for the combined samples of males and females, as well as separately for each sex. Our results indicate that the Tsimane exhibit a significantly slower decrease in BV with age than populations in the United States and Europe. Such reduced rates of BV decrease, together with a subsistence lifestyle and low CVD risk, may protect brain health despite considerable chronic inflammation related to infectious burden.
Assuntos
Encéfalo , Doença da Artéria Coronariana , Inflamação/etnologia , Estilo de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Bolívia/epidemiologia , Encéfalo/diagnóstico por imagem , Doença da Artéria Coronariana/etnologia , Feminino , Humanos , Povos Indígenas , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , América do Sul/epidemiologiaRESUMO
Synaptic aging has been associated with neuronal circuit dysfunction and cognitive decline. Reduced mitochondrial function may be an early event that compromises synaptic integrity and neurotransmission in vulnerable brain regions during physiological and pathological aging. Thus, we aimed to measure mitochondrial function in synapses from three brain regions at two different ages in the 3xTg-AD mouse model and in wild mice. We found that aging is the main factor associated with the decline in synaptic mitochondrial function, particularly in synapses isolated from the cerebellum. Accumulation of toxic compounds, such as tau and Aß, that occurred in the 3xTg-AD mouse model seemed to participate in the worsening of this decline in the hippocampus. The changes in synaptic bioenergetics were also associated with increased activation of the mitochondrial fission protein Drp1. These results suggest the presence of altered mechanisms of synaptic mitochondrial dynamics and their quality control during aging and in the 3xTg-AD mouse model; they also point to bioenergetic restoration as a useful therapeutic strategy to preserve synaptic function during aging and at the early stages of Alzheimer's disease (AD).
Assuntos
Envelhecimento/genética , Disfunção Cognitiva/genética , Dinaminas/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Envelhecimento/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Dinaminas/metabolismo , Feminino , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Especificidade de Órgãos , Sinapses/metabolismo , Sinapses/patologia , Sinaptossomos/metabolismo , Sinaptossomos/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
El ejercicio ha demostrado efectividad para promover la plasticidad cerebral en los procesos de envejecimiento neural. Esta revisión narrativa de literatura tiene como objetivo analizar el efecto neural del ejercicio para promover la plasticidad cerebral en el envejecimiento. Los resultados incluyeron publicaciones que mencionan los efectos de la plasticidad cerebral mediada por el ejercicio empleando protocolos de ejercicio con duración, intensidad y frecuencia clínicamente significativa. La revisión documental se organizó en tres apartados: a) envejecimiento neural y procesos fisiológicos interrelacionados, b) plasticidad cerebral mediada por el ejercicio, c) ejercicio para promover el envejecimiento neural saludable. Se pudo concluir que el fisioterapeuta, aplicando protocolos de ejercicio, puede promover cambios positivos en la función cerebral lo cual se traducen en la mejoría del desempeño físico y funcional de los adultos mayores..(AU)
Exercise has shown effectiveness in promoting brain plasticity in neural aging processes.This narrative review of literature aims to analyze the neural effect of exercise to promote brain plasticity in aging. The results included publications that mention the effects of brain plasticity mediated by exercise, using exercise protocols with clinically significant duration, intensity and frequency. Through the documentary review three sections were determined: Neural Aging: Interrelated physiological processes; Exercisemediated brain plasticity; Exercise to promote healthy neural aging. It was concluded that the physiotherapist, applying exercise protocols, can promote positive changes in brain function, which translates into an improvement in the physical and functional performance of older adults..(AU)
Assuntos
Senescência Celular , FisioterapeutasRESUMO
There is a growing interest in the potential of adult stem cells for implementing regenerative medicine in the brain. We assessed the effect of intracerebroventricular (icv) administration of human umbilical cord perivascular cells (HUCPVCs) on spatial memory of senile (27 mo) female rats, using intact senile counterparts as controls. Approximately one third of the animals were injected in the lateral ventricles with a suspension containing 4.8 X 105 HUCPVC in 8 µl per side. The other third received 4.8 X 105 transgenic HUCPVC overexpressing Insulin-like growth factor-1 (IGF-1) and the last third of the rats received no treatment. Spatial memory performance was evaluated using a modified version of the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent (permanence) by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. Fluorescence microscopy revealed the prescence of Dil-labeled HUCPVC in coronal sections of treated brains. The HUCPVC were located in close contact with the ependymal cells with only a few labeled cells migrating into the brain parenchyma. After treatment with naïve or IGF-1 transgenic HUCPVC, permanence in GS1 and GS3 increased significantly whereas there were no changes in the intact animals. We conclude that HUCPVC injected icv are effective to improve some components of spatial memory in senile rats. The ready accessibility of HUCPVC constitutes a significant incentive to continue the exploration of their therapeutic potential on neurodegenerative diseases.
Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Transplante de Células , Transtornos da Memória/terapia , Memória Espacial , Cordão Umbilical , Animais , Feminino , Humanos , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine in the brain as they have shown neurogenic and immunomodulatory activities. We assessed the effect of intracerebroventricular (icv) administration of human bone marrow-derived MSCs (hBM-MSCs) on spatial memory and hippocampal morphology of senile (27 months) female rats, using 3-months-old counterparts as young controls. Half of the animals were injected in the lateral ventricles (LV) with a suspension containing 5 × 105hBM-MSCs in 8 µl per side. The other half received no treatment (senile controls). Spatial memory performance was assessed with a modified version of the Barnes maze test. We employed one probe trial, one day after training in order to evaluate learning ability as well as spatial memory retention. Neuroblast (DCX) and microglial (Iba-1 immunoreactive) markers were also immunohistochemically quantitated in the animals by means of an unbiased stereological approach. In addition, hippocampal presynaptic protein expression was assessed by immunoblotting analysis. After treatment, the senile MSC-treated group showed a significant improvement in spatial memory accuracy and extended permanence in a one- and 3-hole goal sectors as compared with senile controls. The MSC treatment increased the number of neuroblasts in the hippocampal dentate gyrus, reduced the number of reactive microglial cells, and restored presynaptic protein levels as compared to senile controls. We conclude that icv injected hBM-MSCs are effective in improving spatial memory in senile rats and that the strategy improves some functional and morphologic brain features typically altered in aging rats.
Assuntos
Envelhecimento/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/métodos , Memória Espacial/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Proteína Duplacortina , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Microglia/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismoRESUMO
Aging is associated with a progressive increase in the incidence of neurodegenerative diseases, with Alzheimer's (AD) and Parkinson's (PD) disease being the most conspicuous examples. Within this context, the absence of efficacious therapies for most age-related brain pathologies has increased the interest in regenerative medicine. In particular, cell reprogramming technologies have ushered in the era of personalized therapies that not only show a significant potential for the treatment of neurodegenerative diseases but also promise to make biological rejuvenation feasible. We will first review recent evidence supporting the emerging view that aging is a reversible epigenetic phenomenon. Next, we will describe novel reprogramming approaches that overcome some of the intrinsic limitations of conventional induced-pluripotent-stem-cell technology. One of the alternative approaches, lineage reprogramming, consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage-specific transcription factors (TF). Another strategy, termed pluripotency factor-mediated direct reprogramming, uses universal TF to generate epigenetically unstable intermediates able to differentiate into somatic cell types in response to specific differentiation factors. In the third part we will review studies showing the potential relevance of the above approaches for the treatment of AD and PD.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Reprogramação Celular/fisiologia , Medicina Regenerativa/métodos , Rejuvenescimento/fisiologia , Envelhecimento/patologia , Animais , Encéfalo/patologia , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Pluripotentes Induzidas/transplante , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Medicina Regenerativa/tendências , Fatores de Transcrição/metabolismoRESUMO
In rats, learning and memory performance decline during normal aging, which is paralleled by a severe reduction of the levels of neurogenesis in the hippocampal dentate gyrus (DG). A promising therapeutic strategy to restore neurogenesis in the hippocampus of old rats and their spatial memory involves the use of insulin-like growth factor-I (IGF-I). The peptide exerts pleiotropic effects in the brain, regulating multiple cellular processes. Thus, 4-week intracerebroventricular (ICV) perfusion of IGF-I significantly restored spatial memory and hippocampal neurogenesis in old male rats. Similar results were achieved by ICV IGF-I gene therapy in aging female rats. Thus, the treatment seemed to increase the number of immature neurons in the DG of 28 mo old rats, which was paralleled by an increase in the accuracy of the animals to remember specific patterns, which is known as pattern separation memory. The DG is thought to be the main hippocampal structure involved in pattern separation memory and there is evidence that the level of neurogenesis in the DG is directly related to pattern separation performance in rodents. Summing up, IGF-I emerges as a promising restorative molecule for increasing hippocampal neurogenesis and memory accuracy in aged individuals and possibly, in neurodegenerative pathologies.
RESUMO
Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer's disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain.
RESUMO
The present study aimed to analyze the morphology of the peripheral nerve, postsynaptic compartment, skeletal muscles and weight-bearing capacity of Wistar rats at specific ages. Twenty rats were divided into groups: 10 months-old (ADULT) and 24 months-old (OLD). After euthanasia, we prepared and analyzed the tibial nerve using transmission electron microscopy and the soleus and plantaris muscles for cytofluorescence and histochemistry. For the comparison of the results between groups we used dependent and independent Student's t-test with level of significance set at p ≤ 0.05. For the tibial nerve, the OLD group presented the following alterations compared to the ADULT group: larger area and diameter of both myelinated fibers and axons, smaller area occupied by myelinated and unmyelinated axons, lower numerical density of myelinated fibers, and fewer myelinated fibers with normal morphology. Both aged soleus and plantaris end-plate showed greater total perimeter, stained perimeter, total area and stained area compared to ADULT group (p < 0.05). Yet, aged soleus end-plate presented greater dispersion than ADULT samples (p < 0.05). For the morphology of soleus and plantaris muscles, density of the interstitial volume was greater in the OLD group (p < 0.05). No statistical difference was found between groups in the weight-bearing tests. The results of the present study demonstrated that the aging process induces changes in the peripheral nerve and postsynaptic compartment without any change in skeletal muscles and ability to carry load in Wistar rats.
RESUMO
The increase in clinical trials assessing the efficacy of cell therapy for structural and functional regeneration of the nervous system in diseases related to the aging brain is well known. However, the results are inconclusive as to the best cell type to be used or the best methodology for the homing of these stem cells. This systematic review analyzed published data on SPION (superparamagnetic iron oxide nanoparticle)-labeled stem cells as a therapy for brain diseases, such as ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and dementia. This review highlights the therapeutic role of stem cells in reversing the aging process and the pathophysiology of brain aging, as well as emphasizing nanotechnology as an important tool to monitor stem cell migration in affected regions of the brain.