scholarly journals Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice

2020 ◽  
Vol 245 (17) ◽  
pp. 1584-1593 ◽  
Author(s):  
Pichet Termsarasab ◽  
Thananan Thammongkolchai ◽  
Ju Gao ◽  
Luwen Wang ◽  
Jingjing Liang ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Neuronal Loss ◽  
Critical Factor ◽  
Brain Regions ◽  
Normal Aging ◽  
Age Related ◽  
Wide Range ◽  
Cytoplasmic Accumulation ◽  
Young Mice

Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n =  3 for 26- or 36-month-old) compared to young ( n =  3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

scholarly journals The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 124
Author(s):  
Alexandra Moreno-García ◽  
Alejandra Kun ◽  
Miguel Calero ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.

scholarly journals The Neuromelanin Paradox and its Dual Role in Oxidative Stress and Neurodegeneration

2020 ◽  
Author(s):  
Alexandra Moreno García ◽  
Alejandra Kun ◽  
Miguel Calero Lara ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

scholarly journals Activity in the brain’s valuation and mentalizing networks is associated with propagation of online recommendations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elisa C. Baek ◽  
Matthew Brook O’Donnell ◽  
Christin Scholz ◽  
Rui Pei ◽  
Javier O. Garcia ◽  
...  
Keyword(s):  
Social Media ◽  
Word Of Mouth ◽  
Mental States ◽  
Brain Regions ◽  
Prior Work ◽  
Opinion Change ◽  
Wide Range ◽  
The Mind ◽  
Mentalizing System

AbstractWord of mouth recommendations influence a wide range of choices and behaviors. What takes place in the mind of recommendation receivers that determines whether they will be successfully influenced? Prior work suggests that brain systems implicated in assessing the value of stimuli (i.e., subjective valuation) and understanding others’ mental states (i.e., mentalizing) play key roles. The current study used neuroimaging and natural language classifiers to extend these findings in a naturalistic context and tested the extent to which the two systems work together or independently in responding to social influence. First, we show that in response to text-based social media recommendations, activity in both the brain’s valuation system and mentalizing system was associated with greater likelihood of opinion change. Second, participants were more likely to update their opinions in response to negative, compared to positive, recommendations, with activity in the mentalizing system scaling with the negativity of the recommendations. Third, decreased functional connectivity between valuation and mentalizing systems was associated with opinion change. Results highlight the role of brain regions involved in mentalizing and positive valuation in recommendation propagation, and further show that mentalizing may be particularly key in processing negative recommendations, whereas the valuation system is relevant in evaluating both positive and negative recommendations.

PHYSICAL ACTIVITY AS HEALTHY INTERVENTION AGAINST SEVERE OXIDATIVE STRESS IN ELDERLY POPULATION

2013 ◽  
pp. 1-9
Author(s):  
C. TOMAS-ZAPICO ◽  
E. IGLESIAS-GUTIERREZ ◽  
B. FERNANDEZ-GARCIA ◽  
D. DE GONZALO-CALVO
Keyword(s):  
Oxidative Stress ◽  
Physical Activity ◽  
Elderly Population ◽  
Physiological Basis ◽  
Related Disease ◽  
Age Related ◽  
Wide Range ◽  
Health Related ◽  
Relevant Risk Factor

Severe oxidative stress is a relevant risk factor for major deleterious health-related events in olderpeople and is thought to be an important contributor to age-related disease. Literature has suggested oxidativestress as a therapeutic target for mitigating the biological decline and attenuating the occurrence of adverseclinical events in aged individuals. However, definitive treatments are not known. Regular and moderate physicalactivity has been proposed as possible intervention for slowing age-related decline. This healthy strategy presentsa wide range of beneficial aspects for elderly, from the reduction of morbidity, disability, frailty and mortalityrates to treatment of many age-related disorders. Importantly, the global benefits on health are not shared by anyother strategies. Nevertheless, the physiological basis by which exercise produces its benefits to the organism isnot fully understood. This review summarizes the evidence for the role of physical activity as potential healthyintervention for mitigating the negative aspects of aging through the modulation of the oxidative mechanisms.

Introduction

2020 ◽  
pp. 1-6
Author(s):  
Alisoun Milne
Keyword(s):  
Mental Health ◽  
Mental Illness ◽  
Health Outcomes ◽  
Later Life ◽  
Social Categories ◽  
Age Related ◽  
Wide Range ◽  
Life Itself ◽  
Life Course Analysis

Despite much emphasis on mental illness in later life, limited work has focused on mental health. This book aims to address this deficit by exploring, and explaining, mental health outcomes in later life through the lens of critical social gerontology and via the conduit of life course analysis. It adopts an approach underpinned by a commitment to understanding, and making visible, the role of lifecourse, and age related inequalities in creating or amplifying risks to mental health, as well as exploring those issues that afford protection. It aims to offer a critical review of existing discourse and disrupt the ‘taken for granted’ paradigm, including in the dementia arena. This approach not only recognises that mental health in later life is a complex multi-dimensional issue that cuts across time, cohort, social categories and individual experiences but that it is affected by a wide range of lifecourse and age related issues. It also encourages the development of understanding that adopts a wide lens of analysis and of policy and service related responses that reduce risks to mental health during the lifecourse and in later life itself. Further, it engages with the potential to learn from older people’s perspectives and lives.

scholarly journals Microglia in Prion Diseases: Angels or Demons?

2020 ◽  
Vol 21 (20) ◽  
pp. 7765
Author(s):  
Caterina Peggion ◽  
Roberto Stella ◽  
Paolo Lorenzon ◽  
Enzo Spisni ◽  
Alessandro Bertoli ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Cellular Prion Protein ◽  
Normal Brain ◽  
Primary Microglia ◽  
Neuroinflammatory Response ◽  
Brain Physiology ◽  
The Central Nervous System

Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the cellular prion protein (PrPC) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or—conversely—a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrPC in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrPC in cytokine secretion by activated primary microglia.

scholarly journals Epigenetics of aging and disease: a brief overview

2019 ◽  
Author(s):  
Christina Pagiatakis ◽  
Elettra Musolino ◽  
Rosalba Gornati ◽  
Giovanni Bernardini ◽  
Roberto Papait
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Disorders ◽  
Potential Role ◽  
Molecular Level ◽  
Physiological Function ◽  
Regulate Gene Expression ◽  
Age Related ◽  
Genetic And Environmental Factors ◽  
Different Tissues

AbstractAging is an important risk factor for several human diseases such as cancer, cardiovascular disease and neurodegenerative disorders, resulting from a combination of genetic and environmental factors (e.g., diet, smoking, obesity and stress), which, at molecular level, cause changes in gene expression underlying the decline of physiological function. Epigenetics, which include mechanisms regulating gene expression independently of changes to DNA sequence, regulate gene expression by modulating the structure of chromatin or by regulating the binding of transcriptional machinery to DNA. Several studies showed that an impairment of epigenetic mechanisms promotes alteration of gene expression underlying several aging-related diseases. Alteration of these mechanisms is also linked with changes of gene expression that occurs during aging processes of different tissues. In this review, we will outline the potential role of epigenetics in the onset of two age-related pathologies, cancer and cardiovascular diseases.

scholarly journals Sirtuins, Bioageing, and Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
D. McGuinness ◽  
D. H. McGuinness ◽  
J. A. McCaul ◽  
P. G. Shiels
Keyword(s):  
Cell Cycle ◽  
Genomic Stability ◽  
Degenerative Diseases ◽  
Critical Junctures ◽  
Age Related ◽  
Wide Range ◽  
Telomere Function ◽  
And Function ◽  
High Degree

The Sirtuins are a family of orthologues of yeast Sir2 found in a wide range of organisms from bacteria to man. They display a high degree of conservation between species, in both sequence and function, indicative of their key biochemical roles. Sirtuins are heavily implicated in cell cycle, cell division, transcription regulation, and metabolism, which places the various family members at critical junctures in cellular metabolism. Typically, Sirtuins have been implicated in the preservation of genomic stability and in the prolongation of lifespan though many of their target interactions remain unknown. Sirtuins play key roles in tumourigenesis, as some have tumour-suppressor functions and others influence tumours through their control of the metabolic state of the cell. Their links to ageing have also highlighted involvement in various age-related and degenerative diseases. Here, we discuss the current understanding of the role of Sirtuins in age-related diseases while taking a closer look at their roles and functions in maintaining genomic stability and their influence on telomerase and telomere function.

Vitamins and Cognition: A Nutrigenomics Perspective

2020 ◽  
Vol 16 ◽  
Author(s):  
Ayyappan Anitha ◽  
Vijitha Viswambharan ◽  
Ismail Thanseem ◽  
Mary Iype ◽  
Rahna Parakkal ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Cognitive Functions ◽  
Cognitive Impairments ◽  
Cognitive Disorders ◽  
Therapeutic Strategies ◽  
Epigenetic Factors ◽  
Future Studies ◽  
Age Related ◽  
Novel Approaches

: The rise in the prevalence of neurodegenerative and neurodevelopmental cognitive disorders combined with a lack of efficient therapeutic strategies has necessitated the need to develop alternate approaches. Dietary supplements are now being considered as a complementary and alternative medicine for cognitive impairments. Considerable evidence suggests the role of vitamins in modulating the genetic and epigenetic factors implicated in neuropsychiatric, neurodevelopmental and neurodegenerative disorders. In this review, we provide an overview on the implications of nutrigenomics with reference to vitamins that are suggested to boost cognitive functions (nootropic vitamins). Several vitamins have been found to possess antioxidant and anti-inflammatory properties which make them potential candidates in preventing or delaying age-related neurodegeneration and cognitive decline. Well-designed longitudinal studies are essential to examine the association between vitamins and cognitive functions. Future studies linking nutrition with advances in neuroscience, genomics and epigenomics would provide novel approaches to the management of cognitive disorders.

Abstract 1485: Ischemic Postconditioning’s Protection Is Lost In Aged And Stat3-deficient Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kerstin Boengler ◽  
Astrid Buechert ◽  
Yvonne Heinen ◽  
Denise Hilfiker-Kleiner ◽  
Gerd Heusch ◽  
...  
Keyword(s):  
List Type ◽  
Area At Risk ◽  
Lower Efficiency ◽  
Age Related ◽  
Transcription 3 ◽  
Phosphorylated Stat3 ◽  
Deficient Mice ◽  
Mediated Reduction ◽  
Young Mice

The cardioprotection by ischemic preconditioning is lost in aged wildtype (WT) mice and in STAT3-deficient mice (signal transducer and activator of transcription 3). The aim of the present study was to analyze whether or not ischemic postconditioning (iPo) is effective in aged WT mice hearts, and whether or not it is dependent on the presence of STAT3. Young (3 months) and aged (>13 months) C57Bl6/J female mice underwent 30 min of ischemia and 2 h reperfusion (I/R) without or with iPo (3 cycles of 10 s ischemia and 10 s reperfusion (iPo3) or 5 cycles of 5 s ischemia and 5 s reperfusion (iPo5) at the beginning of reperfusion). In young mice hearts, iPo3 and iPo5 reduced the infarct size (IS, % of the area at risk) to a similar extent from 65.8±2.8 (n=11) to 50.7±2.8 (3×10, n=10, p<0.05) and to 49.8±3.8 (5×5, n=10, p<0.05). In contrast, in aged WT hearts IS was similar following I/R and iPo3 (60.1±3.2, n=10 vs. 66.4±3.0, n=7), but was reduced by iPo5 (46.5±4.2, n=7, p<0.05). Western blot analysis on right ventricular protein extracts from aged WT mice hearts indicated a reduction of phosphorylated STAT3 (Ser727) to 72.0±7.6% (n=19, p<0.05) and of total STAT3 to 72.1±5.5% (n=27, p<0.05) of that in young WT mice, which was set as 100% (n=18). In young mice (3 months) with a cardiomyocyte-restricted deletion of STAT3 (STAT3-KO) only iPo3 failed to reduce IS compared to I/R (62.2±3.5, n=5 vs. 64.4±3.1, n=8), whereas the stronger stimulus iPo5 once again significantly reduced IS (55.0±2.8, n=9, p<0.05). In conclusion, lower efficiency of iPO protection against I/R in aged mice hearts was associated with a reduced cardiac expression of STAT3. In line with a crucial role of STAT3 for iPO protection in I/R, STAT3-KO mice displayed also an attenuated susceptibility for iPO mediated protection in I/R. Thus age mediated reduction of cardiac STAT3 expression may contribute to the age-related reduced efficienty of iPo to protect from I/R injury.

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