Murine models of brain aging and age-related neurodegenerative diseases

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.

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Flavonoid-Rich Ethanol Extract from the Leaves of Diospyros kaki Attenuates D-Galactose-Induced Oxidative Stress and Neuroinflammation-Mediated Brain Aging in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8938207 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Yingjuan Ma ◽

Bin Ma ◽

Yuying Shang ◽

Qingqing Yin ◽

Dejie Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Nuclear Translocation ◽

Brain Aging ◽

Ethanol Extract ◽

Neurological Impairment ◽

Diospyros Kaki ◽

Neuroprotective Effects ◽

Age Related ◽

Y Maze

Aging is a major factor that contributes to neurological impairment and neuropathological changes, such as inflammation, oxidative stress, neuronal apoptosis, and synaptic dysfunction. Flavonoids act as protective antioxidant and anti-inflammatory agents against various age-related neurodegenerative diseases. Here, we investigated the protective effect and mechanisms of the flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FELDK) in the cortex and hippocampus of D-galactose- (gal-) aged mice. Our results showed that FELDK treatment restored memory impairment in mice as determined by the Y-maze and Morris water maze tests. FELDK decreased oxidative stress levels via inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production and elevating antioxidative enzymes. FELDK also alleviated D-gal-induced neuroinflammation via suppressing the expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) and activating microgliosis and astrocytosis, nuclear factor kappa B (NF-κB) nuclear translocation, and downstream inflammatory mediators. Moreover, FELDK inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and C-jun N-terminal kinase (JNK) apoptotic signaling pathways and ameliorated the impairment of synapse-related proteins. Hence, these results indicate that FELDK exerts neuroprotective effects on D-gal-induced brain aging. Thus, FELDK may be a potential therapeutic strategy for preventing and treating age-related neurodegenerative diseases such as Alzheimer’s disease.

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Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

Antioxidants ◽

10.3390/antiox10060824 ◽

2021 ◽

Vol 10 (6) ◽

pp. 824

Author(s):

Andrea Capucciati ◽

Fabio A. Zucca ◽

Enrico Monzani ◽

Luigi Zecca ◽

Luigi Casella ◽

...

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Experimental Models ◽

Test Tube ◽

Age Related ◽

And Function ◽

Endogenous Metabolites ◽

High Degree

Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson’s and Alzheimer’s, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.

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Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.662242 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xin Zhang ◽

Nadine Alshakhshir ◽

Liqin Zhao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Redox Homeostasis ◽

Critical Role ◽

Glycolytic Flux ◽

Glycolytic Metabolism ◽

Age Related ◽

Brain Resilience

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases

F1000Research ◽

10.12688/f1000research.21599.1 ◽

2020 ◽

Vol 9 ◽

pp. 68 ◽

Cited By ~ 6

Author(s):

Yiwei Wang ◽

Aarti Mishra ◽

Roberta Diaz Brinton

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Aging Process ◽

Brain Aging ◽

Hormone Replacement ◽

Low Grade ◽

Chronological Aging ◽

Age Related ◽

Female Brain

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally connecting genetic risk factors for Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer’s disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

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Associations between sleep apnea and advanced brain aging in a large-scale population study

SLEEP ◽

10.1093/sleep/zsaa204 ◽

2020 ◽

Author(s):

Antoine Weihs ◽

Stefan Frenzel ◽

Katharina Wittfeld ◽

Anne Obst ◽

Beate Stubbe ◽

...

Keyword(s):

Sleep Apnea ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Mediating Effect ◽

Apnea Hypopnea Index ◽

P Value ◽

Subclinical Inflammation ◽

Age Related ◽

Obstructive Sleep ◽

Brain Age

Abstract Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer’s dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea–hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.

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Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging

Biomedicines ◽

10.3390/biomedicines9111635 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1635

Author(s):

Chuan-Chuan Chao ◽

Po-Wen Shen ◽

Tsai-Yu Tzeng ◽

Hsing-Jien Kung ◽

Ting-Fen Tsai ◽

...

Keyword(s):

Human Brain ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Primary Neuronal Culture ◽

In Vitro Aging ◽

Age Related ◽

Immortalized Cell ◽

Aging Models ◽

Human Ipsc

With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models—especially for neurological disorders, where access to human brain tissues is limited—has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field.

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Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases

Annual Review of Genetics ◽

10.1146/annurev-genet-120417-031534 ◽

2018 ◽

Vol 52 (1) ◽

pp. 271-293 ◽

Cited By ~ 66

Author(s):

Jerome Mertens ◽

Dylan Reid ◽

Shong Lau ◽

Yongsung Kim ◽

Fred H. Gage

Keyword(s):

Neurodegenerative Diseases ◽

Brain Aging ◽

Neurological Diseases ◽

Induced Pluripotent Stem Cell ◽

Model Systems ◽

Biological Aging ◽

Drug Induced ◽

Age Related ◽

Human Neurons ◽

Induced Neurons

Age-associated neurological diseases represent a profound challenge in biomedical research as we are still struggling to understand the interface between the aging process and the manifestation of disease. Various pathologies in the elderly do not directly result from genetic mutations, toxins, or infectious agents but are primarily driven by the many manifestations of biological aging. Therefore, the generation of appropriate model systems to study human aging in the nervous system demands new concepts that lie beyond transgenic and drug-induced models. Although access to viable human brain specimens is limited and induced pluripotent stem cell models face limitations due to reprogramming-associated cellular rejuvenation, the direct conversion of somatic cells into induced neurons allows for the generation of human neurons that capture many aspects of aging. Here, we review advances in exploring age-associated neurodegenerative diseases using human cell reprogramming models, and we discuss general concepts, promises, and limitations of the field.

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The killifish visual system as an in vivo model to study brain aging and rejuvenation

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00077-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sophie Vanhunsel ◽

Steven Bergmans ◽

An Beckers ◽

Isabelle Etienne ◽

Jolien Van houcke ◽

...

Keyword(s):

Visual System ◽

Neurodegenerative Diseases ◽

Healthy Aging ◽

Molecular Mechanisms ◽

Brain Aging ◽

Age Related Macular Degeneration ◽

In Vivo Model ◽

Elderly Age ◽

Age Related

AbstractWorldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer’s and Parkinson’s disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish’s aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

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