Metabolomics of Human Brain Aging and Age-Related Neurodegenerative Diseases

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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Genetic control of age-related gene expression and complex traits in the human brain

10.1101/125195 ◽

2017 ◽

Cited By ~ 1

Author(s):

Trevor Martin ◽

Hunter B. Fraser

Keyword(s):

Gene Expression ◽

Human Brain ◽

Neurodegenerative Diseases ◽

Genetic Variants ◽

Complex Traits ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Expression Patterns ◽

Related Gene ◽

Age Related

AbstractAge is the primary risk factor for many of the most common human diseases—particularly neurodegenerative diseases—yet we currently have a very limited understanding of how each individual’s genome affects the aging process. Here we introduce a method to map genetic variants associated with age-related gene expression patterns, which we call temporal expression quantitative trait loci (teQTL). We found that these loci are markedly enriched in the human brain and are associated with neurodegenerative diseases such as Alzheimer’s disease and Creutzfeldt-Jakob disease. Examining potential molecular mechanisms, we found that age-related changes in DNA methylation can explain some cis-acting teQTLs, and that trans-acting teQTLs can be mediated by microRNAs. Our results suggest that genetic variants modifying age-related patterns of gene expression, acting through both cis- and trans-acting molecular mechanisms, could play a role in the pathogenesis of diverse neurological diseases.

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Neuroprotective Potential of GDF11: Myth or Reality?

International Journal of Molecular Sciences ◽

10.3390/ijms20143563 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3563 ◽

Cited By ~ 1

Author(s):

Luc Rochette ◽

Gabriel Malka

Keyword(s):

Neurodegenerative Diseases ◽

Blood Plasma ◽

Neurodegenerative Disorders ◽

Brain Aging ◽

Therapeutic Strategies ◽

Blood Concentrations ◽

Age Related ◽

Novel Therapeutic Strategies ◽

The Brain ◽

Novel Therapeutic

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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Murine models of brain aging and age-related neurodegenerative diseases

Behavioural Brain Research ◽

10.1016/s0166-4328(96)02243-7 ◽

1997 ◽

Vol 85 (1) ◽

pp. 1-25 ◽

Cited By ~ 64

Author(s):

Mathias Jucker ◽

Donald K. Ingram

Keyword(s):

Neurodegenerative Diseases ◽

Brain Aging ◽

Murine Models ◽

Age Related

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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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Bidirectional Association Between Sleep and Brain Atrophy in Aging

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.726662 ◽

2021 ◽

Vol 13 ◽

Author(s):

Viktória Kokošová ◽

Pavel Filip ◽

David Kec ◽

Marek Baláž

Keyword(s):

Human Brain ◽

Brain Atrophy ◽

Brain Aging ◽

Brain Activity ◽

Brain Regions ◽

Electrical Brain Activity ◽

Age Related ◽

Bidirectional Association ◽

Quality Sleep ◽

Brain Functional Connectivity

Human brain aging is characterized by the gradual deterioration of its function and structure, affected by the interplay of a multitude of causal factors. The sleep, a periodically repeating state of reversible unconsciousness characterized by distinct electrical brain activity, is crucial for maintaining brain homeostasis. Indeed, insufficient sleep was associated with accelerated brain atrophy and impaired brain functional connectivity. Concurrently, alteration of sleep-related transient electrical events in senescence was correlated with structural and functional deterioration of brain regions responsible for their generation, implying the interconnectedness of sleep and brain structure. This review discusses currently available data on the link between human brain aging and sleep derived from various neuroimaging and neurophysiological methods. We advocate the notion of a mutual relationship between the sleep structure and age-related alterations of functional and structural brain integrity, pointing out the position of high-quality sleep as a potent preventive factor of early brain aging and neurodegeneration. However, further studies are needed to reveal the causality of the relationship between sleep and brain aging.

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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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