Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer’s, Parkinson’s, and Huntington’s disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the “aged” context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.

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Mitochondrial Dysfunction in Stem Cell Aging

The Indonesian Biomedical Journal ◽

10.18585/inabj.v7i1.18 ◽

2015 ◽

Vol 7 (1) ◽

pp. 15

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mitochondrial Dysfunction ◽

Stress Responses ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Tissue Homeostasis ◽

Cell Aging ◽

Aging Research ◽

Age Related

BACKGROUND: Regardless of the precise underlying molecular mechanisms, the fundamental defining manifestation of aging is an overall decline in the functional capacity of various organs to maintain baseline tissue homeostasis and to respond adequately to physiological needs under stress. There is an increasingly urgent need for a more complete understanding of the molecular pathways and biological processes underlying aging and age-related disorders.CONTENT: Mitochondria constitute the most prominent source of adenosine triphosphate (ATP) and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses and control non-apoptotic cell death routines. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. Age-associated telomere damage, diminution of telomere ‘capping’ function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, ‘stemness’ and metabolism provides a framework for how diverse factors contribute to aging and age-related disorders.SUMMARY: Cellular senescence defined as an irreversible proliferation arrest promotes age-related decline in mammalian tissue homeostasis. The aging of tissue-specific stem cell and progenitor cell compartments is believed to be central to the decline of tissue and organ integrity and function in the elderly. Taken into consideration that the overwhelming majority of intracellular reactive oxygen species (ROS) are of mitochondrial origin, it is reasonable to posit that the elevated ROS production might be caused by alteration in mitochondrial function during senescence. It is likely that mitochondria and stem cells will remain at the forefront of aging research also for the next decade.KEYWORDS: aging, stem cell, mitochondrial biogenesis, mitophagy, senescence, telomeres

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Age-specific gene signatures underlying the transcriptomes and functional connectomes of human cerebral cortex

10.1101/2020.09.15.297754 ◽

2020 ◽

Author(s):

Xingzhong Zhao ◽

Jingqi Chen ◽

Peipei Xiao ◽

Jianfeng Feng ◽

Ning Qing ◽

...

Keyword(s):

Cerebral Cortex ◽

Molecular Mechanisms ◽

Early Adulthood ◽

Structural Features ◽

Magnetic Resonance Images ◽

Specific Gene ◽

Human Cerebral Cortex ◽

Gene Signatures ◽

Brain Functions ◽

Age Related

AbstractThe human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method TCA (Transcriptome-connectome Correlation Analysis), which integrates the brain functional MR magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood, and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets.

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Proteome and Secretome Dynamics of Stem Cell-Derived Retinal Pigmented Epithelium in Response to Acute and Chronic ROS

10.1101/529271 ◽

2019 ◽

Author(s):

Jesse G. Meyer ◽

Thelma Garcia ◽

Birgit Schilling ◽

Bradford W. Gibson ◽

Deepak A. Lamba

Keyword(s):

Reactive Oxygen Species ◽

Stem Cell ◽

Molecular Mechanisms ◽

Reactive Oxygen ◽

Age Related Macular Degeneration ◽

Oxygen Species ◽

Urotensin Ii ◽

Retinal Pigmented Epithelium ◽

Age Related ◽

Pigmented Epithelium

AbstractAge-related macular degeneration (AMD) is the leading cause of blindness in developed countries, and is characterized by slow retinal degeneration linked to chronic oxidative stress in the retinal pigmented epithelium (RPE). The exact molecular mechanisms that lead to RPE death and dysfunction in response to chronic reactive oxygen species (ROS) are still unclear. In this work, human stem cell-derived RPE samples were treated with a low dose of paraquat (PQ) for 1 week or 3 weeks to induce chronic reactive oxygen species (ROS) stress. Cells were then harvested and both the intracellular and secreted RPE proteomes were quantified by mass spectrometry. Inside the RPE, chronic ROS caused concerted increase of glycolytic proteins but decreased mitochondrial proteins, as well as decreased extracellular matrix proteins and membrane proteins required for endocytosis. From the secreted proteins, we found that stressed RPE secrete over 1,000 detectable proteins, and the composition of the proteins secreted from RPE changes due to chronic ROS. Notably, secreted APOE is decreased 4-fold due to 3 weeks of chronic ROS stress, and urotensin-II, the strongest known vasoconstrictor, doubles. Further, secreted TGF-beta is increased, and its cognate signaler BMP1 decreased in the secretome. Together, these alterations of the RPE proteome and protein secretome paint a detailed molecular picture of the retinal stress response in space and time.

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Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms

Cells ◽

10.3390/cells10123570 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3570

Author(s):

Qin-Qi Wang ◽

Gang Yin ◽

Jiang-Rong Huang ◽

Shi-Jun Xi ◽

Feng Qian ◽

...

Keyword(s):

Ionizing Radiation ◽

Global Economy ◽

Molecular Mechanisms ◽

Brain Aging ◽

Healthcare Services ◽

Cell Aging ◽

Extrinsic Factors ◽

Neuropsychological Disorders ◽

Age Related ◽

Radiation Induced

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer’s disease and Parkinson’s disease. Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.

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Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts

eLife ◽

10.7554/elife.18648 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 67

Author(s):

Christine J Huh ◽

Bo Zhang ◽

Matheus B Victor ◽

Sonika Dahiya ◽

Luis FZ Batista ◽

...

Keyword(s):

Late Onset ◽

Human Fibroblasts ◽

Cellular Reprogramming ◽

Epigenetic Clock ◽

Age Related ◽

Human Neurons ◽

Highly Correlated ◽

Epigenetic Biomarker ◽

Neuronal Conversion ◽

Age Estimates

Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures. Application of an epigenetic biomarker of aging (referred to as epigenetic clock) to DNA methylation data revealed that the epigenetic ages of fibroblasts were highly correlated with corresponding age estimates of reprogrammed neurons. Transcriptome and microRNA profiles reveal genes differentially expressed between young and old neurons. Further analyses of oxidative stress, DNA damage and telomere length exhibit the retention of age-associated cellular properties in converted neurons from corresponding fibroblasts. Our results collectively demonstrate the maintenance of age after neuronal conversion.

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Identifying age-specific gene signatures of the human cerebral cortex with joint analysis of transcriptomes and functional connectomes

Briefings in Bioinformatics ◽

10.1093/bib/bbaa388 ◽

2020 ◽

Author(s):

Xingzhong Zhao ◽

Jingqi Chen ◽

Peipei Xiao ◽

Jianfeng Feng ◽

Qing Nie ◽

...

Keyword(s):

Cerebral Cortex ◽

Molecular Mechanisms ◽

Magnetic Resonance Images ◽

Joint Analysis ◽

P Value ◽

Specific Gene ◽

Human Cerebral Cortex ◽

Gene Signatures ◽

Brain Functions ◽

Age Related

Abstract The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method transcriptome-connectome correlation analysis (TCA), which integrates the brain functional magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets. Availability: All scripts are written in R. Scripts for the TCA method and related statistics result can be freely accessed at https://github.com/Soulnature/TCA. Additional data related to this paper may be requested from the authors.

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Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome

Cytogenetic and Genome Research ◽

10.1159/000516386 ◽

2021 ◽

Vol 161 (6-7) ◽

pp. 297-304

Author(s):

Ruben Gudmundsrud ◽

Tarjei H. Skjånes ◽

Brian C. Gilmour ◽

Domenica Caponio ◽

Sofie Lautrup ◽

...

Keyword(s):

Dna Damage ◽

Stem Cell ◽

Mitochondrial Dysfunction ◽

Clinical Features ◽

Molecular Mechanisms ◽

Werner Syndrome ◽

Dna Helicase ◽

Accelerated Ageing ◽

Metabolic Dysfunction ◽

Underlying Mechanisms

Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD<sup>+</sup> depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD<sup>+</sup> and mitophagy may shed light on potential therapeutic strategies for the WS patients.

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Extracellular Vesicles and Hematopoietic Stem Cell Aging

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314643 ◽

2021 ◽

Author(s):

Laura R. Goldberg

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Critical Role ◽

Natural Aging ◽

Cell Aging ◽

Hematopoietic Stem ◽

Age Related ◽

Effects Of Aging

Extracellular vesicles (EVs), important mediators of intercellular communication, play a critical role in modulating hematopoiesis within the bone marrow microenvironment. Although few studies have explicitly examined the connections between EVs and hematopoietic stem cell (HSC) aging, there is a growing body of evidence that implicates EVs in numerous age-related biologic processes and diseases. This, coupled with their tremendous capacity to influence hematopoiesis, suggests EVs may be key mediators of HSC aging. This review provides an overview of the effects of aging on HSCs, the role of EVs in aging in general, and then details key work in EV modulation of normal and malignant hematopoiesis, with a particular focus on how these effects may translate into the ability of EVs to drive HSC aging. Finally, it describes an exciting emerging literature that provides direct evidence for EV modulation of HSC phenotypes during natural aging and highlights their potential in HSC rejuvenation. Taken collectively, this body of research has profound implications for the future of HSC aging studies. More clearly defining how EVs modify HSC function in an age-dependent fashion and determining the molecular mechanisms by which they drive these age-related HSC phenotype changes will undoubtedly yield innovative strategies to delay or even reverse age-related hematologic dysfunction.

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Dietary Polyphenols as Modulators of Brain Functions: Biological Actions and Molecular Mechanisms Underpinning Their Beneficial Effects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/914273 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 169

Author(s):

David Vauzour

Keyword(s):

Cognitive Function ◽

Molecular Mechanisms ◽

Inflammatory Stress ◽

Dietary Polyphenols ◽

Beneficial Effects ◽

Brain Functions ◽

Expression Of Genes ◽

Age Related ◽

Neuroprotective Actions ◽

Protective Signaling

Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and to improve cognitive function. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Despite significant advances in our understanding of the biology of polyphenols, they are still mistakenly regarded as simply acting as antioxidants. However, recent evidence suggests that their beneficial effects involve decreases in oxidative/inflammatory stress signaling, increases in protective signaling and neurohormetic effects leading to the expression of genes that encode antioxidant enzymes, phase-2 enzymes, neurotrophic factors, and cytoprotective proteins. Specific examples of such pathways include the sirtuin-FoxO pathway, the NF-κB pathway, and the Nrf-2/ARE pathway. Together, these processes act to maintain brain homeostasis and play important roles in neuronal stress adaptation and thus polyphenols have the potential to prevent the progression of neurodegenerative pathologies.

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Regeneration in the Pituitary After Cell-Ablation Injury: Time-Related Aspects and Molecular Analysis

Endocrinology ◽

10.1210/en.2015-1741 ◽

2015 ◽

Vol 157 (2) ◽

pp. 705-721 ◽

Cited By ~ 18

Author(s):

Christophe Willems ◽

Qiuli Fu ◽

Heleen Roose ◽

Freya Mertens ◽

Benoit Cox ◽

...

Keyword(s):

Stem Cell ◽

Young Adult ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Side Population ◽

Recovery Period ◽

Regenerative Capacity ◽

Mesenchymal Transition ◽

Cell Clustering ◽

Age Related

Abstract We recently showed that the mouse pituitary holds regenerative competence. Young-adult GHCre/iDTR mice, expressing diphtheria toxin (DT) receptor in GH-producing cells, regenerate the GH+ cells, as ablated by 3-day DT treatment (3DT), up to 60% after 5 months. The pituitary's stem cells participate in this restoration process. Here, we characterized this regenerative capacity in relation to age and recovery period and started to search for underlying molecular mechanisms. Extending the recovery period (up to 19 mo) does not result in higher regeneration levels. In addition, the regenerative competence disappears at older age, coinciding with a reduction in pituitary stem cell number and fitness. Surprisingly, prolonging DT treatment of young-adult mice to 10 days (10DT) completely blocks the regeneration, although the stem cell compartment still reacts by promptly expanding, and retains in vitro stem cell functionality. To obtain a first broad view on molecular grounds underlying reparative capacity and/or failure, the stem cell-clustering side population was analyzed by whole-genome expression analysis. A number of stemness factors and components of embryonic, epithelial-mesenchymal transition, growth factor and Hippo pathways are higher expressed in the stem cell-clustering side population of the regenerating pituitary (after 3DT) when compared with the basal gland and to the nonregenerating pituitary (after 10DT). Together, the regenerative capacity of the pituitary is limited both in age-related terms and final efficacy, and appears to rely on stem cell-associated pathway activation. Dissection of the molecular profiles may eventually identify targets to induce or boost regeneration in situations of (injury-related) pituitary deficiency.

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