Ageing as a risk factor for neurodegenerative disease

Y, Hou; Dan, Xiuli; Babbar, Mansi; Wei, Yong; Hasselbalch, Steen G.; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.1038/s41582-019-0244-7

Cited by 2,099 publications

(1,507 citation statements)

References 194 publications

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“…Aging is a primary factor for the development and progression of neuro-degenerative diseases (Hou et al, 2019), and alterations in lipid metabolism that impact NSC function have been shown to play a role in this process. For instance, in Alzheimer's disease patients, oleic acid-enriched LDs accumulate in the forebrain, which correlate with a decrease in proliferation of NSCs (Hamilton et al, 2015).…”

Section: Aging and Degenerative Diseasesmentioning

confidence: 99%

Lipid Mediated Regulation of Adult Stem Cell Behavior

Clémot

Demarco

Jones

2020

Front. Cell Dev. Biol.

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Adult stem cells constitute an important reservoir of self-renewing progenitor cells and are crucial for maintaining tissue and organ homeostasis. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and it is now becoming apparent that metabolism plays instructive roles in stem cell fate decisions. Lipids are an extremely vast class of biomolecules, with essential roles in energy homeostasis, membrane structure and signaling. Imbalances in lipid homeostasis can result in lipotoxicity, cell death and diseases, such as cardiovascular disease, insulin resistance and diabetes, autoimmune disorders and cancer. Therefore, understanding how lipid metabolism affects stem cell behavior offers promising perspectives for the development of novel approaches to control stem cell behavior either in vitro or in patients, by modulating lipid metabolic pathways pharmacologically or through diet. In this review, we will first address how recent progress in lipidomics has created new opportunities to uncover stem-cell specific lipidomes. In addition, genetic and/or pharmacological modulation of lipid metabolism have shown the involvement of specific pathways, such as fatty acid oxidation (FAO), in regulating adult stem cell behavior. We will describe and compare findings obtained in multiple stem cell models in order to provide an assessment on whether unique lipid metabolic pathways may commonly regulate stem cell behavior. We will then review characterized and potential molecular mechanisms through which lipids can affect stem cell-specific properties, including self-renewal, differentiation potential or interaction with the niche. Finally, we aim to summarize the current knowledge of how alterations in lipid homeostasis that occur as a consequence of changes in diet, aging or disease can impact stem cells and, consequently, tissue homeostasis and repair.

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Section: Aging and Degenerative Diseasesmentioning

confidence: 99%

Lipid Mediated Regulation of Adult Stem Cell Behavior

Clémot

Demarco

Jones

2020

Front. Cell Dev. Biol.

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“…These include neurovascular dysfunction manifesting in blood-brain barrier (BBB) breakdown associated with microscopic pathological changes of vascular cells 9,[18][19][20] . Forming the innermost lining of the vasculature, brain endothelial cells (ECs) closely interact with other cell types of the neurovascular unit (NVU) to regulate diverse functions including BBB integrity 8,12,13 , immune signaling and brain metabolism, all of which are altered in the aged brain 18,[21][22][23] . These imply that ECs play crucial roles in the brain ageing process that are still incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zhao

Vong

et al. 2019

Preprint

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With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail 1,2 , yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases 3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed -the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions [8][9][10][11][12][13][14][15][16][17] . Furthermore, an overrepresentation of Alzheimer's disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with 2 exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

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“…This genomic instability is known to be a prerequisite for the development of cancer and may contribute to particular degenerative diseases, such as Alzheimer's. [ 11 ] Double strand breaks, which are the most critical lesions in terms of cell fate, can be obtained by immunolocalization of DNA damage‐induced histone γ‐H2AX (phosphorylated form of the histone variant H2AX) or by other specialized proteins involved in DNA repair machinery. [ 12 ] More detailed measures of DNA damage can be performed by DNA sequencing; however, this is not as easy as it sounds since each cell in a tissue acquires different mutations that get lost in bulk sequencing efforts.…”

Section: Molecular and Cellular Biomarkersmentioning

confidence: 99%

Aging Biomarkers: From Functional Tests to Multi‐Omics Approaches

Kudryashova¹,

Burka²,

Kulaga

et al. 2020

Proteomics

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Aging results in various deleterious changes in the human body that may lead to loss of function and the manifestation of chronic diseases. While diseases can generally be reliably diagnosed, the aging process itself requires more sophisticated approaches to evaluate its progression. Numerous attempts have been made to establish biomarkers to quantify human aging at the cellular, tissue, and organismal level. Here, an up‐to‐date overview of biomarkers related to human aging with an emphasis on biomarkers that take into account different mechanisms of aging between individuals is provided. Classical discrete molecular and non‐molecular biomarkers handpicked by researches on the base of their strong correlation with age, as well as emerging omics‐based biomarkers, are discussed and potential future directions and developments in the field of aging assessment are outlined.

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Ageing as a risk factor for neurodegenerative disease

Cited by 2,099 publications

References 194 publications

Lipid Mediated Regulation of Adult Stem Cell Behavior

Lipid Mediated Regulation of Adult Stem Cell Behavior

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Aging Biomarkers: From Functional Tests to Multi‐Omics Approaches

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