Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

Mattson, Mark P.; Arumugam, Thiruma V.

doi:10.1016/j.cmet.2018.05.011

Cited by 799 publications

(815 citation statements)

References 343 publications

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“…Both aging and AD are associated with decreased brain glucose utilization, while ketone utilization is maintained (Cunnane et al, 2016;Mattson & Arumugam, 2018). Efforts to exploit ketones as an energy fuel source are being investigated.…”

Section: Ad Drug Development Pipeline: Bioenergetics Beyond Mitochomentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

317

178

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Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Ad Drug Development Pipeline: Bioenergetics Beyond Mitochomentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

317

178

View full text Add to dashboard Cite

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“…Potentially, a disease has both a specific impact but also may trigger a sequence of events which result in an acceleration of the biological processes seen in normal ageing, both systemically 7 and in the brain. 8,9 by the lack of a simple and powerful outcome measure. MRI-assessed brain atrophy is a surrogate outcome for this process, but the need for precise longitudinal assessments, usually over at least a 12-month interval, reduces the feasibility of use.…”

Section: Introductionmentioning

confidence: 99%

Accelerated brain ageing and disability in multiple sclerosis

Cole

Raffel

Friede

et al. 2019

Preprint

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BackgroundBrain atrophy occurs in both normal ageing and in multiple sclerosis (MS), but it occurs at a faster rate in MS, where it is the major driver of disability progression. Here, we employed a neuroimaging biomarker of structural brain ageing to explore how MS influences the brain ageing process. MethodsIn a longitudinal, multi-centre sample of 3,565 MRI scans in 1,204 MS/clinically isolated syndrome (CIS) patients and 150 healthy controls (HCs) (mean follow-up time: patients 3·41 years, HCs 1·97 years) we measured 'brain-predicted age' using T1-weighted MRI. Brain-predicted age difference (brain-PAD) was calculated as the difference between the brain-predicted age and chronological age. Positive brain-PAD indicates a brain appears older than its chronological age. We compared brain-PAD between MS/CIS patients and HCs, and between disease subtypes. In patients, the relationship between brain-PAD and Expanded Disability Status Scale (EDSS) at study entry and over time was explored. FindingsAdjusted for age, sex, intracranial volume, cohort and scanner effects MS/CIS patients had markedly older-appearing brains than HCs (mean brain-PAD 11·8 years [95% CI 9·1-14·5] versus -0·01 [-3·0-3·0], p<0·0001). All MS subtypes had greater brain-PAD scores than HCs, with the oldest-appearing brains in secondary-progressive MS (mean brain-PAD 18·0 years [15·4-20·5], p<0·05). At baseline, higher brain-PAD was associated with a higher EDSS, longer time since diagnosis and a younger age at diagnosis. Brain-PAD at study entry significantly predicted time-to-EDSS progression (hazard ratio 1·02 [1·01-1·03], p<0·0001): for every 5 years of additional brain-PAD, the risk of progression increased by 14·2%.Interpretation MS increases brain ageing across all MS subtypes. An older-appearing brain at baseline was associated with more rapid disability progression, suggesting 'brain-age' could be an individualised prognostic biomarker from a single, cross-sectional assessment. Evidence before this studyWe searched Pubmed and Scopus with the terms "multiple sclerosis" and "brain ageing" or "brain age" and "neuroimaging" or "MRI" for studies published before 15 th March 2019. This searched return no studies of brain ageing in multiple sclerosis. We also searched the pre-print server for biology, bioRxiv, and found one manuscript deposited, though this study has yet to appear in a peer-reviewed journal. This study found a strong effect of multiple sclerosis on the apparent age of the brain, though was only cross-sectional, was from a single centre, did not consider disease subtypes and did not consider the relevance of clinical characteristics for brain ageing. Therefore, although there is strong prior evidence of the importance of brain atrophy in multiple sclerosis, there was no information on how the nature of this atrophy relates to brain ageing. Added value of this studyHere we demonstrate for the first time that the progressive atrophy in multiple sclerosis patients results in an acceleration of age-related changes to brain structure....

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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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Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

Cited by 799 publications

References 343 publications

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Accelerated brain ageing and disability in multiple sclerosis

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

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