Genomic integrity and the ageing brain

Chow, Hei Man; Herrup, Karl

doi:10.1038/nrn4020

Cited by 162 publications

(143 citation statements)

References 201 publications

(161 reference statements)

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“…This pattern is quite similar to that seen in neurons with compromised genomic integrity during brain aging where genomic instability is elegantly balanced by an array of DNA repair mechanisms (Chow and Herrup, 2015). This comparison naturally raises the question of whether, in OLs as in neurons, mutations in proteins that contribute to the DNA damage response and produce symptoms of premature aging also compromise the biology of the OL and might serve as a root cause of WM loss in the aging brain.…”

Section: Dna Damage In Oligodendrocytes Is Commonly Found In Wm Lesupporting

confidence: 68%

DNA damage in the oligodendrocyte lineage and its role in brain aging

Tse

Herrup

2017

Mechanisms of Ageing and Development

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Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia-telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease.

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Section: Dna Damage In Oligodendrocytes Is Commonly Found In Wm Lesupporting

confidence: 68%

DNA damage in the oligodendrocyte lineage and its role in brain aging

Tse

Herrup

2017

Mechanisms of Ageing and Development

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“…DNA in the mitochondria and nucleus is regularly damaged by ROS during the normal course of cellular function and aging, and in neurons such DNA damage is increased following excitatory synaptic activity (Chow and Herrup, 2015; Yang et al, 2010). In healthy, young cells, damaged DNA bases are rapidly removed and replaced with undamaged bases by the coordinated activities of proteins in DNA repair pathways that include homologous recombination, mismatch repair, nucleotide excision repair, and base excision repair (BER).…”

Section: Cellular and Molecular Hallmarks Of Brain Agingmentioning

confidence: 99%

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

2018

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During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca2+ homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer’s and Parkinson’s diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging. Here we provide an overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health.

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“…PARP1 may also participate in the detection of G4 structures [95]. The accumulation of nuclear DNA damage, which occurs with age [96], can lead to persistent activation of PARP1, which depletes cellular levels of NAD + and reduces sirtuin activity [97]. In C. elegans , when the ortholog of PARP-1, pme-1 , was knocked down, mitochondrial function improved due to increased NAD + levels and Sir2.1 (the C. elegans ortholog of SIRT1) activity and through UPR mt activation.…”

Section: Sirtuins and Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun

et al. 2017

Neurochemistry International

304

183

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Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

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Genomic integrity and the ageing brain

Cited by 162 publications

References 201 publications

DNA damage in the oligodendrocyte lineage and its role in brain aging

DNA damage in the oligodendrocyte lineage and its role in brain aging

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

Mitophagy in neurodegeneration and aging

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