Cellular Senescence and Brain Aging

Chinta, Shankar J.; Wood, Georgia; Lieu, Chris; Rane, Anand; Demaria, Marco; Campisi, J.; Andersen, Julie K.

doi:10.1016/j.freeradbiomed.2014.10.013

Cited by 28 publications

(36 citation statements)

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“…Our findings, taken together with the results of earlier studies (reviewed in Warrington et al (2013)), point to potential benefits of interventions that rescue glio-vascular coupling mechanisms and promote microvascular health for prevention of cognitive decline both in WBI-treated patients and the elderly. There is increasing realization that DNA damage-induced cellular senescence programs play a critical role in brain aging process (reviewed in Chinta et al (2014)), thus we propose that the present clinically relevant model of fractionated WBI should be considered to study fundamental mechanisms of brain and cognitive aging as well.…”

Section: Discussionmentioning

confidence: 99%

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

et al. 2017

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Whole brain irradiation (WBI) is a mainstream therapy for patients with both identifiable brain metastases and prophylaxis for microscopic malignancies. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients surviving long term after treatment, due to γ-irradiation-induced cerebromicrovascular injury. Moment-to-moment adjustment of cerebral blood flow ( C B F ) v i a n e u r o n a l a c t i v i t y -d e p e n d e n t cerebromicrovascular dilation (functional hyperemia) has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with impaired cerebromicrovascular function, C56BL/6 mice (3 months) subjected to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), sensorimotor coordination (computerized gait analysis, CatWalk), and cerebromicrovascular function (whisker-stimulation-induced increases in CBF, measured by laser Doppler flowmetry) at 3 to 6 months post-irradiation. We found that mice with WBI exhibited impaired cerebromicrovascular function at 3 months post-irradiation, which was associated with impaired performance in the radial arm water maze. At 6 months, post-irradiation progressive impairment in gait coordination (including changes in the regularity index and phase dispersion) was also evident. Collectively, our findings provide evidence for early and persisting neurovascular impairment after a clinically relevant protocol of fractionated WBI, which predict early manifestations of cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

et al. 2017

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“…Originally derived from the study of cancer cells, cellular senescence implied a loss of the ability to divide (Campisi ). However, more recently this has come to imply an age‐related change in the secretory profile, as in the senescence‐associated secretory phenotype (SASP) (Coppe et al ; Chinta et al ). Dystrophic on the other hand is a term derived from a morphological change as observed from the study of brain sections (Streit et al ).…”

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confidence: 99%

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Angelova

Brown

2019

Journal of Neurochemistry

181

125

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The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer’s disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer’s disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron‐overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.

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“…Increasing evidences are showing that senescent cells are detectable in mammalian brains along with the aging process, and may also be implicated in NDDs. (8,98,99) As an indicator of cellular senescence telomere length has been proposed as a biomarker of human aging. (100) In general, telomere length reflects the balance between additions and losses of TTAGGG repeats (101) and it can be accelerated by many factors, such as oxidative stress, replication stress, and inflammation (102).…”

Section: Dna Damage and Nddmentioning

confidence: 99%

“…The disappointing outcomes of dozens of phase III clinical trials of treatments for AD and PD indicate a need for fresh approaches to identify novel targets that drive processes that cause agerelated neuropathology. (8) Currently available treatments (social supports, mobility aides, and "Band-Aid" treatments for end-stage, downstream symptoms) are not directed at the root causes of age-related dysfunction. Treating chronic diseases one at a time does not suffice.…”

Section: Introductionmentioning

confidence: 99%

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

2018

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B ACKGROUND:Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT:The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer's disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescenceassociated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYwORDS

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Cellular Senescence and Brain Aging

Cited by 28 publications

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Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

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