The old guard: Age-related changes in microglia and their consequences

Costa, J. M. Caridade; Martins, Solange; Ferreira, Pedro A.; Cardoso, Ana M.; Guedes, Joana; Peça, João

doi:10.1016/j.mad.2021.111512

Cited by 41 publications

(31 citation statements)

References 211 publications

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“…This makes retinal microglia possible candidates for chronic senescence and may suggest that microglial senescence plays a role in age-dependent neurodegenerative diseases of the retina, such as AMD. It has been widely established that resident microglia in the retina and brain undergo various morphological and functional changes during physiological immunosenescence or other cues affecting their homeostasis [27][28][29][30]. Our study shows that retinal microglia cell density increases with age, thus recapitulating the findings of previous studies [13] and revealing that this increase is associated with significant transcriptional changes in senescent microglia.…”

Section: Discussionsupporting

confidence: 88%

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Schlecht

Thien

Wolf

et al. 2021

IJMS

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Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1GFP/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.

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Section: Discussionsupporting

confidence: 88%

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Schlecht

Thien

Wolf

et al. 2021

IJMS

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“…Several intracellular microglial properties were shown to be affected by aging ( Cho et al, 2019 ). In agreement with observations made in other cell types, aged microglia show several signs of cellular aging such as epigenetic changes via the hypomethylation of IL-β associated with elevated Il-β transcript in microglia ( Cho et al, 2015 ), which are described in Figure 1 , along with an impaired DNA repair capability, altered transcription machinery and diminished ability of chromatin remodeling, as revealed by proteomic analysis of aged primary mouse microglia ( Figure 1 ; Raj et al, 2014 ; Flowers et al, 2017 ; Costa et al, 2021 ). This inadequate microglial remodeling may underlie their impaired ability to dynamically change states according to the needs of the CNS during aging ( Flowers et al, 2017 ).…”

Section: Microglial Metabolic and Morphological Changes In Stress And Agingsupporting

confidence: 88%

Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk

Carrier

Šimončičová

St‐Pierre

et al. 2021

Front. Mol. Neurosci.

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The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

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“…Our flowcytometric and immunofluorescence microscopic observations of aged rat brain (Figure 1) showed similar findings, with a reduced population of microglia over the total number of live cells in the rat prefrontal cortex. Furthermore, profound modifications in the transcriptome profile, secretome, morphology, and phagocytic activity of aged microglia are associated with the housekeeping and defensive functions of microglia [69]. In addition, the functional properties of senescent microglial changes are sex specific [70], and changes in energy metabolism are considered responsible for their reduced phagocytotic capacity [71].…”

Section: Senescent Microgliamentioning

confidence: 99%

Microglia and the Aging Brain: Are Geriatric Microglia Linked to Poor Sleep Quality?

Choudhury

Miyanishi

Tamano

et al. 2021

IJMS

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Poor sleep quality and disrupted circadian behavior are a normal part of aging and include excessive daytime sleepiness, increased sleep fragmentation, and decreased total sleep time and sleep quality. Although the neuronal decline underlying the cellular mechanism of poor sleep has been extensively investigated, brain function is not fully dependent on neurons. A recent antemortem autographic study and postmortem RNA sequencing and immunohistochemical studies on aged human brain have investigated the relationship between sleep fragmentation and activation of the innate immune cells of the brain, microglia. In the process of aging, there are marked reductions in the number of brain microglial cells, and the depletion of microglial cells disrupts circadian rhythmicity of brain tissue. We also showed, in a previous study, that pharmacological suppression of microglial function induced sleep abnormalities. However, the mechanism underlying the contribution of microglial cells to sleep homeostasis is only beginning to be understood. This review revisits the impact of aging on the microglial population and activation, as well as microglial contribution to sleep maintenance and response to sleep loss. Most importantly, this review will answer questions such as whether there is any link between senescent microglia and age-related poor quality sleep and how this exacerbates neurodegenerative disease.

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The old guard: Age-related changes in microglia and their consequences

Cited by 41 publications

References 211 publications

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk

Microglia and the Aging Brain: Are Geriatric Microglia Linked to Poor Sleep Quality?

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