Age-dependent lipid droplet-rich microglia worsen stroke outcome in old mice

Arbaizar-Rovirosa, Maria; Gallizioli, Mattia; Pedragosa, Jordi; Lozano, Juan José; Casal, Carme; Pol, Albert; Planas, Anna M.

doi:10.1101/2022.03.14.484305

Cited by 5 publications

(5 citation statements)

References 67 publications

(92 reference statements)

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“…Furthermore, preliminary evidence reported in a recent preprint indicates that ischemia triggers lipid accumulation in microglia of young mice, promoting premature aging of microglia [237]. Lipid droplet accumulation has been reported to be a feature of aged microglia [238] and it has been suggested that after stroke, an increase of lipid droplets in microglia may contribute to poor stroke outcome in old mice [237]. Given that this effect might be attributable to phagocytosis of cell debris due to brain injury leading to intracellular accumulation of lipids in microglial cells, this further links the inflammatory response in stroke to mitochondrial metabolism as well as lipophagy (see above).…”

Section: Metabolic Regulation Of Immune Cellsmentioning

confidence: 97%

Section: Metabolic Regulation Of Immune Cellsmentioning

confidence: 99%

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Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Walther

Kirsch

Hellwig

et al. 2022

Transl. Stroke Res.

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The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain’s central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

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Section: Metabolic Regulation Of Immune Cellsmentioning

confidence: 97%

Section: Metabolic Regulation Of Immune Cellsmentioning

confidence: 99%

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Walther

Kirsch

Hellwig

et al. 2022

Transl. Stroke Res.

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show abstract

“…Alzheimer's disease neurons, glia, myeloid cells, ependymal cells, astrocytes [319][320][321][322][323] Parkinson's disease neurons, microglia [319,324,325] Age-related macular degeneration retinal pigment epithelium [326] Stroke microglia [327] Atherosclerosis Foam cells [328,329] Cardiovascular disease myocardium [330,331] Sarcopenia muscle cells [332,333] Rheumatoid arthritis T-cells [334] Chronic obstructive pulmonary disease (COPD) macrophages [327] Periodontitis monocytes, macrophages [335,336] Osteopenia osteoblasts, osteocytes [337,338] Osteoarthritis chondrocytes, cartilage [339][340][341] Diabetes β-cells [342,343] Liver disease (NAFLD) 1 parenchymal hepatocytes [344] 2…”

Section: Disease Main Affected Cell Type/tissue Referencesmentioning

confidence: 99%

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

et al. 2023

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It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues.

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“…For example, Elmore et al demonstrated this shift using a colony-stimulating factor 1 receptor inhibitor to noninvasively eliminate senescent microglia, discontinue the drug, restimulate the proliferation of new microglia in the senescent brain, and reverse cognitive, synaptic, and neuronal deficits in aging mice [ 75 ]. Recent investigations have shown that aging brains accumulate lipid droplets in the microglia after stroke, possibly due to impaired phagocytosis, exacerbated innate immune responses, and increased expression of certain lipid droplet-associated proteins [ 76 , 77 ]. Defective phagocytosis results in the excessive production of ROS and proinflammatory cytokines [ 78 ].…”

Section: Aging-related Immune System Alterations In Strokementioning

confidence: 99%

Age-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke

2023

Aging dis

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The aging of the global population poses significant scientific challenges. Moreover, the biological process of aging is the most significant risk factor for most chronic illnesses; therefore, understanding the molecular and cellular mechanisms underlying these aging-related challenges is crucial for extending the healthy lifespan of older individuals. Preventing brain aging remains a priority public health goal, and integrative and comprehensive aging analyses have revealed that immunosenescence is a potential cause of age-related brain damage and disease (e.g., stroke). Importantly, the neuroinflammatory and immune systems present two-way contact and thus can affect each other. Emerging evidence supports the numerous effects of immunosenescence- and inflammation-mediated immunity in neurologically injured brains. In this study, we briefly outline how aging alters the pathophysiology and transcriptional amplitude in patients who experienced stroke and then discuss how the immune system and its cellular components and molecular mechanisms are affected by age after stroke. Finally, we highlight emerging interventions with the potential to slow down or reduce aging and prevent stroke onset.

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Age-dependent lipid droplet-rich microglia worsen stroke outcome in old mice

Cited by 5 publications

References 67 publications

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

Age-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke

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