{"doi":"10.1093/lifemeta/loae031","title":"Senescent glia—bridging neuronal mitochondrial dysfunction and lipid accumulation in aging","abstract":"Identifying cellular mechanisms that underlie senescence development in vivo has been challenging in the field of aging research. In a recent article published in Nature, Byrns et al. identified a population of naturally occurring senescent glial cells that emerge in response to aging-associated neuronal mitochondrial dysfunction. These senescent glial cells promote the accumulation of lipid droplets (LDs) in non-senescent glial cells and can be targeted to extend healthspan. Cellular senescence is a state of irreversible growth arrest that cells enter in response to various stressors, including DNA damage, oxidative stress, and oncogenic signals. Senescent cells play several roles: they prevent the proliferation of damaged cells, thereby acting as a tumor-suppressive mechanism, but their accumulation over time contributes to aging and various age-related diseases through the secretion of a range of pro-inflammatory cytokines, chemokines, and proteases known as the senescence-associated secretory phenotype (SASP). The composition of the SASP is highly variable and dynamic depending on the factor that induces the senescence and the cell type involved. In the central nervous system, glial cells—comprising astrocytes, oligodendrocytes, and microglia—are essential for maintaining neuronal health and function. However, in aging, senescent glial cells accumulate and contribute to age-related pathologies [1]. Furthermore, mouse models of neurodegeneration have provided evidence that clearance of senescent glial cells alleviates tau-dependent neurodegeneration and decreases inflammation as well as β-amyloid plaque size [2], further supporting the role of senescence in neurodegenerative processes. While a rapidly growing body of literature supports the detrimental effects of senescence on aging-related declines in tissue function including neurodegeneration, the findings of the current study highlight the role of the transcription factor activator protein 1 (AP1) as a critical regulator of glial cell senescence during natural aging [3] (Fig. 1). AP1 has been characterized as a major regulator of the transcriptional program that drives senescence [4] and can drive tau pathology in glial cells [5]. However, mechanisms underpinning the formation of these senescence-like AP1+ glial cells remain elusive. In response to aging-induced mitochondrial dysfunction, neurons promote activator protein 1 (AP1)-driven senescence in glia. Intermittent blockade of AP1 signaling in glia reduces lipid droplet (LD) accumulation in non-senescent glia and extends healthspan. AP1+ glia promote LD accumulation in non-senescent glia through speculative secretory mechanisms. The figure was made using BioRender. In their most recent work, Byrns et al. sought to characterize the functional roles of these AP1+ glial cells in aged Drosophila brain. Using a transgenic line expressing dsRed under the control of an AP1 binding motif to monitor the appearance and distribution of AP1+ glia, it was found that AP1+ glia accumulated in a regionally progressive manner as the brain ages. The senescence-associated features of AP1+ glia were confirmed by elevated β-galactosidase (SA-β-Gal) activity, increased DNA damage marker γH2Av (the phosphorylated histone variant H2Av), and increased expression of cell cycle arrest and pro-inflammatory genes. The comparison of gene expression profiles between young (5 days) and aged (40 days) neurons suggested an upregulated expression of inflammatory genes and downregulated genes in pathways related to mitochondrial function. Mitochondrial dysfunction is a hallmark of aging, and its resulting oxidative stress can drive senescence [6]. Thus, to further investigate whether this mitochondrial dysfunction in neurons contributes to glial senescence, the authors performed a targeted RNAi screen against the inner mitochondrial complex genes in neurons using a drug-inducible (RU-486) neuron-specific GAL4 line with a fluorescent AP1 reporter. 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