Aging microglia

Abstract

Microglia are the tissue-resident macrophage population of the brain, specialized in supporting the CNS environment and protecting it from endogenous and exogenous insults. Nonetheless, their function declines with age, in ways that remain to be fully elucidated. Given the critical role played by microglia in neurodegenerative diseases, a better understanding of the aging microglia phenotype is an essential prerequisite in designing better preventive and therapeutic strategies. In this review, we discuss the most recent literature on microglia in aging, comparing findings in rodent models and human subjects.

Keywords: Aging; Human microglia; Microglia; Neuroinflammation; RNAseq; Senescence.

Fig. 1

Signaling pathways altered in aging microglia. Aging is characterized by changing in metabolism, such as increased levels of eicosanoids, such as prostaglandin E2 (PGE2) [54], growth factors and cytokines that lead to the activation of the PI3K-AKT-mTOR signaling pathway in microglia [27]. AKT activation promotes sequestration of glucose into glycogen, causing energy depletion and accumulation of succinate [54]. Succinate is known to stabilize the transcription factor HIF1a, which is also induced by mTOR signaling [150] and promotes transcription of pro-inflammatory genes [54]. In parallel, mTORC1 induces transcription of ribosomal genes through multiple mechanisms [–153]. Collectively, this results in increased translation of pro-inflammatory factors such as TNF, IL-1b, and IL-6 in aged microglia [27]. Downstream of mTOR, the transcription factor PPARγ, among others, promote lipid droplet formation in myeloid cells [154], suggesting a potential similar mechanism in microglia. COX2, which is located at the droplet membrane, in turn produces more PGE2, leading to a feed-forward loop [154]. The PI3K-AKT-mTOR pathway is activated by TREM2 and is required for microglia ability to respond to amyloid-β deposition [60]. TREM2 variants resulting in reduced expression are associated with neurodegeneration [61, 62].

Fig. 2

Gene signatures of aged microglia subsets. Different single-cell RNAseq studies have analyzed aged microglia. Their findings show the majority of cells to have a homeostatic gene signature, characterized by housekeeping genes that support healthy microglia function (in blue). The morphology of homeostatic microglia is highly ramified with extended and arborized processes [8]. In addition, aged mice show an enrichment of two subpopulations of microglia (in light pink, red). Although the signatures described in different studies are not completely overlapping, they share common features such as the upregulation of IFN-regulated genes (IRM, OA3) or genes related to inflammation, phagocytosis and lipid metabolism (ARM, OA2, WAM) [50, 58, 65, 67]. Aged microglia display shorter and thickened processes, with inclusions that arise from either phagocytosis or lipid accumulations [17, 134]; however, it remains to be clarified if the two subtypes have similar or distinctive morphological characteristics