Abstract
Microglia are highly active and vigilant housekeepers of the central nervous system that function to promote neuronal growth and activity. With advanced age, however, dysregulated inflammatory signaling and defects in phagocytosis impede their ability to perform the most essential of homeostatic functions, including immune surveillance and debris clearance. Microglial activation is one of the hallmarks of the aging brain and coincides with age-related neurodegeneration and cognitive decline. Age-associated microglial dysfunction leads to cellular senescence and can profoundly alter the response to sterile injuries and immune diseases, often resulting in maladaptive responses, chronic inflammation, and worsened outcomes after injury. Our knowledge of microglia aging and the factors that regulate age-related microglial dysfunction remain limited, as the majority of pre-clinical studies are performed in young animals, and human brain samples are difficult to obtain quickly post-mortem or in large numbers. This review outlines the impact of normal aging on microglial function, highlights the potential mechanisms underlying age-related changes in microglia, and discusses how aging can shape the recovery process following injury.
Highlights
Introduction and OverviewThe U.S population is aging at a historic pace
TThhee nneewwllyy ccooiinneedd ‘‘ddaarrkk’’ mmiiccrroogglliiaa pphheennoottyyppee ddeefifinneedd bbyy ccoonnddeennsseedd eelleeccttrroonn--ddeennssee ccyyttooppllaassmm aanndd nnuucclleeooppllaassmm, nnuucclleeaarr cchhrroommaattiinn rreemmooddeelliinngg, aanndd hhiigghh lleevveellss ooff ssyynnaappttiicc ssttrriippppiinngg aaccttiivviittyy aanndd ooxxiiddaattiivvee ssttrreessss aapppplliieess nnoott oonnllyy ttoo mmiiccrroogglliiaa ppooppuullaattiioonnss associated with pathological states such as chronic stress and Alzheimer’s disease, but to the microglia that are observed in normal aging [14]
Stress ↑ weight loss, exaggerated ↑ hippocampal and hypothalamic IL-1β mRNA expression in aged; exaggerated ↑ corticosterone in aged Higher hippocampal MHCII mRNA and immunohistochemistry staining in aged mice at baseline, and increased in aged mice following stress
Summary
The U.S population is aging at a historic pace. The population of those over 65 years is expected to double over the three decades, and those aged 80 and older are projected to triple in number [1]. TThhee nneewwllyy ccooiinneedd ‘‘ddaarrkk’’ mmiiccrroogglliiaa pphheennoottyyppee ddeefifinneedd bbyy ccoonnddeennsseedd eelleeccttrroonn--ddeennssee ccyyttooppllaassmm aanndd nnuucclleeooppllaassmm,, nnuucclleeaarr cchhrroommaattiinn rreemmooddeelliinngg,, aanndd hhiigghh lleevveellss ooff ssyynnaappttiicc ssttrriippppiinngg aaccttiivviittyy aanndd ooxxiiddaattiivvee ssttrreessss aapppplliieess nnoott oonnllyy ttoo mmiiccrroogglliiaa ppooppuullaattiioonnss associated with pathological states such as chronic stress and Alzheimer’s disease, but to the microglia that are observed in normal aging [14]. While these alterations at the ultrastructural level are only beginning to be described, it has been well known that aged microglia are highly. The accumulation of lipofuscin and other non-degradable autofluorescent byproducts is believed to be due to impairment in disposal mechanisms and has been implicated in several neurodegenerative diseases including Alzheimer’s disease [17,18]
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