The Contribution of Aging Astrocytes to Brain Inflammation and Disease
Astrocytes are supporting glial cells in the brain, and help to maintain much of the metabolism and structure of brain tissue. A sizable fraction of the brain is made up of astrocytes. In response to stress, infection, or injury astrocytes change to adopt a reactive state. Much like the inflammatory reaction of immune cells, this is helpful in the short term, but when sustained over the long term in response to the cell and tissue damage that drives aging, it contributes to the chronic inflammation and lost function of the aging brain.
Normal aging leads to a decline in homeostasis maintenance across tissues, particularly in regulation of organelle functions and response to damage. Across organ systems, key mitochondrial, proteostatic, and damage handling pathways decline during aging. In the central nervous system many of these regulatory functions are allocated to astrocytes under homeostatic conditions to enable efficient neuronal functioning. Astrocytes are key regulators of metabolism and energy generation that also sense and handle damage downstream of these and other cellular processes. Astrocytes are required for maintenance and regulation of synapse stability and neuronal activity, which become perturbed in advanced aging. Neurons also offload damaged species like dysfunctional organelles and reactive oxygen species-affected lipids to astrocytes for degradation. Understanding how astrocytes regulate these processes under homeostatic conditions and how normal functions decline during aging is crucial to our analysis of brain aging phenotypes and degeneration.
Astrocytes are perhaps best described for their roles in responding to insults, such as disease, infection/inflammation, neuronal trauma, and perturbations of organismal metabolism. In addition to the many functions performed by these cells under homeostasis, astrocytes under stress react to unique circumstances by enacting unique responses. These stress-responsive astrocytes, termed "reactive astrocytes," can lose homeostatic capabilities and/or gain additional functions such as proliferation and scar formation, neurotoxicity, or immune cell regulation, among others. The context dependent and multifaceted nature of astrocyte reactivity suggests that states of astrocytes during normal aging are likely reliant on extrinsic cues that accumulate across the lifespan. For example, aging is associated with increased inflammation and infection, as well as senescence and metabolic disease. How astrocytes synthesize these cues during aging and alter their baseline states is largely unknown.
Specific changes in aged astrocytes, both intrinsic and related to their long-term cell-cell interactions as organisms age, are poorly understood and have been difficult to interrogate with high fidelity. New and developing analytical tools such as single cell sequencing and multi-omic characterization strategies have begun to describe aged astrocytes, but more work is needed to fully understand the functional consequences of these alterations and how changes occur in different contexts and disease conditions. Improved functional characterization of aged astrocytes will likely provide insight into aging-related disease mechanisms and propose avenues to address aging brain phenotypes moving forward.