Neuroimmunology of healthy brain aging

Abstract

Aging involves progressive deterioration away from homeostasis. Whereas the healthy adult brain maintains neuroimmune cells in a surveillant and homeostatic state, aged glial cells have a hyperreactive phenotype. These age-related pro-inflammatory biases are driven in part by cell-intrinsic factors, including increased cell priming and pro-inflammatory cell states. In addition, the aged inflammatory milieu is shaped by an altered environment, such as amplified danger signals and cytokines and dysregulated glymphatic function. These cell-instrinsic and environmental factors conspire to heighten the age-related risk for neuroimmune activation and associated pathology. In this review, we discuss cellular and molecular neuroimmune shifts with "healthy" aging; how these age-related changes affect physiology and behavior; and how recent research has revealed neuroimmune pathways and targets for improving health span.

Figure 1

Aging is associated with compensatory shifts in CNS physiology and function, which collaborate to increase neuroimmune priming and pro-inflammatory bias. Left schematic: The neuroimmune system involves several key components: (1) parenchymal neuroimmune cells; (2) glymphatic flow, communication, and clearance via lymphatic vessels, dural venous sinuses, and cervical lymph nodes; and (3) bi-directional communication with the periphery via the vagus nerve, the gut-CNS axis, and other routes (omitted for clarity). Letters A-C highlight representative areas described in the right panel. Letters A-C highlight representative areas described in the right panel. a. The healthy adult CNS parenchyma contains homeostatic microglia and astrocytes, which maintain low baseline inflammatory tone, efficiently phagocytose cells and debris, and resolve sickness and inflammatory responses. The healthy aged CNS parenchyma includes neuroimmune cells with a “primed” phenotype - these cells are hyperreactive to insult, show impaired phagocytic capacity and processing, and have less effective immune resolution ability. The aged CNS also exhibits increased accumulation of inflammatory mediators, such as cytokines and damage-associated molecular patterns (DAMPs). Aging is also associated with aberrant parenchymal accumulation of immune cells typically found in the periphery, such as T cells. b. The healthy adult BBB maintains a cohesive barrier, enabling bi-directional active transport of specific proteins. The glymphatic system clears debris and excess metabolites. In the aged CNS, BBB integrity is reduced, enabling aberrant entry of toxins and cells, in parallel with reduced solute-specific transport. Glymphatic flow is less efficient at clearing debris; this amplifies accumulation of immunomodulatory mediators. c. CNS-periphery communication in the healthy adult contributes to low inflammatory tone at baseline; with aging, increased T cell numbers and shifted T cell proportions contribute to increased pro-inflammatory bias.

Figure 2

Timeline of aging and neuroimmunity in humans and mice. Top: Comparison of life history phases of humans (in years) and mice (in months) – including pre-puberty, young adult, middle aged, and aged phases. The final age of the “aged” phase is a stage at which ~85% of individuals (humans or mice) remain alive. Bottom: Neuroimmune activities across the lifespan. Neuroimmunity through young adulthood is characterized by high inflammatory resolution capacity and phagocytic efficiency, and low baseline inflammatory tone. Middle age is a time of shifting neuroinflammatory milieu. The aged human and mouse has amplified neuroinflammatory priming and reactivity, and impaired ability to phagocytose and resolve inflammation.