Reviewing the Aging of Microglia
Microglia are a form of specialized immune cell resident in the central nervous system, responsible for mounting a defense against pathogens and clearing out harmful waste materials from brain tissue. They also assist more directly in the function of neurons and neural connections, however. Like all other parts of the immune system, microglia become damaged and dysfunctional with advancing age, and the research community is attempting to better understand this failure in order to address it in some way. There have been initial attempts to try to reverse the signaling environment for microglia in older animals, for example, though it may be that delivering young microglia will turn out to be a more effective stopgap approach. Ultimately, the underlying damage that causes aging and all its dysfunction will have to be repaired in order to put a stop to this and all other forms of degeneration.
The effects of aging on the central nervous system (CNS) are widespread, as are systemic changes in peripheral tissues. The importance of communication between the CNS and the periphery is increasingly recognized, and may be mediated by systemic factors, the autonomic nervous system, commensal bacteria (i.e., the microbiome) and/or the neuro-immune axis. Age-related changes in CNS homeostasis are not solely intrinsic in nature, but are mediated through bidirectional communication between the CNS and the systemic environment. Differences in neuronal function have been observed in the CNS with age, but it is becoming increasingly apparent that it is possible to slow, or even reverse, aging by restoring "youthful" peripheral tissue compartments. This includes the bone marrow niche that gives rise to the body's immune system, which can have a beneficial positive feedback effect on distant areas including the CNS.
No cell is protected from the detrimental effects of aging, and this includes the primary immune cell of the CNS, the resident tissue macrophages known as microglia. These cells represent 5%-15% of all brain cells, and are considered to be the housemaids of the CNS, providing nourishment and support to neighboring neurons, clearing debris, and being the first responders to foreign stimuli. Like their neuronal counterparts, microglia are believed to be post-mitotic and long-lived, with minimal, if any, turnover. Although recent depletion studies imply the existence of latent microglia progenitors, it is not clear what role this proposed population of cells may have in replenishing microglia populations under normal homeostatic conditions across the lifespan. Thus, these cells may still be viewed as especially vulnerable to the cumulative effects of aging, and thus poised to negatively impact the neurovascular niche as a result of a compromised ability to perform essential 'house-keeping' functions. While the role of aging on circulating macrophages and other lymphoid-associated myeloid cells has received significant attention in recent years, our understanding of the age-related changes in the function of CNS-resident microglia is less clear.
Young microglia gradually transition from a ramified morphological state to a deramified, spheroid formation with abnormal processes with chronological age. Several cytoplasmic features are hallmarks of microglial senescence including increased granule formation, autofluorescent pigments such as lipofuscin, and process fragmentation. Age-related neuronal loss reduces the overall level of immunoinhibitory molecules required to maintain microglia in a quiescent state. Basal increases in inflammatory signaling are associated with enhanced reactive oxygen species (ROS) production which results in the generation of free radicals, lipid peroxidation, and DNA damage. This positive feedback loop is further compounded by defects in lysosomal digestion and autophagy, resulting in the potentially toxic buildup of indigestible material. Concurrent reductions in process motility and phagocytic activity lead to decreased immune surveillance and debris clearance, resulting in plaque formation. In turn, microglia activation triggers astrocyte activation and promotes the recruitment of T cells into the aging brain.
These pathological features of microglial aging are highly influenced by the systemic environment. Diminished levels of circulating anti-aging factors in conjunction with increased concentrations of pro-aging factors are critical drivers of microglial senescence. For example, diminished estrogen levels in older females are associated with elevated expression of macrophage-associated genes in the brain. Therapeutic interventions intended to increase anti-aging factors and decrease pro-aging factors appear to be able to halt or delay microglia aging, enhance neurogenesis, and improve cognitive function.