Senescent Microglia Harm the Brain via Lactate Generation

A sizable body of evidence supports a role for inflammatory microglia in the aging of the brain. Microglia are innate immune cells resident in the central nervous system, analogous to macrophages elsewhere in the body, but with an additional portfolio of duties relating to maintenance of the synapses that connect neurons. Most of the inflammatory microglia present in the aged brain are merely overactive, a maladaptive response to signs of damage and dysfunction characteristic of aging. This can include the presence of protein aggregates, unwanted molecules, cells, and bacteria passing through a leaking blood-brain barrier, or issues internal to the microglia themselves such as mislocalization of mitochondrial DNA into parts of the cell where it is inappropriately recognized as foreign.

Some inflammatory microglia are senescent, however. Cells become senescent constantly throughout life, but the immune system destroys them, or they undergo programmed cell death, and in youth this happens efficiently enough to prevent any accumulation. With advancing age, clearance of senescent cells falters, and their numbers steadily increase. While the proportion of cells that are senescent at any given time is never very large, even in late life, senescent cells energetically secrete a potent mix of inflammatory signals. They are very disruptive to normal tissue function, even through comparatively few in number. Today's open access paper examines one of the many specific ways in which the metabolites produced by senescent microglia may be disruptive to brain tissue.

H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear.

Compelling evidence suggests that abnormal histone modifications influences the translation of cellular metabolic intermediates into changes in gene transcription and expression. This is mediated by cellular intermediary metabolites which serve as cofactors that either add or remove chromatin modifications, induced by chromatin modifying enzymes. Concentration changes in these cellular metabolic intermediates may up- or down-regulate gene expression by altering chromatin states. A recent study found that lactate, a product of glycolysis and a significant energy source, can regulates gene transcription via lactylation of histones through fluctuations in lactate content in cells, representing a new post-translational modification contributor to the epigenetic landscape.

Several lines of evidence suggest that senescent cells are still metabolically active, and can induce changes in their environment through secreted molecules or by switching energy metabolism fashion. Senescent cells are associated with a shift towards glycolysis. In this work, we found that lactate levels are significantly increased in senescent microglia, indicating that senescent microglia switch their metabolism from OXPHOS to aerobic glycolysis, which produces ATP rapidly but also generates massive lactate. Moreover, senescent microglia-trigged accumulation of lactate caused enhanced histone lysine lactylation (Kla) levels, contributing to the development and progression of brain aging and Alzheimer's disease pathogenesis. These preliminary results suggest that the metabolic transition to aerobic glycolysis of senescent microglia may also affect itself and its local environment by affecting neuroinflammation through histone Kla-mediated epigenetics.