FIGURE 6.

m⁶A regulation in the brain with age and disease. Model of m⁶A regulation in the brain with aging. Top: m⁶A levels increase with age and in the brains of animals expressing human Aβ42 in neurons. m⁶A transcripts were mostly downregulated with age and with disease, and are enriched for neurogenesis and signaling pathways. Bottom: Knockdown of Mettl3 in neurons decreases lifespan and health span, increases translation efficiency of m⁶A transcripts, and increases DNA damage. These data suggest Mettl3 function is normally protective to neurons. Knockdown of Mettl3 in glia promotes lifespan and health span, and decreases translation efficiency of m⁶A modified transcripts. Mettl3 knockdown in glial cells also extends lifespan of animals expressing human tau, and mitigates tau phosphorylation pathology. These data indicate that Mettl3 activity is normally deleterious to glial function.