Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.

Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.

Vitamin D-RAAS Connection: An Integrative Standpoint into Cardiovascular and Neuroinflammatory Disorders.

BACKGROUND: The neuroinflammatory process is associated with the pathogenesis of many cardiovascular disorders, particularly with hypertension. In this regard, the deficiency of vitamin D seems to increase the risk of cardiovascular pathologies related to neuroinflammation. Long-term lack of vitamin D leads to over-activation of the renin-angiotensin-aldosterone system (RAAS), one of the essential mechanisms of blood pressure regulation. PURPOSE OF REVIEW: This review summarizes the latest studies carried out to evaluate the primary mechanisms underlying the neuroprotective effect of vitamin D and its receptors (VDR) in the central nervous system. Besides, the present article condenses the evidence supporting the link between vitamin D and the RAAS in hypertension and neuroinflammation. Highlights Standpoints: Vitamin D deficiency is highly prevalent in the world, and the rising prevalence of neuroinflammatory diseases and associated pathologies such as hypertension around the world justifies the urgent need of searching new and more effective therapeutic methods that could be related to RAAS modulation and vitamin D levels management.