Astrocytic metabolism-driven epigenetics at the cornerstone of cognitive aging

Cognitive impairment is a major source of disability and dependence during aging. Up to 40% of dementia cases are attributable to modifiable environmental risk factors, namely lifestyle, which can be actionable for prevention before the onset of cognitive decline. Physical activity and nutrition comprise promising modifiable factors affecting cognitive aging, but how the lifestyle affects cognition is not fully explained. Because of their unique location at the interface between blood vessels and synapses, astrocytes are strategically positioned to translate lifestyle contexts into specific cognitive shapes. Work from our group has demonstrated that astrocytic metabolism is remarkably dynamic and alternates lactate, ß-hydroxybutyrate and acetyl-coenzyme A production. Importantly, preliminary data indicate that these metabolites directly bind histones within astrocytes as epigenetic regulatory adaptive mechanisms. In NeuroSTARS, we will address whether such epigenetic adaptation is dictated by lifestyle-driven modulation of astrocytic metabolism to underpin cognitive performance across the lifespan. In mice subjected to controlled physical activity and dietary contexts, in combination with genetic manipulation of pivotal metabolic pathways in astrocytes, using cutting-edge metabolism and cognition assessment tools, we will (i) identify how astrocytic metabolism adapts to different lifestyle contexts throughout life, (ii) decipher the lifestyle-induced metabolic pathways that impact on metabolites-driven epigenetic regulation in astrocytes, and (iii) define the mechanism that causally links lifestyle-induced metabolism-driven epigenetic regulation within astrocytes with cognition across the lifespan. The expected output will reveal that the metabolism of astrocytes is instrumental in the coupling between lifestyle and age-associated cognitive decline, challenging the view that it merely serves to meet the energy needs of neurotransmission.