ASTROCYTE METABOLISM MEETS EPIGENETICS

In recent decades, increasing life expectancy has brought a rising prevalence of cognitive decline and age-related brain disorders. A hallmark of the aging brain is the progressive loss of aerobic glycolysis; a metabolic trait tightly linked to synaptic plasticity and learning processes in which astrocytic-derived lactate plays a key role.
Positioned at the interface between neurons and the brain vasculature, astrocytes act as systemic metabolic sensors and supply neurons with lactate to sustain synaptic activity. Beyond its metabolic role, lactate serves as a signalling molecule capable of modifying chromatin through histone lysine lactylation (Kla).
In this context, lifestyle is a modifiable factor determinant for brain metabolism and cognitive performance. Our work investigates the differential impact of sedentary or active aging on the metabolism-driven epigenetic modifications in mice astrocytes.
Ex vivo metabolic flux analyses in isolated astrocytes reveal a glycolytic decline during sedentary aging, an effect that is prevented by sustained physical activity. In parallel, we describe that astrocytic histone Kla correlates with glycolytic activity. Altogether, our findings support a model in which lifestyle modulates metabolism-dependent epigenetic regulation in astrocytes, suggesting that histone lactylation may act as a molecular link between glycolytic activity, gene expression, and cognitive fitness during aging.