Aging-related cognitive decline begins for most of us when we are in our late 40s. Deterioration is mosty pronounced the ability to recall facts and experiences (declarative memory) and has been associated with aberrant changes in gene expression in the brain's hippocampus and frontal lobe. Peleg et al. now find support for an emerging hypothesis that changes in the epigenetic modification of chromatin in the adult central nervous system drive cognitive decline. They show that restoring a reaction that places acetyl groups on the histone proteins that regulate gene expression reinstates the expression of learning-induced genes.
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.