title: Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.
abstract: Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.
authors.affiliation: Laboratory of Experimental Gerontology, National Institute on Aging, Baltimore, Maryland, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Castellano
authors.forename: Bonnie R
authors.initials: BR
authors.lastname: Fletcher
authors.forename: Bennett
authors.initials: B
authors.lastname: Kelley-Bell
authors.forename: David H
authors.initials: DH
authors.lastname: Kim
authors.forename: Michela
authors.initials: M
authors.lastname: Gallagher
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rapp
mesh_terms: D000107:Acetylation; D000375:Aging / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006624:Hippocampus / Q000503:physiopathology*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D015999:Multivariate Analysis; D011499:Protein Processing, Post-Translational; D051381:Rats; D020318:Rats, Long-Evans; D013037:Spatial Behavior / Q000502:physiology; D057170:Translational Research, Biomedical
chemical_list: D006657:Histones; D050882:CREB-Binding Protein; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1