Targeting neuronal epigenomes for brain rejuvenation

Abstract

Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain.

Keywords: Cognitive Decline; Epigenetic Rejuvenation; Epigenome Editing; Neuron Aging; Neuronal Epigenome.

Figure 1. The aging neuronal epigenome.

Neuron-specific epigenetic patterns are profoundly altered in the aged brain, contributing to impaired gene regulation and ultimately neuron dysfunction. The age-related degradation of the nuclear lamina affects the distribution of chromatin in the nucleus and leads to heterochromatin instability. At constitutively silenced, heterochromatin regions, loss of repressive H3K9me3 and DNA hypomethylation have been associated with spurious transcriptional activation of retrotransposons and neuroinflammation. Altered patterns of DNA methylation, histone marks and RNA methylation at regulatory elements and gene bodies of neuronal plasticity-related genes have been associated with impaired neuronal gene expression in the aged brain. Please note that the boxes “intact/impaired neuronal gene regulation” depict schematic summaries of age-related epigenetic changes reported for different neuronal genes in separate studies. The simultaneous profiling of the depicted epigenetic marks in the same neuron type has not yet been reported, and the depicted epigenetic patterns will likely differ depending on the specific genomic locus.

Figure 2. Epigenetic rejuvenation strategies to counteract cognitive decline.

Summarized are potential strategies to specifically target neuronal epigenomes (top) and systemic brain rejuvenation interventions, for which modulating effects on the neuronal epigenome have been reported (bottom).