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.
It should be noted that the majority of studies that have assessed epigenetic effects of rejuvenation strategies in the brain have analyzed epigenetic patterns in dissected hippocampus tissue and not selectively in neurons.
Due to the predominant abundance of neurons in the hippocampus, the detected epigenetic alterations likely originate from neurons, but a contribution of other cell types cannot be excluded.
Besides neurons, also glial cells, including microglia, astrocytes, oligodendrocytes and neural stem cells, are affected by aging but stimulated by rejuvenating interventions, and their age-related impairments critically contribute to cognitive decline.
Accumulating evidence suggests that epigenetic control is also important for glial cell function and age-related epigenetic and transcriptomic alterations have also been described in glial cells.
For instance, Li and colleagues have reported enhanced chromatin acces-sibility at the promoters of immune activation-associated genes in aged microglia, which correlated with enhanced transcription of those genes and might mediate the elevated neuroinflammation found in the aged brain.
Analyzing cell type-specific epigenetic aging signatures in the brain and the potential for their rejuvenation might aid our understanding of brain aging and cognitive decline in the future.
Moreover, there is considerable communication between cell types in the brain, with neuronal function being controlled by signaling cues from glial cells.
Comentarios