Neural Epigenetic Aging as a Driver of Cognitive Decline
Ever-shifting epigenetic marks on the genome determine its structure in the cell nucleus, and thus which portions of the genome are accessible to the machinery of gene expression, and thus which proteins are produced at a given time. This epigenetic regulation of gene expression changes in characteristic ways with age, and many of those alterations are clearly maladaptive. Hence the present interest in epigenetic reprogramming, in which researchers adapt some of the processes that take place during embryonic development in order to restore a youthful epigenetic state to adult cells. It is very much a work in progress, but early results in animal studies are promising.
Neurons undergo pronounced alterations in morphology and function throughout the lifespan, and these have been related to disturbed neuronal signaling and impaired information processing in the aged brain. The function of different neuron types in multiple brain areas is affected by aging, with the hippocampus and prefrontal cortex - both brain regions with key roles in memory storage and cognitive flexibility - being particularly compromised.
Since neurons are post-mitotic and mostly generated during early development, they represent one of the oldest cell types in the body. Therefore, to preserve their function throughout life, neurons are dependent on the long-term maintenance of molecular programs that define their neuronal identity and enable activity-induced plasticity in response to environmental cues. Yet, multiple studies have reported impairments in neuron-specific gene expression programs in the aging brain, including alterations in transcription, RNA processing, and protein levels, which have been linked to neuronal dysfunction. The long-term maintenance of neuronal gene expression programs critically depends on the epigenetic machinery, and accumulating evidence suggests impairments of epigenetic regulation as cell-intrinsic drivers of aging in neurons.
Intriguingly, recent studies suggest that neuronal epigenetic aging can be slowed down or reversed by rejuvenating interventions that are known to counteract age-related impairments in brain function, thus opening the field for therapeutic anti-aging strategies. Interventions shown to be effective include changes to lifestyle (such as exercise, environmental enrichment, and caloric restriction), the transfer of young blood factors or cellular reprogramming, among others. The malleability of the neuronal epigenome during aging suggests that it can be targeted to prevent epigenetic aging or even restore a youthful epigenetic state in aged neurons.