The Epigenetics of Aging: Understanding neurodegeneration at the gene transcription level

Martinos News

Over the past century, life expectancy has doubled. Consider for a moment the impact of this factoid on our interpretation of the aging brain. Prior to the 20thcentury – indeed, throughout nearly all of history – there was likely no evolutionary pressure for humans to live beyond reproductive age. What does this mean for how the human brain ages at the gene transcription level?

In a paper published today in the journal Nature Communications, investigators with the Hooker Research Group at the MGH Martinos Center sought to answer this question. In the study reported in the paper, they measured, for the first time, biological mechanisms possibly underpinning age-driven changes in gene expression in the human brain.

The work was prompted by a desire to understand better the root causes of neurodegenerative disease. “Aging is the main risk factor for many neurodegenerative diseases and is associated with the deterioration of brain structure and function,” says Tonya Gilbert, a postdoctoral fellow in the Hooker Research Group and co-first author of the paper with the group’s Nicole Zürcher. “Animals models suggest that histone deacetylases (HDACs), enzymes that directly regulate gene transcription, may tip the balance from healthy to pathological aging. We wanted to learn whether HDAC expression changes across the human lifespan and relate HDAC expression levels to age-related alterations in brain structure.”

Using simultaneous MR-PET imaging, they measured in vivo HDAC expression concurrent with white matter microstructure across aging adults and between sexes. This was possible through the advance of [11C]Martinostat, a PET radiotracer discovered and developed by the Hooker Research Group. Martinostat enables, for the first time, imaging of epigenetic changes in the body.

The results of the study suggest that HDAC expression (and the resulting transcriptional changes) may be a significant driver of human neurobiology, including neurodegeneration in the aging human brain.

“The localization of HDAC changes with age in the white matter lead us to speculate that HDAC may be important in programming or reprogramming gene transcription in response to demyelination,” says the Martinos Center’s Jacob Hooker, senior author of the study. “This may have implications in many neurodegenerative diseases and we’re currently looking at the association of HDAC changes in multiple sclerosis. We are also developing methods to reverse engineer the biology of the signal as it relates to aging.”