Complex Regulation of Protocadherin Epigenetics on Aging-Related Brain Health

Life expectancy continues to increase in the high-income world due to advances in medical care; however, quality of life declines with increasing age due to normal aging processes. Current research suggests that various aspects of aging are genetically modulated and thus may be slowed via genetic modification. Here, we show evidence for epigenetic modulation of the aging process in the brain from over 1800 individuals as part of the Framingham Heart Study. We investigated the methylation of genes in the protocadherin (PCDH) clusters, including the alpha (PCHDA), beta (PCDHB), and gamma (PCDHG) clusters. Reduced PCDHG, elevated PCDHA, and elevated PCDHB methylation levels were associated with substantial reductions in the rate of decline of regional white matter volume as well as certain cognitive skills, independent of overall accelerated or retarded aging as estimated by a DNA clock. These results are likely due to the different effects of the expression of genes in the alpha, beta, and gamma PCHD clusters and suggest that experience-based aging processes related to a decline in regional brain volume and select cognitive skills may be slowed via targeted epigenetic modifications.