A Novel Epigenetic Clock for Brain Aging

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ABSTRACT Biomarkers of aging are critical to effective research promoting the healthspan. There is a particularly urgent need for molecular biomarkers of brain aging; deaths due to neurodegenerative diseases have increased, in contrast to decreases in heart disease and cancer mortality. Epigenetic dysregulation is clearly implicated in brain aging, Alzheimer dementia, and other neurologic diseases. Epigenetic clock biomarkers combine DNAm levels across select CpG sites to estimate biologic age; epigenetic clocks strongly predict mortality, and several are modestly associated with neurologic outcomes. However, while specific pediatric clocks have now been developed to target biologic aging in younger age groups, no clocks to date target older populations or focus on pathways mechanistically implicated in aging. We propose here a novel epigenetic clock, built on ribosomal DNA methylation (rDNAm). The rDNA locus harbors fundamental, evolutionarily conserved aging mechanisms, and rDNAm has greater association with age than any other segment of the genome - yielding an efficient and effective epigenetic clock biomarker. In initial work, we reported an rDNAm clock trained in mouse blood was well-calibrated in humans and canids. Thus, the rDNA may represent a compelling dimension of epigenetic regulation, providing complementary strengths to established clocks. We propose research constructing a rDNAm clock of brain aging. Indeed, a recent review of epigenetic clocks recommended new development of such specialized clocks, rooted in specific tissues and pathways, to advance research in the field. The proposed Aims utilize the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), with 1450 brain specimens (including a subset with blood samples), and extensive phenotypic data. In Aim 1, we will document rDNAm states in dorsolateral pre-frontal cortex (DLPFC), and train a rDNAm clock in 800 specimens age >65 years, to enhance applications to aging brain. We will then test relations of the rDNAm brain clock to Alzheimer disease neuropathologic traits in the remaining 650 ROSMAP DLPFC. In Aim 2, we will evaluate the rDNAm brain clock in two further brain regions (primary occipital cortex, inferior anterior temporal cortex), and in blood samples as a more accessible tissue for research. In Aim 3, we will contrast the rDNAm brain clock to existing clocks. IMPACT: Our focus on the highly conserved rDNA locus may improve application of the rDNAm clock across tissues, while links of rDNA to aging and neurobiology could enhance applications to brain health. Proposed Aims can yield novel tools to evaluate brain age, predict risk of neurodegenerative diseases, provide new insights into mechanisms underlying neuro-degeneration, and identify interventions to delay brain aging. Additionally, given the centrality of rDNA in cellular metabolism and aging, we will add to a wealth of high-dimensional data for larger research in these Cohorts.