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OFHHD: Age-related cognitive decline is an important concern in the United States, as approximately 20% of the US population is expected to be age 65 or older by year 2030. Understanding the molecular mechansims of brain aging to prolong healthy cognitive function is therefore increasingly important as the population ages and older people remain in the work force. Brain cells exhibit profound and heterogeneous changes during aging at molecular and cellular levels. The simple intervention of physical exercise has emerged as a major positive modulator of cognitive function in aging. In response to RFA-RM-20-005, we have formed an interdisciplinary team with expertise in single-cell genomics, neural circuitry, and aging, to investigate age- and physical activity- related changes of 4D nucleome in post-mortem human brain hippocampus cells across the lifespan with single- cell resolution. We hypothesize that cell-type-specific re-organization of nucleome occurs in the human hippocampal brain region during aging and with physical activity. The changes in nucleome in turn control brain epigenome and transcriptome, modulating neural circuit functionality. The “Methyl-HiC”, a new approach for joint profiling of DNA methylation and chromatin contacts in single cells, combined with “Paired-seq”, an ultra- high-throughput method for single-cell joint analysis of open chromatin and transcriptome, will be used to interrogate the chromatin architecture along with DNA methylation, chromatin accessibility and gene expression in the human hippocampus. In Aim 1, we will determine changes in nucleome in major cell types of post-mortem human hippocampus across the life-span with 4 age ranges (20–39, 40–59, 60–79, and 80–99 years old). We will further correlate these changes in nucleome with epigenome and transcriptome in each cell type, to identify vulnerable cell types during aging, and uncover potential gene regulatory programs that could be impacted by aging. In Aim 2, we will determine how physical activity modifies and restores nucleome in specific human hippocampal cell types. We will study two age-matched cognitively–healthy cohorts (70-99 years old) with either high level or low level physical activity, as measured by wearable activity monitors. We will correlate restorative effects on nucleome with epigenome and transcriptome. In Aim 3, we will map how aging and exercise alter nucleome in specific hippocampal cell types with highly controlled quantifiable physical activity in the mouse model, for comparison with human data. These mouse studies allow the exercise variable to be investigated in isolation from effects of other lifestyle factors that can affect hippocampal nucleome, which is not possible with human subjects. The proposed research will help to transform our ability to understand the mechanisms of chromatin organization and function in the context of human brain aging.