GESTALT-Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing

National Institute On Aging

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Abstract

Progress in 2021: 1- GESTALT donors' recruitment is still ongoing. Donors' follow-up visits for years 2 and 4 are completed while follow up visits for year 6 just started. 2-Transcriptome: The RNA sequencing of the immune cells was completed for around 1400 samples. The cell-specific gene expression analysis was determined for 6 immune cells of 50 donors and published in 2022. The age-associate changes in gene expression analysis are ongoing and a manuscript is in preparation. The coding and long noncoding RNAs present in cultured primary Skin fibroblast from 82 donors were identified and this study was published this year in Aging cell. 3- Proteome: Proteomic studies of the 13 immune cells (around 1000 sample) from the 99 GESTALT donors was completed and the data analysis is in progress. 4- Epigenetics a. Chromatin Accessibility: Age-associate changes in chromatin accessibility were studied in monocytes and B cells (naive and memory). Monocytes open chromatin studies were performed in 21 donors (young: 20-55year n=12, old: 60-85 years n=9). PCA analysis of differentially open chromatin (DOC) identified three major clusters, only old (n=5), only young (n=7) and old and young together (n=4 O+5 Y). This heterogeneous healthy old population was characterized by significant enrichment of DOC comprising NF-kappaB and ETS motifs. The genes associated with DOCs corresponded to the enrichment of pro-inflammatory pathways involving NF-kappaB and NOD-like receptor signaling, demonstrating heterogenous inflamm-aging process. Furthermore, the monocytes of the 5 old donors show distinct cytokine expression profile in intracellular cytokine assays. Inflammatory cytokines such as IL-6 and IL-1beta were already expressed in the baseline status. However, TNFalpha was neither expressed at the baseline nor after endotoxin activation (LPS). The current analysis of chromatin accessibility variations with DNA methylation, transcriptome, and serum cytokine levels are determined and a manuscript is in preparation. B cell open chromatin studies identified the naive and memory features of lymphocytes such as presence of OCT motif in memory specific open chromatin and ETS in naive B cells. Manuscript describing the lymphocytes differentiation properties is in preparation. b. Methylome: DNA methylation data was obtained from 99 donor and the cell specific methylation analysis was published last year. This year the age-associate changes in DNA methylation data was published in elife. We further assayed DNA methylation and gene expression changes of naive to memory lymphocytes (B, CD4 and CD8 T cells) differentiation. These differentiation studies were accompanied with activation assays and a manuscript is in preparation.