ABSTRACT: Summary Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility, especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and BBC3, and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity. Graphical Abstract Highlights • The molecular footprint of aging in metabolic tissues is tissue specific• Distinct omic layers have common functional enrichments of aging-related gene sets• Few conserved transcription factors (TFs) may control the molecular footprint of aging• Mendelian randomization shows evidence of these TFs’ implications in human aging Bou Sleiman et al. use multiple genomic methods to characterize the global footprint of aging in different mouse and human tissues. They identify regulators of gene expression that may play a role in the process and show evidence of their relevance in aging in human population data.
