RNA dynamics and co-translational decay in aging and aging-related disease

National Institute On Aging

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Abstract

While genomes encode the information for cellular function, biological complexity arises from higher-order interactions and gene regulatory programs. Dissecting these mechanisms is essential for understanding polygenic processes such as aging. We investigate how aging disrupts post-transcriptional gene regulation through widespread, low-effect changes that collectively impair homeostasis and resilience. We combine high-throughput short- and long-read RNA sequencing at single-cell and spatial resolution with machine learning to model RNA metabolism, processing, translation, and decay. We study stress response regulation in normal conditions and in senescence using ribosome profiling, nanopore sequencing, and proteomics to define how RNA dynamics shape the senescence-associated secretory phenotype. In the aging brain, we map transcriptomic complexity using direct RNA, single-cell and spatial transcriptomics, and statistical modeling to uncover isoform diversity and RNA modifications. We also examine RNA-binding proteins and alternative splicing in aging-associated diseases, such as neurodegeneration.