Translatomic Changes During Cardiac Aging: Ribosomal Protein and Initiation Factor Interactions - Project Summary Translatomic Changes during cardiac aging: Ribosomal Protein and Initiation Factor interactions Montana State University Aging profoundly impacts cardiac structure and function, predisposing individuals to cardiovascular disease (CVD)—the leading cause of death in the U.S. As the population ages, understanding how aging remodels the heart at the molecular level is crucial for identifying strategies to improve healthspan and reduce mortality. Cardiac aging is characterized by proteomic remodeling, fibrosis, loss of proteostasis, and mitochondrial dysfunction, yet the mechanisms driving these changes remain poorly understood. Emerging evidence suggests that aging disrupts translational control, creating discordance between mRNA and protein levels. Ribosomes, the central machinery for protein synthesis, undergo compositional changes with age due to altered ribosomal protein (RP) expression, loss of stoichiometry, and impaired assembly. Interestingly, knockdown or overexpression of specific RPs can extend lifespan, suggesting that the ribosome actively shapes proteomic and aging outcomes, potentially through selective mRNA translation. We hypothesize that changes in RP subunits—using the large subunit protein RpL13 as a prototype— reprogram the cardiac translatome, thereby influencing proteostasis and aging. Preliminary studies show that RpL13 knockdown (KD) in the Drosophila heart induces transcriptomic, functional, and structural phenotypes that mimic cardiac aging, including fibrosis and contractile decline. Moreover, RpL13 genetically interacts with translation initiation factors (eIF3e, eIF3m) and extracellular matrix genes, suggesting that RpL13 coordinates translational and structural remodeling of the heart. Aim 1 will determine how RpL13 KD and overexpression (OE) influence cardiac aging phenotypes—contractility, rhythm, fibrosis, and proteostasis—and test genetic interactions with eIF3 subunits to identify modifiers of aging outcomes. Aim 2 will compare translatomic profiles of aged hearts and RpL13-perturbed hearts using Ribo-STAMP, an innovative in vivo method that captures ribosome-bound mRNAs through RNA editing. These analyses will identify mRNA targets whose translation changes with age or RpL13/eIF3 manipulation, revealing pathways that shape cardiac aging. Using the genetically tractable Drosophila model, which permits precise, tissue- and age-specific control of gene expression, we will dissect how RP–eIF3 interactions remodel translation during aging. This work establishes a new conceptual framework where specific ribosomal subunits and translation factors determine selective mRNA translation to modulate cardiac aging. Understanding these mechanisms could uncover novel therapeutic targets to preserve proteostasis, maintain cardiac function, and delay age-associated disease.
