Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY Concurrent increase in life expectancy and the prevalence of age-related metabolic diseases highlights how the biology of aging and metabolic dysfunction are intertwined. Dietary restriction (DR) promotes healthy aging and disease resistance through the manipulation of canonical nutrient sensing pathways, like TORC1 (target of rapamycin complex I) signaling. However, manipulation of such critical metabolic pathways results in pleiotropic effects, making it critical to understand their distinct downstream mechanisms. Previous studies in C. elegans suggest a critical role for the spliceosome component REPO-1 (reverse polarity 1) in modulating lipid accumulation and longevity downstream of DR and TORC1 specifically. Knockdown of REPO-1 causes an increase in lipid accumulation in genetic models of DR and reduced TORC1 signaling. We have identified specific lipid species such as the C18:1 fatty acid as targets of REPO-1 modulation. Additionally, REPO-1 binds pod-2 (polarity and osmotic sensitivity defect 1) Pre- mRNA and pod-2 is similarly and specifically required for DR and TORC1 lifespan extension. Further, knockdown of pod-2 phenotypically mimics knockdown of repo-1 causing increased lipid accumulation. However, it remains to be determined whether this constitutes a causal pathway. Therefore, the overarching aim of this proposal is to uncover the contribution of pre-mRNA splicing and lipid metabolism in TORC1 lifespan extension. My central hypothesis is that REPO-1 regulates TORC1 lifespan extension by modulating alternative splicing and specific lipid species through POD-2. In aim 1, we will use Crispr/Cas9 mediated tagging of endogenous REPO-1 to assess tissue-specific effects of REPO-1 on alternative splicing, modulation of lipid accumulation and longevity downstream of TORC1 signaling. In aim 2, we will achieve tissue- specific degradation of POD-2 to determine the tissue where it modulates longevity and fat reserves in TORC1 signaling. We will also define the changes to the lipidome of TORC1 regulated by POD-2, compare them to REPO-1 dependent changes, and test their contribution to longevity. Altogether this work will broaden our mechanistic understanding of RNA homeostasis as a novel paradigm of aging and physiology and expand our knowledge of target pathways to promote healthy aging.
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