Language
English
Publication Date
11-1-2025
Journal
PLOS Biology
DOI
10.1371/journal.pbio.3003504
PMID
41270125
PMCID
PMC12671814
PubMedCentral® Posted Date
11-21-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using RNAseq analysis of young, isogenic, subpopulations of Caenorhabditis elegans selected solely on the basis of the splicing pattern of an in vivo minigene reporter that is predictive of future life expectancy, we find a strong correlation in young animals between predicted life span and alternative splicing of mRNAs related to lipid metabolism. The activity of two RNA splicing factors, Reversed Polarity-1 (REPO-1) and Splicing Factor 1 (SFA-1), early in life is necessary for C. elegans response to specific longevity interventions and leads to context-specific changes to fat content that is mirrored by knockdown of their direct target POD-2/ACC1. Moreover, POD-2/ACC1 is required for the same longevity interventions as REPO-1/SFA-1. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together, we propose that splicing factor activity establishes a cellular landscape early in life that enables responsiveness to specific longevity interventions and may explain variance in efficacy between individuals.
Keywords
Animals, Caenorhabditis elegans, Longevity, Caenorhabditis elegans Proteins, RNA Splicing Factors, Alternative Splicing, Lipid Metabolism, Aging
Published Open-Access
yes
Recommended Citation
Dutta, Sneha; Perez Matos, Maria Camila; Heintz, Caroline; et al., "The Efficacy of Longevity Interventions in Caenorhabditis elegans Is Determined by the Early Life Activity of RNA Splicing Factors" (2025). Faculty, Staff and Students Publications. 6470.
https://digitalcommons.library.tmc.edu/baylor_docs/6470