Data supplement for Fig 4.

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.衰老科学（Geroscience）旨在靶向衰老过程以延长健康寿命（healthspan）。然而，即便同基因个体（isogenic individuals）在自然衰老速率和对促长寿干预措施的响应性上也存在异质性，这限制了其转化应用潜力。本研究通过对仅根据可预测未来寿命的活体内小基因报告基因（minigene reporter）剪接模式筛选出的年轻同基因秀丽隐杆线虫（Caenorhabditis elegans）亚群进行RNA测序（RNAseq）分析，发现年轻线虫体内的预测寿命与脂质代谢（lipid metabolism）相关mRNA的可变剪接（alternative splicing）之间存在显著相关性。两种RNA剪接因子（RNA splicing factors）——逆转极性蛋白-1（Reversed Polarity-1, REPO-1）和剪接因子1（Splicing Factor 1, SFA-1）——在生命早期的活性，是秀丽隐杆线虫响应特定长寿干预措施的必要条件，且会导致脂肪含量发生情境特异性变化，这一变化可通过敲低其直接靶标POD-2/ACC1得以重现。此外，POD-2/ACC1与REPO-1/SFA-1一样，也是对应长寿干预措施所必需的。此外，在生命早期抑制REPO-1会使线虫对晚期启动的TORC1通路（TORC1 pathway）抑制产生抗性。综上，我们认为剪接因子活性可在生命早期构建细胞微环境，赋予机体对特定长寿干预措施的响应能力，这或可解释不同个体间干预疗效的差异。