Data supplement for S2 and S3 Figs.

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）旨在靶向衰老进程以延长健康寿命（healthspan）。然而，即便同基因个体，其自然衰老速率与对促长寿干预手段的响应性仍存在异质性，这极大限制了相关研究的转化潜力。本研究仅通过可预测未来寿命的体内迷你基因报告基因（minigene reporter）的剪接模式，筛选得到年轻同基因秀丽隐杆线虫（Caenorhabditis elegans）亚群，并对其开展RNA测序（RNAseq）分析，结果发现：年轻线虫中，预测寿命与脂质代谢相关mRNA的可变剪接存在显著相关性。两种RNA剪接因子——反向极性因子1（Reversed Polarity-1, REPO-1）与剪接因子1（Splicing Factor 1, SFA-1）——在生命早期的活性，是秀丽隐杆线虫对特定长寿干预手段产生响应的必要条件，且会引发脂肪含量的情境特异性变化；该变化可通过敲低其直接靶标POD-2/ACC1得以重现。此外，POD-2/ACC1同样是秀丽隐杆线虫响应REPO-1/SFA-1对应长寿干预手段的必需因子。不仅如此，在生命早期抑制REPO-1，会使线虫对晚期启动的TORC1通路抑制干预失去响应。综上，本研究提出：剪接因子在生命早期的活性可塑造细胞微环境，使机体能够响应特定的长寿干预手段，这或可解释个体间长寿干预疗效的差异。