Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans

Cholesterol has attracted significant attention as a possible lifespan regulator. It has been reported that serum cholesterol levels have an impact on mortality due to age-related disorders such as cardiovascular disease. Diet is also known to be an important lifespan regulator. Dietary restriction retards the onset of age-related diseases and extends lifespan in various organisms. Although cholesterol and dietary restriction are known to be lifespan regulators, it remains to be established whether cholesterol is involved in dietary restriction-induced longevity. Here, we show that cholesterol deprivation suppresses longevity induced by intermittent fasting, which is one of the dietary restriction regimens that effectively extend lifespan. We also found that cholesterol is required for the fasting-induced upregulation of transcriptional target genes such as the insulin/IGF-1 pathway effector DAF-16 and that cholesterol deprivation suppresses the long lifespan of the insulin/IGF-1 receptor daf-2 mutant. Remarkably, we found that cholesterol plays an important role in the fasting-induced nuclear accumulation of DAF-16. Moreover, knockdown of the cholesterol-binding protein NSBP-1, which has been shown to bind to DAF-16 in a cholesterol-dependent manner and to regulate DAF-16 activity, suppresses both fasting-induced longevity and DAF-16 nuclear accumulation. Furthermore, this suppression was not additive to the cholesterol deprivation-induced suppression, which suggests that NSBP-1 mediates, at least in part, the action of cholesterol to promote fasting-induced longevity and DAF-16 nuclear accumulation. These findings identify a novel role for cholesterol in the regulation of lifespan.胆固醇作为潜在的寿命调控因子，已受到广泛关注。已有研究表明，血清胆固醇水平会影响心血管疾病等年龄相关性疾病所致的死亡率。饮食同样被证实是关键的寿命调控因子：饮食限制可延缓多种生物的年龄相关性疾病发作，并延长其寿命。尽管胆固醇与饮食限制均为已知的寿命调控因子，但胆固醇是否参与饮食限制诱导的寿命延长，仍有待阐明。本研究证实，胆固醇剥夺可抑制间歇性禁食诱导的寿命延长——间歇性禁食是一类可有效延长寿命的饮食限制方案。我们还发现，禁食诱导的转录靶基因（如胰岛素/胰岛素样生长因子1通路效应因子DAF-16）的上调过程依赖于胆固醇，而胆固醇剥夺可抑制胰岛素/胰岛素样生长因子1受体daf-2突变体的长寿表型。值得注意的是，我们发现胆固醇在禁食诱导的DAF-16核积累过程中发挥关键作用。此外，胆固醇结合蛋白NSBP-1可通过胆固醇依赖方式结合DAF-16并调控其活性，敲低该蛋白可同时抑制禁食诱导的寿命延长与DAF-16核积累。进一步研究发现，该抑制效应与胆固醇剥夺所致的抑制效应无叠加性，这表明NSBP-1至少部分介导了胆固醇促进禁食诱导寿命延长及DAF-16核积累的作用。本研究结果揭示了胆固醇在寿命调控中的全新功能。