title: Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ihara
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Uno
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyatake
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Honjoh
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address: nishida@lif.kyoto-u.ac.jp.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005215:Fasting; D051858:Forkhead Transcription Factors / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D009154:Mutation; D010196:Pancreatic Elastase / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; C108831:daf-16 protein, C elegans; D002784:Cholesterol; C107483:DAF-2 protein, C elegans; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D010196:Pancreatic Elastase; C017130:cholesterol-binding protein
keywords: Aging; Dietary restriction; Signal transduction