Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression

Seung Jae Lee; Coleen T. Murphy; Cynthia Kenyon

doi:10.1016/j.cmet.2009.10.003

Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression

Seung Jae Lee
, Coleen T. Murphy
, Cynthia Kenyon

Research output: Contribution to journal › Article › peer-review

299 Scopus citations

Abstract

Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.

Original language	English (US)
Pages (from-to)	379-391
Number of pages	13
Journal	Cell Metabolism
Volume	10
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2009.10.003
State	Published - Nov 4 2009
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Physiology
Cell Biology

Keywords

HUMDISEASE

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10.1016/j.cmet.2009.10.003

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title = "Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression",

abstract = "Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2\%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.",

keywords = "HUMDISEASE",

author = "Lee, \{Seung Jae\} and Murphy, \{Coleen T.\} and Cynthia Kenyon",

note = "Funding Information: We thank T. Lamitina, G. Ruvkun, and the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources, for providing some strains and all Kenyon lab members for sharing outcrossed strains and for helpful comments on the experiments, data analysis, and manuscript. We also thank T. Lamitina for valuable suggestions on osm-8 and gpdh-1; gpdh-2 mutant experiments, M. Gaglia for initiating experiments on dauer formation, Vera Tenberg for performing some life span experiments, A.B. Hwang and J.S. Yang for technical help during revision, and B. Koo and Y.J. Seok for providing ΔPTS E. coli. S.-J.L. was an Ellison Medical Foundation fellow of the Life Sciences Research Foundation and was also supported by a postdoctoral fellowship from the American Heart Association, Western States Affiliate. This work was supported by NIH grant \#AG11816 to C.K., who is the director of the UCSF Hillblom Center for the Biology of Aging, an American Cancer Society Professor, and a cofounder of the biotechnology company Elixir Pharmaceuticals. The data shown in Figure S7 E, additional experiments requested by reviewers, and the salary of S.-J.L during revision were supported by Korean government grant World Class University Program \#R31-2008-000-10100-0. The majority of the experiments were performed by S.-J.L. C.T.M. discovered that glucose affected insulin gene expression using an ins-7::GFP fusion strain. C.K. performed the initial glucose experiments involving wild-type and daf-16 mutants. S.-J.L and C.K. designed experiments and wrote the paper. ",

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doi = "10.1016/j.cmet.2009.10.003",

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AU - Murphy, Coleen T.

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N1 - Funding Information: We thank T. Lamitina, G. Ruvkun, and the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources, for providing some strains and all Kenyon lab members for sharing outcrossed strains and for helpful comments on the experiments, data analysis, and manuscript. We also thank T. Lamitina for valuable suggestions on osm-8 and gpdh-1; gpdh-2 mutant experiments, M. Gaglia for initiating experiments on dauer formation, Vera Tenberg for performing some life span experiments, A.B. Hwang and J.S. Yang for technical help during revision, and B. Koo and Y.J. Seok for providing ΔPTS E. coli. S.-J.L. was an Ellison Medical Foundation fellow of the Life Sciences Research Foundation and was also supported by a postdoctoral fellowship from the American Heart Association, Western States Affiliate. This work was supported by NIH grant #AG11816 to C.K., who is the director of the UCSF Hillblom Center for the Biology of Aging, an American Cancer Society Professor, and a cofounder of the biotechnology company Elixir Pharmaceuticals. The data shown in Figure S7 E, additional experiments requested by reviewers, and the salary of S.-J.L during revision were supported by Korean government grant World Class University Program #R31-2008-000-10100-0. The majority of the experiments were performed by S.-J.L. C.T.M. discovered that glucose affected insulin gene expression using an ins-7::GFP fusion strain. C.K. performed the initial glucose experiments involving wild-type and daf-16 mutants. S.-J.L and C.K. designed experiments and wrote the paper.

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N2 - Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.

AB - Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.

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Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression

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