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Science 300 (5619): 644-647

Copyright © 2003 by the American Association for the Advancement of Science

DAF-16 Target Genes That Control C. elegans Life-Span and Metabolism

Siu Sylvia Lee,1 Scott Kennedy,1 Andrew C. Tolonen,2 Gary Ruvkun1*

Abstract: Signaling from the DAF-2/insulin receptor to the DAF-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla. To identify genes that mediate the conserved biological outputs of daf-2/insulin-like signaling, we usedcomparative genomics to identify 17 orthologous genes from Caenorhabditis and Drosophila, each of which bears a DAF-16 binding site in the promoter region. One-third of these DAF-16 downstream candidate genes were regulatedby daf-2/insulin-like signaling in C. elegans, and RNA interference inactivation of the candidates showed that many of these genes mediate distinct aspects of daf-16 function, including longevity, metabolism, anddevelopment.

1 Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA.
2 Department of Biology, Massachusetts Institute of Technology, 15 Vassar Street, Building 48-424, Cambridge, MA 02139, USA.

* To whom correspondence should be addressed. E-mail: ruvkun{at}

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G. Depuydt, F. Xie, V. A. Petyuk, N. Shanmugam, A. Smolders, I. Dhondt, H. M. Brewer, D. G. Camp II, R. D. Smith, and B. P. Braeckman (2013)
Mol. Cell. Proteomics 12, 3624-3639
   Abstract »    Full Text »    PDF »
A C-terminal truncated mutation of spr-3 gene extends lifespan in Caenorhabditis elegans.
P. Yang, R. Sun, M. Yao, W. Chen, Z. Wang, and J. Fei (2013)
Acta Biochim Biophys Sin 45, 540-548
   Abstract »    Full Text »    PDF »
Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development.
W. L. Hung, C. Hwang, S. Gao, E. H. Liao, J. Chitturi, Y. Wang, H. Li, C. Stigloher, J.-L. Bessereau, and M. Zhen (2013)
EMBO J. 32, 1745-1760
   Abstract »    Full Text »    PDF »
Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases.
Y. Zhang, Z.-H. Tang, Z. Ren, S.-L. Qu, M.-H. Liu, L.-S. Liu, and Z.-S. Jiang (2013)
Mol. Cell. Biol. 33, 1104-1113
   Abstract »    Full Text »    PDF »
Post-developmental microRNA expression is required for normal physiology, and regulates aging in parallel to insulin/IGF-1 signaling in C. elegans.
N. J. Lehrbach, C. Castro, K. J. Murfitt, C. Abreu-Goodger, J. L. Griffin, and E. A. Miska (2012)
RNA 18, 2220-2235
   Abstract »    Full Text »    PDF »
Integration of {beta}-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity.
J. A. Parker, R. P. Vazquez-Manrique, C. Tourette, F. Farina, N. Offner, A. Mukhopadhyay, A.-M. Orfila, A. Darbois, S. Menet, H. A. Tissenbaum, et al. (2012)
J. Neurosci. 32, 12630-12640
   Abstract »    Full Text »    PDF »
Involvement of the Up-regulated FoxO1 Expression in Follicular Granulosa Cell Apoptosis Induced by Oxidative Stress.
M. Shen, F. Lin, J. Zhang, Y. Tang, W.-K. Chen, and H. Liu (2012)
J. Biol. Chem. 287, 25727-25740
   Abstract »    Full Text »    PDF »
Forkhead Transcription Factor FOXO3a Protein Activates Nuclear Factor {kappa}B through B-cell lymphoma/leukemia 10 (BCL10) Protein and Promotes Tumor Cell Survival in Serum Deprivation.
Z. Li, H. Zhang, Y. Chen, L. Fan, and J. Fang (2012)
J. Biol. Chem. 287, 17737-17745
   Abstract »    Full Text »    PDF »
Aestivation: signaling and hypometabolism.
K. B. Storey and J. M. Storey (2012)
J. Exp. Biol. 215, 1425-1433
   Abstract »    Full Text »    PDF »
Discovery of Functional Gene Variants Associated With Human Longevity: Opportunities and Challenges.
C. Tazearslan, M. Cho, and Y. Suh (2012)
J Gerontol A Biol Sci Med Sci 67A, 376-383
   Abstract »    Full Text »    PDF »
A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila.
L. Palanker Musselman, J. L. Fink, K. Narzinski, P. V. Ramachandran, S. Sukumar Hathiramani, R. L. Cagan, and T. J. Baranski (2011)
Dis. Model. Mech. 4, 842-849
   Abstract »    Full Text »    PDF »
Applications of post-translational modifications of FoxO family proteins in biological functions.
Y. Zhao, Y. Wang, and W.-G. Zhu (2011)
J Mol Cell Biol 3, 276-282
   Abstract »    Full Text »    PDF »
Spontaneous Age-Related Neurite Branching in Caenorhabditis elegans.
E. M. H. Tank, K. E. Rodgers, and C. Kenyon (2011)
J. Neurosci. 31, 9279-9288
   Abstract »    Full Text »    PDF »
Foxo1 Mediates Insulin-like Growth Factor 1 (IGF1)/Insulin Regulation of Osteocalcin Expression by Antagonizing Runx2 in Osteoblasts.
S. Yang, H. Xu, S. Yu, H. Cao, J. Fan, C. Ge, R. T. Fransceschi, H. H. Dong, and G. Xiao (2011)
J. Biol. Chem. 286, 19149-19158
   Abstract »    Full Text »    PDF »
The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C. elegans.
X. Huang, H. Zhang, and H. Zhang (2011)
Development 138, 2059-2068
   Abstract »    Full Text »    PDF »
Two sides of lifespan regulating genes: pro-longevity or anti-longevity?.
S. Honjoh and E. Nishida (2011)
J. Biochem. 149, 381-388
   Abstract »    Full Text »    PDF »
Wnt Signaling and Aging-Related Heart Disorders.
A. T. Naito, I. Shiojima, and I. Komuro (2010)
Circ. Res. 107, 1295-1303
   Abstract »    Full Text »    PDF »
The role of insulin/IGF-like signaling in C. elegans longevity and aging.
R. Kaletsky and C. T. Murphy (2010)
Dis. Model. Mech. 3, 415-419
   Abstract »    Full Text »    PDF »
The Longevity Effect of Tannic Acid in Caenorhabditis elegans: Disposable Soma Meets Hormesis.
N. Saul, K. Pietsch, R. Menzel, S. R. Sturzenbaum, and C. E. W. Steinberg (2010)
J Gerontol A Biol Sci Med Sci 65A, 626-635
   Abstract »    Full Text »    PDF »
Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity.
S. Henis-Korenblit, P. Zhang, M. Hansen, M. McCormick, S.-J. Lee, M. Cary, and C. Kenyon (2010)
PNAS 107, 9730-9735
   Abstract »    Full Text »    PDF »
Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity.
D. C. Love, S. Ghosh, M. A. Mondoux, T. Fukushige, P. Wang, M. A. Wilson, W. B. Iser, C. A. Wolkow, M. W. Krause, and J. A. Hanover (2010)
PNAS 107, 7413-7418
   Abstract »    Full Text »    PDF »
FOXO3 Modulates Endothelial Gene Expression and Function by Classical and Alternative Mechanisms.
T. Czymai, D. Viemann, C. Sticht, G. Molema, M. Goebeler, and M. Schmidt (2010)
J. Biol. Chem. 285, 10163-10178
   Abstract »    Full Text »    PDF »
RNAi screens to identify components of gene networks that modulate aging in Caenorhabditis elegans.
Z. Ni and S. S. Lee (2010)
Briefings in Functional Genomics
   Abstract »    Full Text »    PDF »
C. elegans as Model for the Study of High Glucose- Mediated Life Span Reduction.
A. Schlotterer, G. Kukudov, F. Bozorgmehr, H. Hutter, X. Du, D. Oikonomou, Y. Ibrahim, F. Pfisterer, N. Rabbani, P. Thornalley, et al. (2009)
Diabetes 58, 2450-2456
   Abstract »    Full Text »    PDF »
Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice.
Y. Inuzuka, J. Okuda, T. Kawashima, T. Kato, S. Niizuma, Y. Tamaki, Y. Iwanaga, Y. Yoshida, R. Kosugi, K. Watanabe-Maeda, et al. (2009)
Circulation 120, 1695-1703
   Abstract »    Full Text »    PDF »
Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.
A. Ben-Zvi, E. A. Miller, and R. I. Morimoto (2009)
PNAS 106, 14914-14919
   Abstract »    Full Text »    PDF »
Inhibition of a eukaryotic initiation factor (eIF2B{delta}/F11A3.2) during adulthood extends lifespan in Caenorhabditis elegans.
D. Tohyama, A. Yamaguchi, and T. Yamashita (2008)
FASEB J 22, 4327-4337
   Abstract »    Full Text »    PDF »
Fat Metabolism Links Germline Stem Cells and Longevity in C. elegans.
M. C. Wang, E. J. O'Rourke, and G. Ruvkun (2008)
Science 322, 957-960
   Abstract »    Full Text »    PDF »
How to Live Long and Prosper: Autophagy, Mitochondria, and Aging.
W.-L. Yen and D. J. Klionsky (2008)
Physiology 23, 248-262
   Abstract »    Full Text »    PDF »
A branched-chain fatty acid is involved in post-embryonic growth control in parallel to the insulin receptor pathway and its biosynthesis is feedback-regulated in C. elegans.
M. Kniazeva, T. Euler, and M. Han (2008)
Genes & Dev. 22, 2102-2110
   Abstract »    Full Text »    PDF »
Studying gene function in Caenorhabditis elegans using RNA-mediated interference.
E. M. Maine (2008)
Briefings in Functional Genomics 7, 184-194
   Abstract »    Full Text »    PDF »
The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family: A CAENORHABDITIS ELEGANS MODEL OF TYPE I TYROSINEMIA.
A. L. Fisher, K. E. Page, G. J. Lithgow, and L. Nash (2008)
J. Biol. Chem. 283, 9127-9135
   Abstract »    Full Text »    PDF »
Distinct Activities of the Germline and Somatic Reproductive Tissues in the Regulation of Caenorhabditis elegans' Longevity.
T. M. Yamawaki, N. Arantes-Oliveira, J. R. Berman, P. Zhang, and C. Kenyon (2008)
Genetics 178, 513-526
   Abstract »    Full Text »    PDF »
Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans.
C. T. Murphy, S.-J. Lee, and C. Kenyon (2007)
PNAS 104, 19046-19050
   Abstract »    Full Text »    PDF »
Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants.
A. V. Samuelson, C. E. Carr, and G. Ruvkun (2007)
Genes & Dev. 21, 2976-2994
   Abstract »    Full Text »    PDF »
H. Feng, M. Ren, L. Chen, and C. S. Rubin (2007)
J. Biol. Chem. 282, 31273-31288
   Abstract »    Full Text »    PDF »
Influence of Lactic Acid Bacteria on Longevity of Caenorhabditis elegans and Host Defense against Salmonella enterica Serovar Enteritidis.
T. Ikeda, C. Yasui, K. Hoshino, K. Arikawa, and Y. Nishikawa (2007)
Appl. Envir. Microbiol. 73, 6404-6409
   Abstract »    Full Text »    PDF »
Gravity Force Transduced by the MEC-4/MEC-10 DEG/ENaC Channel Modulates DAF-16/FoxO Activity in Caenorhabditis elegans.
N. Kim, C. M. Dempsey, C.-J. Kuan, J. V. Zoval, E. O'Rourke, G. Ruvkun, M. J. Madou, and J. Y. Sze (2007)
Genetics 177, 835-845
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Proteins That Promote Long Life.
S. K. Kim (2007)
Science 317, 603-604
   Abstract »    Full Text »    PDF »
Quantitative Mass Spectrometry Identifies Insulin Signaling Targets in C. elegans.
M.-Q. Dong, J. D. Venable, N. Au, T. Xu, S. K. Park, D. Cociorva, J. R. Johnson, A. Dillin, and J. R. Yates III (2007)
Science 317, 660-663
   Abstract »    Full Text »    PDF »
Oxidative Stress Enzymes Are Required for DAF-16-Mediated Immunity Due to Generation of Reactive Oxygen Species by Caenorhabditis elegans.
V. Chavez, A. Mohri-Shiomi, A. Maadani, L. A. Vega, and D. A. Garsin (2007)
Genetics 176, 1567-1577
   Abstract »    Full Text »    PDF »
Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex.
A. Ghazi, S. Henis-Korenblit, and C. Kenyon (2007)
PNAS 104, 5947-5952
   Abstract »    Full Text »    PDF »
Inhibition of wild-type p66ShcA in mesangial cells prevents glycooxidant-dependent FOXO3a regulation and promotes the survival phenotype.
J. Chintapalli, S. Yang, D. Opawumi, S. R. Goyal, N. Shamsuddin, A. Malhotra, K. Reiss, and L. G. Meggs (2007)
Am J Physiol Renal Physiol 292, F523-F530
   Abstract »    Full Text »    PDF »
Metabolic Diapause in Pancreatic beta-Cells Expressing a Gain-of-function Mutant of the Forkhead Protein Foxo1.
J. Buteau, A. Shlien, S. Foisy, and D. Accili (2007)
J. Biol. Chem. 282, 287-293
   Abstract »    Full Text »    PDF »
Glyceraldehyde-3-Phosphate Dehydrogenase Mediates Anoxia Response and Survival in Caenorhabditis elegans.
A. R. Mendenhall, B. LaRue, and P. A. Padilla (2006)
Genetics 174, 1173-1187
   Abstract »    Full Text »    PDF »
Delayed development and lifespan extension as features of metabolic lifestyle alteration in C. elegans under dietary restriction.
N. J. Szewczyk, I. A. Udranszky, E. Kozak, J. Sunga, S. K. Kim, L. A. Jacobson, and C. A. Conley (2006)
J. Exp. Biol. 209, 4129-4139
   Abstract »    Full Text »    PDF »
Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity.
V. Singh and A. Aballay (2006)
PNAS 103, 13092-13097
   Abstract »    Full Text »    PDF »
Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum.
D. O'Rourke, D. Baban, M. Demidova, R. Mott, and J. Hodgkin (2006)
Genome Res. 16, 1005-1016
   Abstract »    Full Text »    PDF »
The Mammalian Longevity-associated Gene Product p66shc Regulates Mitochondrial Metabolism.
S. Nemoto, C. A. Combs, S. French, B.-H. Ahn, M. M. Fergusson, R. S. Balaban, and T. Finkel (2006)
J. Biol. Chem. 281, 10555-10560
   Abstract »    Full Text »    PDF »
FOXO Transcription Factors Cooperate with {delta}EF1 to Activate Growth Suppressive Genes in B Lymphocytes..
J. Chen, I. Yusuf, H.-M. Andersen, and D. A. Fruman (2006)
J. Immunol. 176, 2711-2721
   Abstract »    Full Text »    PDF »
Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production.
A. Trifunovic, A. Hansson, A. Wredenberg, A. T. Rovio, E. Dufour, I. Khvorostov, J. N. Spelbrink, R. Wibom, H. T. Jacobs, and N.-G. Larsson (2005)
PNAS 102, 17993-17998
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor {gamma} Coactivator 1 in Caloric Restriction and Other Models of Longevity.
J. C. Corton and H. M. Brown-Borg (2005)
J Gerontol A Biol Sci Med Sci 60, 1494-1509
   Abstract »    Full Text »    PDF »
The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code".
D. C. Love and J. A. Hanover (2005)
Sci. STKE 2005, re13
   Abstract »    Full Text »    PDF »
Interfering with Longevity.
S. S. Lee (2005)
Sci. Aging Knowl. Environ. 2005, pe26
   Abstract »    Full Text »
The Transcriptional Repressor dMnt Is a Regulator of Growth in Drosophila melanogaster.
L. W. M. Loo, J. Secombe, J. T. Little, L.-S. Carlos, C. Yost, P.-F. Cheng, E. M. Flynn, B. A. Edgar, and R. N. Eisenman (2005)
Mol. Cell. Biol. 25, 7078-7091
   Abstract »    Full Text »    PDF »
A systematic RNAi screen for longevity genes in C. elegans.
B. Hamilton, Y. Dong, M. Shindo, W. Liu, I. Odell, G. Ruvkun, and S. S. Lee (2005)
Genes & Dev. 19, 1544-1555
   Abstract »    Full Text »    PDF »
JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16.
S. W. Oh, A. Mukhopadhyay, N. Svrzikapa, F. Jiang, R. J. Davis, and H. A. Tissenbaum (2005)
PNAS 102, 4494-4499
   Abstract »    Full Text »    PDF »
Decreased Lifespan in the Absence of Expression of the Mitochondrial Small Heat Shock Protein Hsp22 in Drosophila.
G. Morrow, S. Battistini, P. Zhang, and R. M. Tanguay (2004)
J. Biol. Chem. 279, 43382-43385
   Abstract »    Full Text »    PDF »
The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span.
K. Jia, D. Chen, and D. L. Riddle (2004)
Development 131, 3897-3906
   Abstract »    Full Text »    PDF »
Ticking Fast or Ticking Slow, Through Shc Must You Go?.
F. M. Martin and J. S. Friedman (2004)
Sci. Aging Knowl. Environ. 2004, pe32
   Abstract »    Full Text »
Emerging Technologies: Trendy RNA Tools for Aging Research.
C. C. Deocaris, S. C. Kaul, K. Taira, and R. Wadhwa (2004)
J Gerontol A Biol Sci Med Sci 59, B771-B783
   Abstract »    Full Text »    PDF »
Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
H. Daitoku, M. Hatta, H. Matsuzaki, S. Aratani, T. Ohshima, M. Miyagishi, T. Nakajima, and A. Fukamizu (2004)
PNAS 101, 10042-10047
   Abstract »    Full Text »    PDF »
The Future of Aging Interventions: Current Status of Efforts to Measure and Modulate the Biological Rate of Aging.
H. R. Warner (2004)
J Gerontol A Biol Sci Med Sci 59, B692-B696
   Abstract »    Full Text »    PDF »
Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans.
O. I. Petriv and R. A. Rachubinski (2004)
J. Biol. Chem. 279, 19996-20001
   Abstract »    Full Text »    PDF »
Mutations in Chemosensory Cilia Cause Resistance to Paraquat in Nematode Caenorhabditis elegans.
M. Fujii, Y. Matsumoto, N. Tanaka, K. Miki, T. Suzuki, N. Ishii, and D. Ayusawa (2004)
J. Biol. Chem. 279, 20277-20282
   Abstract »    Full Text »    PDF »
Serum leptin level is a regulator of bone mass.
F. Elefteriou, S. Takeda, K. Ebihara, J. Magre, N. Patano, C. Ae Kim, Y. Ogawa, X. Liu, S. M. Ware, W. J. Craigen, et al. (2004)
PNAS 101, 3258-3263
   Abstract »    Full Text »    PDF »
Size matters: Workshop on Growth Control in Development and Disease.
D. Pan (2004)
EMBO Rep. 5, 136-139
   Full Text »    PDF »
Regulation of Caenorhabditis elegans RNA Interference by the daf-2 Insulin Stress and Longevity Signaling Pathway.
D. WANG and G. RUVKUN (2004)
Cold Spring Harb Symp Quant Biol 69, 429-432
   Abstract »    PDF »
Regulation of sterol carrier protein gene expression by the Forkhead transcription factor FOXO3a.
T. B. Dansen, G. J. P. L. Kops, S. Denis, N. Jelluma, R. J. A. Wanders, J. L. Bos, B. M. T. Burgering, and K. W. A. Wirtz (2004)
J. Lipid Res. 45, 81-88
   Abstract »    Full Text »    PDF »
Linkage between insulin and the free radical theory of aging.
D. Julian and C. Leeuwenburgh (2004)
Am J Physiol Regulatory Integrative Comp Physiol 286, R20-R21
   Full Text »    PDF »
OutFOXing the Grim Reaper: Novel Mechanisms Regulating Longevity by Forkhead Transcription Factors.
P. Coffer (2003)
Sci. STKE 2003, pe39
   Abstract »    Full Text »    PDF »
SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response.
J. H. An and T. K. Blackwell (2003)
Genes & Dev. 17, 1882-1893
   Abstract »    Full Text »    PDF »
Direct and Indirect Transcriptional Targets of DAF-16.
P. L. Larsen (2003)
Sci. Aging Knowl. Environ. 2003, pe9-9
   Abstract »    Full Text »

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