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ABSTRACT The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity1,2,3,4,5. In _Caenorhabditis elegans_, the single forkhead box O (FOXO) homologue, DAF-16,

functions as the major target of the IIS pathway2,3,6,7. One of two isoforms4,5,8, DAF-16a, is known to regulate longevity, stress response and dauer diapause8,9,10,11. However, it remains

unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show

that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct

and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes

have overlapping and different functions6,12, and in _C. elegans_, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS SUMO PROMOTES LONGEVITY AND MAINTAINS MITOCHONDRIAL HOMEOSTASIS DURING AGEING IN _CAENORHABDITIS ELEGANS_ Article Open access 23 September 2020

SIN-3 FUNCTIONS THROUGH MULTI-PROTEIN INTERACTION TO REGULATE APOPTOSIS, AUTOPHAGY, AND LONGEVITY IN _CAENORHABDITIS ELEGANS_ Article Open access 22 June 2022 CABIN1 DOMAIN-CONTAINING GENE

_PICD-1_ INTERACTS WITH _PRY-1/AXIN_ TO REGULATE MULTIPLE PROCESSES IN _CAENORHABDITIS ELEGANS_ Article Open access 14 July 2022 REFERENCES * Calnan, D. R. & Brunet, A. The FoxO code.

_Oncogene_ 27, 2276–2288 (2008) Article  CAS  Google Scholar  * Antebi, A. Genetics of aging in _Caenorhabditis elegans_ . _PLoS Genet._ 3, e129 (2007) Article  Google Scholar  * Kenyon, C.

J. The genetics of ageing. _Nature_ 464, 504–512 (2010) Article  ADS  CAS  Google Scholar  * Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. _daf-16_: An HNF-3/forkhead family member that

can function to double the life-span of _Caenorhabditis elegans_ . _Science_ 278, 1319–1322 (1997) Article  ADS  CAS  Google Scholar  * Ogg, S. et al. The Fork head transcription factor

DAF-16 transduces insulin-like metabolic and longevity signals in _C. _ _elegans_ . _Nature_ 389, 994–999 (1997) Article  ADS  CAS  Google Scholar  * Narasimhan, S. D., Yen, K. &

Tissenbaum, H. A. Converging pathways in lifespan regulation. _Curr. Biol._ 19, R657–R666 (2009) Article  CAS  Google Scholar  * Mukhopadhyay, A., Oh, S. W. & Tissenbaum, H. A. Worming

pathways to and from DAF-16/FOXO. _Exp. Gerontol._ 41, 928–934 (2006) Article  CAS  Google Scholar  * Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the _Caenorhabditis

elegans_ longevity protein DAF-16 by insulin/IGF-1 and germline signaling. _Nature Genet._ 28, 139–145 (2001) Article  CAS  Google Scholar  * Henderson, S. T. & Johnson, T. E. _daf-16_

integrates developmental and environmental inputs to mediate aging in the nematode _Caenorhabditis elegans_ . _Curr. Biol._ 11, 1975–1980 (2001) Article  CAS  Google Scholar  * Lee, R. Y.,

Hench, J. & Ruvkun, G. Regulation of _C. _ _elegans_ DAF-16 and its human ortholog FKHRL1 by the _daf-2_ insulin-like signaling pathway. _Curr. Biol._ 11, 1950–1957 (2001) Article  CAS 

Google Scholar  * Libina, N., Berman, J. R. & Kenyon, C. Tissue-specific activities of _C. _ _elegans_ DAF-16 in the regulation of lifespan. _Cell_ 115, 489–502 (2003) Article  CAS 

Google Scholar  * Arden, K. C. FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. _Oncogene_ 27, 2345–2350 (2008) Article  CAS  Google Scholar  * Oh, S. W.

et al. JNK regulates lifespan in _Caenorhabditis elegans_ by modulating nuclear translocation of forkhead transcription factor/DAF-16. _Proc. Natl Acad. Sci. USA_ 102, 4494–4499 (2005)

Article  ADS  CAS  Google Scholar  * Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. _Cell_ 125, 987–1001 (2006)

Article  CAS  Google Scholar  * Berdichevsky, A., Viswanathan, M., Horvitz, H. R. & Guarente, L. C. _elegans_ SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life

span. _Cell_ 125, 1165–1177 (2006) Article  CAS  Google Scholar  * Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. _Science_ 303,

2011–2015 (2004) Article  ADS  CAS  Google Scholar  * Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control _C. _ _elegans_ life-span and metabolism.

_Science_ 300, 644–647 (2003) Article  ADS  CAS  Google Scholar  * McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the _Caenorhabditis elegans_ forkhead protein DAF-16.

_Aging Cell_ 2, 111–121 (2003) Article  CAS  Google Scholar  * Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of _Caenorhabditis elegans_ . _Nature_ 424,

277–283 (2003) Article  ADS  CAS  Google Scholar  * Herman, R. K. Mosaic analysis. _Methods Cell Biol._ 48, 123–146 (1995) Article  CAS  Google Scholar  * Padmanabhan, S. et al. A PP2A

regulatory subunit regulates _C. _ _elegans_ insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. _Cell_ 136, 939–951 (2009) Article  CAS  Google Scholar  * Riddle, D. L. &

Albert, P. S. in _C. elegans II_ (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, 1997) Google Scholar  * Honda, Y. &

Honda, S. The _daf-2_ gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in _Caenorhabditis elegans_ . _FASEB J._ 13, 1385–1393

(1999) Article  CAS  Google Scholar  * Murakami, S. & Johnson, T. E. A genetic pathway conferring life extension and resistance to UV stress in _Caenorhabditis elegans_ . _Genetics_ 143,

1207–1218 (1996) CAS  PubMed  PubMed Central  Google Scholar  * Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. _daf-2_, an insulin receptor-like gene that regulates longevity

and diapause in _Caenorhabditis elegans_ . _Science_ 277, 942–946 (1997) Article  CAS  Google Scholar  * Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2

regulates fat metabolism, feeding, growth, and life span in _Caenorhabditis elegans_ . _Genes Dev._ 23, 496–511 (2009) Article  CAS  Google Scholar  * Oh, S. W. et al. Identification of

direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. _Nature Genet._ 38, 251–257 (2005) PubMed  Google Scholar  * Stiernagle, T. Maintenance

of _C. _ _elegans_ . _WormBook_ 10.1895/wormbook.1.101.1 (2006) * Hosono, R., Mitsui, Y., Sato, Y., Aizawa, S. & Miwa, J. Life span of the wild and mutant nematode _Caenorhabditis

elegans_. Effects of sex, sterilization, and temperature. _Exp. Gerontol._ 17, 163–172 (1982) Article  CAS  Google Scholar  * Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V.

Efficient gene transfer in _C._ _elegans_: extrachromosomal maintenance and integration of transforming sequences. _EMBO J._ 10, 3959–3970 (1991) Article  CAS  Google Scholar  Download

references ACKNOWLEDGEMENTS We are grateful to A. Mukhopadhyay and S. Padmanabhan for advice, M. Green and M. Walhout for advice and comments on the manuscript and N. Bhabhalia for technical

support. We thank M. Grabowski Auclair for generating several strains used in this manuscript and G. Ruvkun and M. Walhout for plasmids and strains. We apologize to all those whose original

work was not cited because of space limitations. Some of the strains were provided by T. Stiernagle at the _Caenorhabditis_ Genetics Center, which is funded by the National Institutes of

Health National Center for Research Resources. H.A.T. is a William Randolph Hearst Young Investigator. This project was funded in part by grants from the National Institute of Aging AG025891

and AG031237), the Glenn Foundation for Medical Research, the Ellison Medical Foundation and an endowment from the William Randolph Hearst Foundation. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA Eun-Soo Kwon, Sri Devi Narasimhan, Kelvin Yen & 

Heidi A. Tissenbaum * Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA Heidi A. Tissenbaum Authors * Eun-Soo Kwon View author

publications You can also search for this author inPubMed Google Scholar * Sri Devi Narasimhan View author publications You can also search for this author inPubMed Google Scholar * Kelvin

Yen View author publications You can also search for this author inPubMed Google Scholar * Heidi A. Tissenbaum View author publications You can also search for this author inPubMed Google

Scholar CONTRIBUTIONS E.-S.K. and H.A.T. designed the experiments and analysed the data. E.-S.K., S.D.N. and K.Y. performed the experiments. E.-S.K., S.D.N., K.Y. and H.A.T. wrote the

manuscript. CORRESPONDING AUTHOR Correspondence to Heidi A. Tissenbaum. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY

INFORMATION SUPPLEMENTARY FIGURES This file contains Supplementary Figures 1-15 with legends. (PDF 3414 kb) SUPPLEMENTARY INFORMATION This file contains Supplementary Data, a Supplementary

Discussion, Supplementary Methods, Supplementary Tables 1-5 and References. (PDF 353 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3

POWERPOINT SLIDE FOR FIG. 4 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kwon, ES., Narasimhan, S., Yen, K. _et al._ A new DAF-16 isoform regulates

longevity. _Nature_ 466, 498–502 (2010). https://doi.org/10.1038/nature09184 Download citation * Received: 07 January 2010 * Accepted: 14 May 2010 * Published: 07 July 2010 * Issue Date: 22

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