An antidepressant that extends lifespan in adult caenorhabditis elegans

ABSTRACT The mechanisms that determine the lifespan of an organism are still largely a mystery1. One goal of ageing research is to find drugs that would increase lifespan and vitality when

given to an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult _Caenorhabditis elegans_ nematodes. Here we report that a drug used as an

antidepressant in humans increases _C. elegans_ lifespan. In humans, this drug blocks neural signalling by the neurotransmitter serotonin. In _C. elegans_, the effect of the drug on lifespan

is reduced or eradicated by mutations that affect serotonin synthesis, serotonin re-uptake at synapses, or either of two G-protein-coupled receptors: one that recognizes serotonin and the

other that detects another neurotransmitter, octopamine. _In vitro_ studies show that the drug acts as an antagonist at both receptors. Testing of the drug on dietary-restricted animals or

animals with mutations that affect lifespan indicates that its effect on lifespan involves mechanisms associated with lifespan extension by dietary restriction. These studies indicate that

lifespan can be extended by blocking certain types of neurotransmission implicated in food sensing in the adult animal, possibly leading to a state of perceived, although not real,

starvation. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe

to this journal Receive 51 print issues and online access $199.00 per year only $3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF

Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact

customer support SIMILAR CONTENT BEING VIEWED BY OTHERS SEROTONIN AND DOPAMINE MODULATE AGING IN RESPONSE TO FOOD ODOR AND AVAILABILITY Article Open access 07 June 2022 AN ALTERNATIVE FOOD

SOURCE FOR METABOLISM AND LONGEVITY STUDIES IN _CAENORHABDITIS ELEGANS_ Article Open access 26 February 2021 ON THE BENEFITS OF THE TRYPTOPHAN METABOLITE 3-HYDROXYANTHRANILIC ACID IN

_CAENORHABDITIS ELEGANS_ AND MOUSE AGING Article Open access 14 December 2023 REFERENCES * Kirkwood, T. B. Understanding the odd science of aging. _Cell_ 120, 437–447 (2005) Article  CAS 

Google Scholar  * Kenyon, C. The plasticity of aging: insights from long-lived mutants. _Cell_ 120, 449–460 (2005) Article  CAS  Google Scholar  * Finch, C. E. & Ruvkun, G. The genetics

of aging. _Annu. Rev. Genomics Hum. Genet._ 2, 435–462 (2001) Article  CAS  Google Scholar  * Evason, K., Huang, C., Yamben, I., Covey, D. F. & Kornfeld, K. Anticonvulsant medications

extend worm life-span. _Science_ 307, 258–262 (2005) Article  ADS  CAS  Google Scholar  * Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics. _Science_ 289,

1567–1569 (2000) Article  ADS  CAS  Google Scholar  * Kang, H. L., Benzer, S. & Min, K. T. Life extension in _Drosophila_ by feeding a drug. _Proc. Natl Acad. Sci. USA_ 99, 838–843

(2002) Article  ADS  CAS  Google Scholar  * Wood, J. G. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. _Nature_ 430, 686–689 (2004) Article  ADS  CAS 

Google Scholar  * Terzibasi, E., Valenzano, D. R. & Cellerino, A. The short-lived fish _Nothobranchius furzeri_ as a new model system for aging studies. _Exp. Gerontol._ 42, 81–89 (2007)

Article  CAS  Google Scholar  * Gillman, P. K. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. _Hum. Psychopharmacol._ 21,

117–125 (2006) Article  CAS  Google Scholar  * Dempsey, C. M., Mackenzie, S. M., Gargus, A., Blanco, G. & Sze, J. Y. Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct

5HT receptor signaling to modulate _Caenorhabditis elegans_ egg-laying behavior. _Genetics_ 169, 1425–1436 (2005) Article  CAS  Google Scholar  * Horvitz, H. R., Chalfie, M., Trent, C.,

Sulston, J. E. & Evans, P. D. Serotonin and octopamine in the nematode _Caenorhabditis elegans_ . _Science_ 216, 1012–1014 (1982) Article  ADS  CAS  Google Scholar  * Rodin, G. et al.

Treatment of depression in cancer patients. _Curr. Oncol._ 14, 180–188 (2004) Article  Google Scholar  * Sze, J. Y., Victor, M., Loer, C., Shi, Y. & Ruvkun, G. Food and metabolic

signalling defects in a _Caenorhabditis elegans_ serotonin-synthesis mutant. _Nature_ 403, 560–564 (2000) Article  ADS  CAS  Google Scholar  * Ranganathan, R., Sawin, E. R., Trent, C. &

Horvitz, H. R. Mutations in the _Caenorhabditis elegans_ serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine. _J. Neurosci._ 21,

5871–5884 (2001) Article  CAS  Google Scholar  * Komuniecki, R. W., Hobson, R. J., Rex, E. B., Hapiak, V. M. & Komuniecki, P. R. Biogenic amine receptors in parasitic nematodes: what can

be learned from _Caenorhabditis elegans?_ _Mol. Biochem. Parasitol._ 137, 1–11 (2004) Article  CAS  Google Scholar  * Suo, S., Kimura, Y. & Van Tol, H. H. Starvation induces cAMP

response element-binding protein-dependent gene expression through octopamine-Gq signaling in _Caenorhabditis elegans_ . _J. Neurosci._ 26, 10082–10090 (2006) Article  CAS  Google Scholar  *

Murakami, H. & Murakami, S. Serotonin receptors antagonistically modulate _Caenorhabditis elegans_ longevity. _Aging Cell_ 6, 483–488 (2007) Article  CAS  Google Scholar  * Roeder, T.

Octopamine in invertebrates. _Prog. Neurobiol._ 59, 533–561 (1999) Article  CAS  Google Scholar  * Malnic, B., Hirono, J., Sato, T. & Buck, L. B. Combinatorial receptor codes for odors.

_Cell_ 96, 713–723 (1999) Article  CAS  Google Scholar  * Liberles, S. D. & Buck, L. B. A second class of chemosensory receptors in the olfactory epithelium. _Nature_ 442, 645–650 (2006)

Article  ADS  CAS  Google Scholar  * Offermanns, S. & Simon, M. I. Gα15 and Gα16 couple a wide variety of receptors to phospholipase _C_ . _J. Biol. Chem._ 270, 15175–15180 (1995)

Article  CAS  Google Scholar  * Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates.

_Science_ 310, 683–685 (2005) Article  ADS  CAS  Google Scholar  * Lakowski, B. & Hekimi, S. Determination of life-span in _Caenorhabditis elegans_ by four clock genes. _Science_ 272,

1010–1013 (1996) Article  ADS  CAS  Google Scholar  * Lakowski, B. & Hekimi, S. The genetics of caloric restriction in _Caenorhabditis elegans_ . _Proc. Natl Acad. Sci. USA_ 95,

13091–13096 (1998) Article  ADS  CAS  Google Scholar  * Niacaris, T. & Avery, L. Serotonin regulates repolarization of the _C. elegans_ pharyngeal muscle. _J. Exp. Biol._ 206, 223–231

(2003) Article  CAS  Google Scholar  * Kaeberlein, T. L. et al. Lifespan extension in _Caenorhabditis elegans_ by complete removal of food. _Aging Cell_ 5, 487–494 (2006) Article  CAS 

Google Scholar  * Harris, B. & Harper, M. Unusual appetites in patients on mianserin. _Lancet_ 1, 590 (1980) Article  CAS  Google Scholar  * Johnson, T. E. et al. Relationship between

increased longevity and stress resistance as assessed through gerontogene mutations in _Caenorhabditis elegans_ . _Exp. Gerontol._ 36, 1609–1617 (2001) Article  CAS  Google Scholar  *

Brenner, S. The genetics of _Caenorhabditis elegans_ . _Genetics_ 77, 71–94 (1974) CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We are grateful to J.

Priess for critical reading of an earlier version of the manuscript, to members of the Priess and Buck laboratories for advice and discussions, and to J. Vazquez for technical assistance. We

thank S. Suo for providing the VN11 strain (_ser-3(ad1774_)_;tzIs3[cre::gfp, lin-15(+)])_ and J. Ying Sze for the _ser-4(ok512);yzEx205[ser-4(+); pRF4(rol-6(su1006))]_ strain. All other

strains were provided by the _Caenorhabditis_ Genetics Center, which is funded by the NIH, and the international _C. elegans_ Gene Knockout Consortium. This project was supported by the

Howard Hughes Medical Institute and the Ellison Medical Foundation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Basic Sciences Division, Howard Hughes Medical Institute, Fred Hutchinson

Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA, Michael Petrascheck, Xiaolan Ye & Linda B. Buck Authors * Michael Petrascheck View author

publications You can also search for this author inPubMed Google Scholar * Xiaolan Ye View author publications You can also search for this author inPubMed Google Scholar * Linda B. Buck

View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Linda B. Buck. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION

The file contains Supplementary Figure 1 and Supplementary Tables 1-4 with Legends. (PDF 6204 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Petrascheck, M., Ye, X. & Buck, L. An antidepressant that extends lifespan in adult _Caenorhabditis elegans_. _Nature_ 450, 553–556 (2007). https://doi.org/10.1038/nature05991 Download

citation * Received: 31 July 2007 * Accepted: 11 October 2007 * Issue Date: 22 November 2007 * DOI: https://doi.org/10.1038/nature05991 SHARE THIS ARTICLE Anyone you share the following link

with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative