Caenorhabditis Elegans Research Paper

Research papers:

The genetics of Caenorhabditis elegans. Brenner S. Genetics. 1974 May;77(1):71-94.

Post-embryonic cell lineages of the nematode, Caenorhabditis elegans.Sulston JE, Horvitz HR. Dev Biol. 1977 Mar;56(1):110-56.

The embryonic cell lineage of the nematode Caenorhabditis elegans. Sulston JE, Schierenberg E, White JG, Thomson JN. Dev Biol. 1983 Nov;100(1):64-119.

The structure of the nervous system of the nematode Caenorhabditis elegans. White JG, Southgate E, Thomson JN, Brenner S. Phil. Trans. Royal Soc. London. Series B, Biol Scien. Vol.314, Issue 1165 (Nov 12, 1986), 1-340

 

C. elegans history:

The beginning of connectomics: a commentary on White et al. (1986) ‘The structure of the nervous system of the nematode Caenorhabditis elegans’  Emmons SW, Phil. Trans. Royal Soc. London. Series B 370: 1-11 March 2014

In the Beginning Was the Worm . . .Sydney Brenner, Genetics 182: 413–415 June 2009

The natural history of C.elegans research. Ankeny RA. Nat Rev Genet. 2001 Jun;2(6):474-9.

Of Worms and Programmes: Caenorhabditis Elegans and the Study of Development. Soraya de Chadarevian, Stud. Hist. Phil. Biol. & Biomed. Sci., Vol. 29, No. 1, pp. 81–105, 1998

An interview with Sydney Brenner

The art and design of genetic screens: caenorhabditis elegans. Jorgensen EM, Mango SE. Nat Rev Genet. 2002 May;3(5):356-69.

Super models. Maureen M. Barr, Physiol Genomics 13: 15–24, 2003

On the shoulders of worms Rhiannon Macrae, Trends in Genetics November 2014

 

History of neurons:

Ramón y Cajal: a century after the publication of his masterpiece.Pedro J. Andres-Barquin, Endeavour Vol. 25(1) 2001

A historical reflection of the contributions of Cajal and Golgi to the foundations of neuroscience. De Carlos JA, Borrell J. , Brain Res Rev. 2007 Aug;55(1):8-16.

Cajal, Golgi, Nansen, Schafer and the Neuron Doctrine. Ortwin Bock, Endeavour Vol. 37 No. 4

Cajal and the discovery of a new artistic world: The neuronal forest.Javier DeFelipe, Progress in Brain Research, Volume 203 2013

The death of Cajal and the end of scientific romanticism and individualism.Javier DeFelipe, Eduardo Garrido, and Henry Markram, Trends in Neurosciences, October 2014, Vol. 37, No. 10

Cajal’s debt to Golgi. Edward G. Jones, Brain Research Reviews 66 (2010) 83–91

A unifying concept: the history of cell theory. Paolo Mazzarello, Nature Cell Biology Vol 1 May 1999

The neuron doctrine, the mind, and the artic.  Fodstad H, Kondziolka D, & Lotbiniere A. Neurosurgery 2001 Dec 47(6):1381-1389.

 

General information on C. elegans:

C. elegans outside the Petri dish. Frezal L and Felix M. eLIFE. 2015 Mar 4:e05849.

 

Other:

Sydney Brenner’s Loose Ends column for Current Biology 1994-2000

Using C. elegans for aging research

Heidi A. Tissenbaum a , *

aProgram in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA

* Email: ude.demssamu@muabnessit.idieh

Author information ►Article notes ►Copyright and License information ►

Received 2014 Mar 18; Accepted 2014 Jun 2.

Copyright © 2014 The Author(s). Published by Taylor & Francis

This is an Open Access article. Non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly attributed, cited, and is not altered, transformed, or built upon in any way, is permitted. The moral rights of the named author(s) have been asserted.

This article has been cited by other articles in PMC.

Abstract

Over a century ago, the zoologist Emile Maupas first identified the nematode, Rhabditis elegans, in the soil in Algiers. Subsequent work and phylogenic studies renamed the species Caenorhabditis elegans or more commonly referred to as C. elegans; (Caeno meaning recent; rhabditis meaning rod; elegans meaning nice). However, it was not until 1963, when Sydney Brenner, already successful from his work on DNA, RNA, and the genetic code, suggested the future of biological research lay in model organisms. Brenner believed that biological research required a model system that could grow in vast quantities in the lab, were cheap to maintain and had a simple body plan, and he chose the nematode C. elegans to fulfill such a role. Since that time, C. elegans has emerged as one of the premiere model systems for aging research. This paper reviews some initial identification of mutants with altered lifespan with a focus on genetics and then discusses advantages and disadvantages for using C. elegans as a model system to understand human aging. This review focuses on molecular genetics aspects of this model organism.

Keywords: C. elegans, longevity, aging, insulin/IGF-1, dauer

Introduction

In 1974, a little more than a decade after his first thoughts about working on a model organism, Brenner published four manuscripts, including one entitled ‘The genetics of Caenorhabditis elegans’(Brenner 1974) and a new field began. In this influential paper (Brenner 1974), Brenner outlined methodology for isolation, complementation, and mapping of worm mutants. Importantly, the publication also included the successful isolation of several hundred mutants affecting behavior and morphology, a discussion of the number of defined genes, and an estimation of mutation frequency. Since that time, many discoveries including dissection of programmed cell death (Coulson et al. 1986; Ellis et al. 1991), the systematic cloning of the genome (Coulson et al. 1986; Crawford 2001), the deciphering of the entire DNA sequence (Consortium 1998), microRNAs (Lee et al. 1993; Reinhart et al. 2000), RNA interference (Fire et al. 1998), and the use of GFP (Chalfie et al. 1994) have been done in C. elegans which has led to an expansion in the number of researchers working with C. elegans.

C. elegans for aging research

For research on aging, early studies in C. elegans focused on the feasibility of measuring lifespan and the use of 5-Fluoro-2′-deoxyuridine (FUDR) to maintain synchronous cultures of aged animals (Hosono 1978a, 1978b). In 1977, Klass (1977) published that C. elegans was a good system for aging studies as he established a method to consistently measure lifespan, and he concluded that this could lead to future detailed analysis combining genetics and biochemistry. In these early studies, Klass found that altering either temperature or the amount of food resulted in a change in lifespan. In addition, only small effects on lifespan were observed based on parental age or parental lifespan. Klass performed a clonal genetic screen for mutants with altered lifespan and identified five mutants (Klass 1983). Interestingly, later genetic work on these mutants in the laboratory of Tom Johnson, mapped all of them to a single genetic locus, named age-1 (Friedman & Johnson 1988). This was the first breakthrough in aging research for studies based on C. elegans as this study revealed that it was possible to identify mutants that altered lifespan and more importantly, individual genes could modulate lifespan.

From the initial characterization of mutants that altered lifespan, the words lifespan and aging have often been used interchangeably. However, lifespan is a single measureable parameter that defines the amount of time an organism is alive but does not give any indication for how an animal is actually aging. Lifespan as a measurement gives little detail about the health of the animal. For this reason, healthspan, defined as the time that an individual is active, productive and free from age-associated disease, is starting to become the focus of aging research (reviewed in (Tissenbaum 2012)).

Equally important for aging research is the use of the term regulation. Is aging regulated? Is lifespan regulated? A regulated process should indicate that this is a trait that would be selected for over time. However, fitness competitions between wild type and daf-2 mutants, show that after four generations, none of the daf-2 mutants remained primarily because of the early fertility defects in the daf-2 mutants (Jenkins et al. 2004). Therefore, similar to other studies with long-lived mutants and consistent with the antagonistic pleiotropy theory of aging (Lakowski & Hekimi 1996; Gems et al. 1998; Chen, Pan et al. 2007; Chen, Senturk et al. 2007; Curran & Ruvkun 2007; Anderson et al. 2011), daf-2 mutants exhibit a heavy fitness cost with lifespan extension (Jenkins et al. 2004). Taken together, lifespan and aging should not be used interchangeably and the use of the word regulation should be monitored (reviewed in (Lithgow 2006; Tissenbaum 2012)).

Several years after the age-1 gene was identified, another gene was shown to modulate lifespan. Similar to mutation in age-1, daf-2 mutants showed adult lifespan extension (Kenyon et al. 1993). Interestingly, previously, both daf-2 and age-1 had showed similarity based on a different phenotype. Under favorable growth conditions, C. elegans develop from an egg through four larval stages (L1-L4) each separated by a molt, and then a final molt into a reproductive self-fertilizing adult hermaphrodite. In response to unfavorable growth conditions, in particular, high levels of a secreted pheromone (i.e. crowding, low food), worms can enter an alternative developmental mode (at the L3 stage) forming dauer larvae (Riddle & Albert 1997). Dauer (German for enduring) larvae (alternate L3) maximize survival until conditions become more favorable, whereupon they will molt and form a reproductive adult. Genetic screens identified mutants affecting the ability to enter this dauer program. These mutants were named daf mutants indicating the dauer formation phenotype. Both daf-2 and age-1 were initially isolated in this type of screen because both daf-2 and age-1 (originally identified as daf-23) mutants show a dauer constitutive (daf-c) phenotype such that even under good growth conditions, mutants will enter the dauer stage (Albert et al. 1981). Genetic epistasis analysis placed these two genes in a similar genetic epistasis pathway for dauer formation that was distinct from the other daf-c mutants (Vowels & Thomas 1992). These studies also revealed that both daf-2 and age-1 mutants could be suppressed by a mutation in the daf-16 gene (Albert et al. 1981; Riddle 1988; Vowels & Thomas 1992; Riddle & Albert 1997). daf-16 (also known as daf-17) was also isolated in these early dauer formation genetic screens because daf-16 mutants show a dauer defective (daf-d) phenotype such that even under poor growth conditions, mutants will not enter the dauer stage (Albert et al. 1981; Riddle 1988; Vowels & Thomas 1992; Riddle & Albert 1997).

Subsequent molecular cloning beginning in 1996, explained why these genes were separate and distinct from other pathways. The genes encoded for members of an insulin/IGF-1 signaling (IIS) pathway where daf-2 encoded for an IIS receptor, age-1 encoded for the catalytic subunit of the PI 3-kinase, and daf-16 encoded for a forkhead box O (FOXO) transcription factor downstream of the PI 3-kinase signaling cascade. Since then, studies have shown that the IIS pathway is evolutionarily conserved such that mutations in this pathway in flies and mice are also linked to lifespan extension (Barbieri et al. 2003; Yen et al. 2011).

Molecular and genetic studies in Drosophila and C. elegans have identified FOXO as a central regulator of lifespan (Lin et al. 1997; Ogg et al. 1997; Giannakou et al. 2004; Hwangbo et al. 2004). Modulation of Drosophila FOXO (dFoxo) and C. elegans FOXO (daf-16) dosage can either decrease or increase the lifespan of the organism (Lin et al. 1997; Ogg et al. 1997; Giannakou et al. 2004; Hwangbo et al. 2004). Importantly, advances in genomic research have led to new findings in the area of genome-wide association studies in humans. Multiple human population studies have found an association between single nucleotide polymorphisms (SNPs) in human FOXO3 and human lifespan extension (Lunetta et al. 2007; Willcox et al. 2008; Anselmi et al. 2009; Flachsbart et al. 2009; Li et al. 2009; Soerensen et al. 2010; Zeng et al. 2010; Banasik et al. 2011; Malovini et al. 2011), and the strength of the association appears to increase with age (Flachsbart et al. 2009). Therefore, FOXO3 has emerged as a candidate longevity gene in humans. Taken together, just over a decade from the molecular identification of DAF-16 in C. elegans, multiple studies have linked SNPs associated with human DAF-16/FOXO3 and human lifespan extension.

Dauer and longevity connections

Early studies on dauer larvae showed that dauers were ‘ageless’; namely once a dauer recovers and develops into a reproductive hermaphrodite, the subsequent adult lifespan (post-dauer) is independent from the time spent as a dauer (Klass & Hirsh 1976). Therefore, it was thought that daf-2 and age-1 were long lived merely due to activation of part of the dauer program manifested in the adult. However, (Kenyon et al. 1993) addressed these concerns by performing lifespan analyses on several other daf-c mutants (later shown to be part of a TGF-β signaling cascade) and found that these mutants did not affect lifespan and the issue seemed resolved. However, approaches including genome- wide microarrays and unbiased LC/MS proteomics have shown that the profiles of adult long-lived daf-2 mutants are most similar to wild-type dauer larvae (McElwee et al. 2004; McElwee et al. 2006; Depuydt et al. 2014). Moreover, recent studies (Shaw et al. 2007) re-examined the TGF-β daf-c mutants and found in contrast to earlier studies, these mutants showed lifespan extension. Similarly, recent genetic data revealed that the connections between the IIS pathway and the TGF-β signaling pathway are intertwined to modulate both lifespan and dauer formation (Narasimhan et al. 2011). Taken together, multiple studies suggest that the longevity of daf-2 mutants is due to activation of the dauer program in the adult. Despite the fact that a dauer program, an alternative hibernation state to delay reproduction until growth conditions are favorable, seems worm specific, the signaling pathways that were identified to regulate dauer formation modulate longevity from worms to mice, and are associated with human longevity.

Advantages of worms

Why has C. elegans been used so successfully for aging research? What would make an organism suitable for aging research? As suggested by Sydney Brenner in 1963, the ability to easily and cheaply grow large quantities of worms in the lab is very helpful for aging research, especially when identifying long-lived mutants. C. elegans also have a relatively short lifespan (average approximately 17 days at 20 °C), and the lifespan is largely invariant. The latter allows for identification of mutants that shorten or lengthen average lifespan by a little as 10–15% and still be of statistical significance. Additional benefits of using C. elegans include that the entire genome is sequenced and annotated, the availability of an RNAi library comprising approx. 80% of the genes in the genome, the ease of generating transgenic strains and the recent development of gene-targeting approaches. This has allowed for extensive forward and reverse genetic screens for genes that modulate lifespan. The RNAi library allows RNAi to be done by feeding worms bacteria that produce the desired dsRNA and then either the worm or their progeny are scored for a longevity phenotype (Ahringer 2006). Using genome-wide RNAi feeding libraries, the importance of the mitochondria, signal transduction, the response to stress, protein translation, gene expression, and metabolism were found to modulate lifespan (Dillin et al., 2002; Lee et al., 2003; Hamilton et al. 2005; Hansen, Hsu et al. 2005; Hansen, Taubert et al., 2007). Another advantage working with C. elegans for studying the aging process is that the lifespan assay is straightforward, which allows for large numbers of worms to be assayed in a single experiment. Therefore, statistical significance can be tested in addition to the analysis of mortality rates. Together, these techniques allow one to comprehensively survey the worm genome for genes that modulate lifespan. This has led to the identification of more than 200 genes and regimens that modulate lifespan in C. elegans and revealed evolutionarily conserved pathways that modulate lifespan. Therefore, the combination of the short, invariant lifespan, ease of assays, ample genetic, molecular and genomic tools, and evolutionary conservation has allowed C. elegans to develop into a premiere model system for aging research.

Disadvantages of worms

Despite all the excellent advantages of working with C. elegans for aging research, there are also several disadvantages for C. elegans as a model for human aging. First, C. elegans have a simple body plan, and lack many defined organs/tissues including a brain, blood, a defined fat cell, internal organs, and is evolutionarily distant from humans. Second, C. elegans are also only 1 mm in length which makes biochemistry more difficult. Typically, all biochemistry, microarray, immunoprecipitation, and chromatin immunoprecipitation is performed on whole worm extracts of either mixed-stage animals or animals at a similar growth stage. This may lead to limited understanding of any tissue-specific signaling such as whether a gene is expressed in the hypodermis or the intestine. Finally, C. elegans cell culture is limited with no system equivalent to Drosophila S2 cells.

Conclusion

C. elegans has proved to be an invaluable animal for aging research. Thus far, research has focused on the use of lifespan as a measurement of the aging process. These studies have led to the identification of hundreds of genes and regimens that modulate lifespan. Although the initial studies identified genes that altered lifespan and affected dauer diapause, these signaling pathways have nonetheless identified longevity-associated pathways across phylogeny. However, to truly use C. elegans for aging research, future studies should focus on understanding the connection between longevity and how an animal ages, with a focus on health. Aging is much more than a lifespan measurement. Aging involves the coordination of multiple systems in an organism and how they change as a function of time. We should strive to use model systems to reveal this systemic coordination on a molecular and genetic level, and how this leads to healthy aging rather than simply lifespan extension.

Acknowledgements

I am grateful to Ankita Bansal, Yong-Hak Seo, Micah Belew, and Griffin Walker for advice and discussions. H.A.T. is a William Randolph Hearst Investigator. This project was funded in part by grants from the National Institute of Aging (AG02589) and an endowment from the William Randolph Hearst Foundation. Due to lack of space, this article focused on molecular genetics and the aging process in C. elegans. For additional details of the C. elegans aging process see the following reviews (Ankeny 2001; David 2012; Jung and Suh 2012; McCormick and Kennedy 2012; Volovik et al. 2014; WormClassroom). For early studies, please refer to Nigon and Dougherty 1949.

References

  • Ahringer J. Reverse Genetics. WormBook; 2006. (WormBook, ed. The C. elegans Research Community)
  • Albert PS, Brown SJ, Riddle DL. Sensory control of dauer larva formation in Caenorhabditis elegans. The Journal of Comparative Neurology. 1981;198:435–451. doi: 10.1002/(ISSN)1096-9861.[PubMed][Cross Ref]
  • Anderson JL, Reynolds RM, Morran LT, Tolman-Thompson J, Phillips PC. Experimental evolution reveals antagonistic pleiotropy in reproductive timing but not life span in Caenorhabditis elegans . The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2011;66A:1300–1308. doi: 10.1093/gerona/glr143.[PMC free article][PubMed][Cross Ref]
  • Ankeny RA. The natural history of Caenorhabditis elegans research. Nature Reviews Genetics. 2001;2:474–479. doi: 10.1038/35076538.[PubMed][Cross Ref]
  • Anselmi CV, Malovini A, R Roncarati, V Novelli, Villa F, Condorelli G, Bellazzi R, Puca AA. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Research. 2009;12:95–104. doi: 10.1089/rej.2008.0827.[PubMed][Cross Ref]
  • Banasik K, Ribel-Madsen R, Gjesing AP, Wegner L, Andersson A, Poulsen P, Borglykke A, Witte DR, Pedersen O, Hansen T, Vaag A. The FOXO3A rs2802292 G-allele associates with improved peripheral and hepatic insulin sensitivity and increased skeletal muscle-FOXO3A mRNA expression in twins. The Journal of Clinical Endocrinology & Metabolism. 2011;96:E119–E124. doi: 10.1210/jc.2010-0881.[PubMed][Cross Ref]
  • Barbieri M, Bonafe M, Franceschi C, Paolisso G. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. American Journal of Physiology - Endocrinology and Metabolism. 2003;285:E1064–E1071.[PubMed]
  • Brenner S. The genetics of Caenorhabditis elegans . Genetics. 1974;77:71–94.[PMC free article][PubMed]
  • Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC. Green fluorescent protein as a marker for gene expression. Science. 1994;263:802–805. doi: 10.1126/science.8303295.[PubMed][Cross Ref]
  • Chen D, Pan KZ, Palter JE, Kapahi P. Longevity determined by developmental arrest genes in Caenorhabditis elegans . Aging Cell. 2007;6:525–533. doi: 10.1111/ace.2007.6.issue-4.[PMC free article][PubMed][Cross Ref]
  • Chen J, Senturk D, Wang JL, Muller HG, Carey JR, Caswell H, Caswell-Chen EP. A demographic analysis of the fitness cost of extended longevity in Caenorhabditis elegans . The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2007;62:126–135. doi: 10.1093/gerona/62.2.126.[PMC free article][PubMed][Cross Ref]
  • Coulson A, Sulston J, Brenner S, Karn J. Toward a physical map of the genome of the nematode Caenorhabditis elegans . Proceedings of the National Academy of Sciences. 1986;83:7821–7825. doi: 10.1073/pnas.83.20.7821.[PMC free article][PubMed][Cross Ref]
  • Crawford D. Is life-span the best measure of aging? Science of Aging Knowledge Environment. 2001;2001:vp7.[PubMed]
  • Curran SP, Ruvkun G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genetics. 2007;3:e56. doi: 10.1371/journal.pgen.0030056.[PMC free article][PubMed][Cross Ref]
  • David DC. Aging and the aggregating proteome. Frontiers in Genetics. 2012;3:247.[PMC free article][PubMed]
  • Depuydt G, Xie F, Petyuk VA, Smolders A, Brewer HM, Camp DG, 2nd, Smith RD, Braeckman BP. LC-MS proteomics analysis of the insulin/IGF-1-deficient Caenorhabditis elegans daf-2(e1370) mutant reveals extensive restructuring of intermediary metabolism. Journal of Proteome Research. 2014;13:1938–1956.[PMC free article][PubMed]
  • Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C. Rates of behavior and aging specified by mitochondrial function during development. Science. 2002;298:2398–2401. doi: 10.1126/science.1077780.[PubMed][Cross Ref]
  • Ellis RE, Jacobson DM, Horvitz HR. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans . Genetics. 1991;129:79–94.[PMC free article][PubMed]
  • Fatt HV, Dougherty EC. Genetic control of differential heat tolerance in two strains of the nematode Caenorhabditis elegans . Science. 1963;141:266–267. doi: 10.1126/science.141.3577.266.[PubMed][Cross Ref]
  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans . Nature. 1998;391:806–811.[PubMed]
  • Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proceedings of the National academy of Sciences of the United States of America. 2009;106:2700–2705.[PMC free article][PubMed]
  • Friedman DB, Johnson TE. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988;118:75–86.[PMC free article][PubMed]
  • Gems D, Sutton AJ, Sundermeyer ML, Albert PS, King KV, Edgley ML, Larsen PL, Riddle DL. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans . Genetics. 1998;150:129–155.[PMC free article][PubMed]
  • Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science. 2004;305:361. doi: 10.1126/science.1098219.[PubMed][Cross Ref]
  • Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans . Genes & Development. 2005;19:1544–1555. doi: 10.1101/gad.1308205.[PMC free article][PubMed][Cross Ref]
  • Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genetics. 2005;1:119–128.[PMC free article][PubMed]
  • Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans . Aging Cell. 2007;6:95–110. doi: 10.1111/ace.2007.6.issue-1.[PubMed][Cross Ref]
  • Hosono R. Age dependent changes in the behavior of Caenorhabditis elegans on attraction to Escherichia coli . Experimental Gerontology. 1978a;13:31–36. doi: 10.1016/0531-5565(78)90027-X.[PubMed][Cross Ref]
  • Hosono R. Sterilization and growth inhibition of Caenorhabditis elegans by 5-fluorodeoxyuridine. Experimental Gerontology. 1978b;13:369–374. doi: 10.1016/0531-5565(78)90047-5.[PubMed][Cross Ref]
  • Hwangbo DS, Gersham B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004;429:562–566. doi: 10.1038/nature02549.[PubMed][Cross Ref]
  • Jenkins NL, McColl G, Lithgow GJ. Fitness cost of extended lifespan in Caenorhabditis elegans . Proceedings of the Royal Society B: Biological Sciences. 2004;271:2523–2526. doi: 10.1098/rspb.2004.2897.[PMC free article][PubMed][Cross Ref]
  • Jung HJ, Suh Y. MicroRNA in aging: from discovery to biology. Current Genomics. 2012;13:548–557. doi: 10.2174/138920212803251436.[PMC free article][PubMed][Cross Ref]
  • Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464. doi: 10.1038/366461a0.[PubMed][Cross Ref]
  • Klass M. Aging in the nematode Caenorhabditis elegans:major biological and environmental factos influencing life span. Mechanisms of Ageing and Development. 1977;6:413–429. doi: 10.1016/0047-6374(77)90043-4.[PubMed][Cross Ref]
  • Klass MR. A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mechanisms of Ageing and Development. 1983;22:279–286. doi: 10.1016/0047-6374(83)90082-9.[PubMed][Cross Ref]
  • Klass MR, Hirsh DI. Non-ageing developmental variant of Caenorhabditis elegans. Nature. 1976;260:523–525. doi: 10.1038/260523a0.[PubMed][Cross Ref]
  • Lakowski B, Hekimi S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science. 1996;272:1010–1013. doi: 10.1126/science.272.5264.1010.[PubMed][Cross Ref]
  • Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–854. doi: 10.1016/0092-8674(93)90529-Y.[PubMed][Cross Ref]
  • Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet. 2003;33:40–48.[PubMed]
  • Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Human Molecular Genetics. 2009;18:4897–4904. doi: 10.1093/hmg/ddp459.[PMC free article][PubMed][Cross Ref]
  • Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans . Science. 1997;278:1319–1322. doi: 10.1126/science.278.5341.1319.[PubMed][Cross Ref]
  • Lithgow GJ. Why aging isn’t regulated: a lamentation on the use of language in aging literature. Experimental Gerontology. 2006;41:890–893. doi: 10.1016/j.exger.2006.06.051.[PubMed][Cross Ref]
  • Lunetta KL, D'Agostino Sr. RB, Karasik D, Benjamin EJ, Guo CY, Govindaraju R, Kiel DP, Kelly-Hayes M, Massaro JM, Pencina MJ, et al. Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Medical Genetics. 2007;8:S13. doi: 10.1186/1471-2350-8-S1-S13.[PMC free article][PubMed][Cross Ref]
  • Malovini A, Illario M, Iaccarino G, Villa F, Ferrario A, Roncarati R, Alselmi CV, Novelli V, Cipolletta S, Leggiero E, Orro A, et al. Association study on long-living individuals from Southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. Rejuvenation Research. 2011;14:283–291. doi: 10.1089/rej.2010.1114.[PubMed][Cross Ref]
  • McCormick MA, Kennedy BK. Genome-scale studies of aging: challenges and opportunities. Current Genomics. 2012;13:500–507. doi: 10.2174/138920212803251454.[PMC free article][PubMed][Cross Ref]
  • McElwee JJ, Schuster E, Blanc E, Thornton J, Gems D. Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans . Mechanisms of Ageing and Development. 2006;127:458–472. doi: 10.1016/j.mad.2006.01.006.[PubMed][Cross Ref]
  • McElwee JJ, Schuster E, Blanc E, Thomas JH, Gems D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. Journal of Biological Chemistry. 2004;279:44533–44543. doi: 10.1074/jbc.M406207200.[PubMed][Cross Ref]
  • Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA. PDP-1 links the TGF-beta and IIS pathways to regulate longevity, development, and metabolism. PLoS Genetics. 2011;7:e1001377. doi: 10.1371/journal.pgen.1001377.[PMC free article][PubMed][Cross Ref]
  • Nigon V, Dougherty EC. Reproductive patterns and attempts at reciprocal crossing of Rhabditis elegans Maupas, and Rhabditis briggsae Dougherty and Nigon, 1949 (Nematoda: Rhabditidae) Journal of Experimental Zoology. 1949;112:485–503. doi: 10.1002/(ISSN)1097-010X.[PubMed][Cross Ref]
  • Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans . Nature. 1997;389:994–999.[PubMed]
  • Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Hortviz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans . Nature. 2000;403:901–906.[PubMed]
  • Riddle DL. In: The Nematode Caenorhabditis elegans. Wood WB, editor. Cold Spring Harbor Laboratory: Cold Spring Harbor, NY; 1988. pp. 393–412.
  • Riddle DL, Albert PS. Riddle D BT, Meyer B, Priess J. C. elegans II. Cold Spring Harbor Laboratory; Cold Spring Harbor, NY: 1997. Genetic and environmental regulation of Dauer Larva development; p. 1222.
  • Shaw WM, Luo S, Landis J, Ashraf J, Murphy CT. The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling. Current Biology. 2007;17:1635–1645. doi: 10.1016/j.cub.2007.08.058.[PMC free article][PubMed][Cross Ref]
  • Soerensen M, et al. Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell. 2010;9:1010–1017. doi: 10.1111/j.1474-9726.2010.00627.x.[PMC free article][PubMed][Cross Ref]
  • The C. elegans Sequence Consortium Genome sequence of the nematode C. elegans: a platform for investigating biology. Science. 1998;282:2012–2018.[PubMed]
  • Tissenbaum HA. Genetics, life span, health span, and the aging process in Caenorhabditis elegans . The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2012;67A:503–510. doi: 10.1093/gerona/gls088.[PMC free article][PubMed][Cross Ref]
  • Volovik Y, Marques FC, Cohen E. The nematode Caenorhabditis elegans: a versatile model for the study of proteotoxicity and aging. Methods 2014[PubMed]
  • Vowels JJ, Thomas JH. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans . Genetics. 1992;130:105–123.[PMC free article][PubMed]
  • Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences. 2008;105:13987. doi: 10.1073/pnas.0801030105.[PMC free article][PubMed][Cross Ref]
  • WormClassroom. Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison; http://wormclassroom.org/short-history-c-elegans-research
  • Yen K, Narasimhan SD, Tissenbaum HA. DAF-16/Forkhead box O transcription factor: many paths to a single Fork(head) in the road. Antioxidants & Redox Signaling. 2011;14:623–634. doi: 10.1089/ars.2010.3490.[PMC free article][PubMed][Cross Ref]
  • Zeng Y, Cheng L, Chen H, Cao H, Hauser ER, Liu Y, Xiao Z, Tan Q, Tian XL, Vaupel JW. Effects of FOXO genotypes on longevity: a biodemographic analysis. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2010;65A:1285–1299. doi: 10.1093/gerona/glq156.[PMC free article][PubMed][Cross Ref]

Comments

Leave a Reply

Your email address will not be published. Required fields are marked *