The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans, following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan.
","acknowledgements":"We thank the members of the Phillips lab and all members of CITP for useful discussions.
","authors":[{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","writing_reviewEditing","writing_originalDraft"],"email":"ejohns10@uoregon.edu","firstName":"Erik","lastName":"Johnson","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","formalAnalysis","writing_reviewEditing","visualization"],"email":"csedore@uoregon.edu","firstName":"Christine A.","lastName":"Sedore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["writing_reviewEditing","resources","project","investigation"],"email":"acoleman@uoregon.edu","firstName":"Anna L.","lastName":"Coleman-Hulbert","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0001-8090-551X"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"bdonken@dls.rutgers.edu","firstName":"Brian D.","lastName":"Onken","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8818-4497"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"va242@scarletmail.rutgers.edu","firstName":"Vijaya Madhuri","lastName":"Achanta","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"songy3@dls.rutgers.edu","firstName":"Yuhua","lastName":"Song","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of California Davis, Davis, California, USA"],"departments":["Department of Molecular Biosciences"],"credit":["conceptualization","writing_reviewEditing"],"email":"gcortopassi@ucdavis.edu","firstName":"Gino","lastName":"Cortopassi","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0003-2563-4133"},{"affiliations":["The Buck Institute for Research on Aging, Novato, California, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"glithgow@buckinstitute.org","firstName":"Gordon J.","lastName":"Lithgow","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8953-3043"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"driscoll@dls.rutgers.edu","firstName":"Monica","lastName":"Driscoll","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8751-7429"},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","supervision","writing_reviewEditing"],"email":"pphil@uoregon.edu","firstName":"Patrick C.","lastName":"Phillips","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":"","orcid":"0000-0001-7271-342X"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"This work was supported by funding from National Institutes of Health grants (U01 AG045844, U01 AG045864, U01 AG045829, and U24 AG056052).
","image":{"url":"https://portal.micropublication.org/uploads/e117fb3a1c705cabcc049d3a1c77f496.png"},"imageCaption":"(A) Survival curves for C. elegans strain N2 exposed to 0, 1, 3, 10, 30, and 100 µM cinnarizine (orange) or meclizine (green) starting on the first day of adulthood, measured in a single lab (Oregon). (B) The highest non-toxic dose for both compounds (3 µM) replicated across two labs (Oregon and Rutgers). Each dot represents the percent change in median lifespan of a single compound plate as compared to its specific control. The shape indicates the lab in which the replicate was tested (circles: Oregon; diamonds: Rutgers). The bars represent the mean and standard error of the mean. All statistical comparisons were made with a Cox proportional hazards (CPH) mixed-model using the coxme v.2.2-22 package in R. Asterisks represent p-values from the CPH model such that ****p<.0001, ***p<.001, **p<.01, and *p<.05.
","imageTitle":"Longevity of C. elegans under adult drug exposure
","methods":"For all experiments, C. elegans N2 worms were age-synchronized by timed egg-lays on standard 60 mm diameter Nematode Growth Media (NGM) plates and transferred at a density of 50 individuals per 35 mm treated plate in triplicate upon onset of adulthood (for control plates, there were six replicates of 50 animals each). Both cinnarizine and meclizine were dissolved in DMSO and diluted appropriately such that addition of 132.5 µl of solution to 35 mm diameter plates containing NGM with lawns of E. coli OP50-1 and 51 µm FUdR would generate the following final concentrations: 0 µM (control), 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. Final concentration of DMSO in all plates was 0.25%. Animals were maintained at 20 °C and 80% RH and moved to fresh plates on the first, second, and fifth day of adulthood, then once weekly afterward. Three times weekly, we observed animals for spontaneous movement or movement after gentle perturbation with a 0.2 mm diameter platinum wire. Death was scored as a lack of movement.
Statistical analyses were performed as previously described (Lucanic et al. 2017). In brief, survival was analyzed both with a generalized linear model using the lme4 package (version 1.1-35.5), and with a mixed-model Cox-Proportional Hazards (CPH) using the coxme package (version 2.2-22; Therneau 2020) in the R statistical language (R Core Team 2021; version 4.4.1). Compound effects were analyzed as a planned comparison between individuals exposed to compound (cinnarizine or meclizine) or vehicle control (DMSO) (multcomp package, version 1.4-26). The raw data can be accessed on the CITP Data Portal (citpaging.org/portal v2.1), and on figshare.com along with CITP SOPs and the R scripts used for analysis (https://doi.org/10.6084/m9.figshare.c.7561101).
","reagents":"Experiments were performed using C. elegans N2_PD1073 (Banse et al. 2019; Yoshimura et al. 2019) from the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). For chemical interventions, cinnarizine (Alfa Aesar CAS: 298-57-7) and meclizine (Millipore Sigma CAS: 1104-22-9) were obtained in solid form and dissolved in DMSO (Sigma-Aldrich).
","patternDescription":"The Caenorhabditis Intervention Testing Program (CITP) is a multi-institute research consortium with the aim of identifying compounds that robustly extend lifespan with reproducible effects across genetically diverse Caenorhabditis species and strains (Lucanic et al., 2017). Prioritization of compounds for testing is based on recommendations made by our scientific Access Panel and the CITP Steering Committee; nominations for compounds to test can be made by any individual, nonprofit, academic group, or business during the CITP’s annual call-for-submissions period (https://citpaging.org/submissions). Several factors, such as predicted or known interactions with established lifespan-regulating pathways, computational predictions for effects on lifespan or health-span (Coleman-Hulbert et al., 2019), or previous reports of life- or health-span extension in laboratory animals are considered when evaluating a compound for testing in the CITP pipeline.
Both cinnarizine and meclizine are piperazine-based antihistamines. Clinically, both are used in the treatment of nausea and vomiting associated with motion sickness and in the treatment of vestibular disorders such as vertigo (Pianese et al., 2002; Patel et al., 2011). Like the well-characterized lifespan-extending compound rapamycin, cinnarizine and meclizine were also both recently identified in a screen of more than 1600 human medicines targeting mTORC1-specific inhibitors (Allen et al., 2018). The mTOR kinase forms two complexes, mTORC1 and mTORC2, which are composed of discrete protein binding partners that are sensitive to distinct stimuli (Panwar et al., 2023). Numerous studies have found that genetic inhibition of mTORC1 or its downstream signaling pathways extends lifespan (Vellai et al., 2003; Kaeberlein et al., 2005; Lamming et al., 2013), whereas inhibition of mTORC2 has been associated with decreased lifespan in worms and mice (Lamming et al., 2012; Lamming et al., 2014). Both cinnarizine and meclizine were recently shown to significantly inhibit mTORC1 but not mTORC2 (Allen et al., 2018; Sandoval et al., 2020), raising the possibility that, like rapamycin, these novel mTORC1 inhibitors might also extend lifespan in model organisms, yet with fewer side effects than rapamycin. Previously, cinnarizine was shown to increase longevity in C. elegans (Ye et al., 2014) and, more recently, the Mouse Intervention Testing Program (ITP) found that meclizine extends lifespan in male mice (Harrison et al., 2023). Cinnarizine and meclizine have a smaller size (369 g/mol and 391g/mol, respectively) compared to rapamycin (914g/mol). They are approved for use in humans (cinnarizine since 1955 and meclizine since 1953) and display a relatively mild profile of known side-effects (e.g. drowsiness and dry mouth) as compared to the more serious adverse immunosuppressive effects in patients treated with rapamycin (Kraig et al., 2017). Although cinnarizine has also been associated with drug-induced parkinsonism (Martí-Massó & Poza, 1998; Terland & Flatmark, 1999), we were interested in testing the longevity effects of both compounds in C. elegans.
Here, we tested whether cinnarizine and meclizine could reproducibly and robustly increase lifespan in C. elegans using our recently revised workflow. C. elegans N2 worms were assayed on five different concentrations of cinnarizine and meclizine at a single research site (University of Oregon). Both cinnarizine and meclizine had no effect on lifespan at the two lowest doses tested (1 µM and 3 µM, along with 10 µM for meclizine alone; Fig.1A). Conversely, both compounds exerted a toxic effect at the higher concentrations tested (10, 30, and 100 µM for cinnarizine and 30 and 100 µM for meclizine), significantly shortening lifespan (Fig. 1A). Following the CITP protocol for null or negative results, the experiment was repeated at the highest non-toxic dose (3 µM) for both compounds at a second research site (Rutgers University); results from this assay demonstrated that 3 µM of meclizine at both the Rutgers and Oregon sites had no significant effect, while treatment with 3 µM of cinnarizine showed a significantly negative lifespan effect when the data from both sites were pooled (Fig 1B).
Overall, our findings may seem surprising given the observed pro-longevity effects of the mTORC-1 inhibiting compound rapamycin in numerous model organisms (Mannick & Lamming, 2023). However, previous CITP studies on rapamycin also showed a null effect on lifespan in C. elegans underscoring the consistency of the current results (Banse et al., 2024). This fact, combined with results from other studies showing the ability of rapamycin to extend life in C. elegans, indicates that cinnarizine and meclizine’s potential ability to extend lifespan may be dependent on the specific protocols used, and further experimentation is likely warranted. Others in the field acknowledge the effect of assay conditions on outcomes of aging interventions, including those who previously reported a positive effect from cinnarizine on C. elegans lifespan (Ye et al., 2014). Given the aims of the CITP to identify compounds that robustly and reproducibly increase lifespan (with an effect size of 20% or more) following a standardized pipeline, and the fact that cinnarizine and meclizine showed null or negative lifespan effects using our protocol, further investigation under the CITP workflow was not pursued.
","references":[{"reference":"Allen SA, Tomilov A, Cortopassi GA. 2018. Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochem Pharmacol 155: 298-304.
","pubmedId":"30028993","doi":""},{"reference":"Banse SA, Lucanic M, Sedore CA, Coleman-Hulbert AL, Plummer WT, Chen E, et al., Phillips PC. 2019. Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions. Geroscience 41(6): 945-960.
","pubmedId":"31820364","doi":""},{"reference":"Banse SA, Sedore CA, Johnson E, Coleman-Hulbert AL, Onken B, Hall D, et al., Phillips PC. 2024. Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes. Geroscience 46(2): 2239-2251.
","pubmedId":"37923874","doi":""},{"reference":"Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, et al., Miller RA. 2024. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. Geroscience 46(1): 795-816.
","pubmedId":"38041783","doi":""},{"reference":"Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, et al., Kennedy BK. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751): 1193-6.
","pubmedId":"16293764","doi":""},{"reference":"Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al., Kellogg DL Jr. 2018. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105: 53-69.
","pubmedId":"29408453","doi":""},{"reference":"Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al., Baur JA. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076): 1638-43.
","pubmedId":"22461615","doi":""},{"reference":"Lamming DW, Ye L, Sabatini DM, Baur JA. 2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 123(3): 980-9.
","pubmedId":"23454761","doi":""},{"reference":"Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, et al., Sabatini DM. 2014. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13(5): 911-7.
","pubmedId":"25059582","doi":""},{"reference":"Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al., Phillips PC. 2017. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nat Commun 8: 14256.
","pubmedId":"28220799","doi":""},{"reference":"Mannick JB, Lamming DW. 2023. Targeting the biology of aging with mTOR inhibitors. Nat Aging 3(6): 642-660.
","pubmedId":"37142830","doi":""},{"reference":"Martí-Massó JF, Poza JJ. 1998. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 13(3): 453-6.
","pubmedId":"9613736","doi":""},{"reference":"Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al., Garg M. 2023. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 8(1): 375.
","pubmedId":"37779156","doi":""},{"reference":"Patel PN, Ambizas EM. 2011. Meclizine: Safety and Efficacy in the Treatment and Prevention of Motion Sickness. Clinical Medicine Insights: Therapeutics 3: 10.4137/cmt.s6237.
","pubmedId":"","doi":"10.4137/CMT.S6237"},{"reference":"Pianese CP, Hidalgo LO, González RH, Madrid CE, Ponce JE, Ramírez AM, et al., F GV. 2002. New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational, double-blind study. Otol Neurotol 23(3): 357-63.
","pubmedId":"11981396","doi":""},{"reference":"R Core Team, 2021 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
","pubmedId":"","doi":""},{"reference":"Sandoval JA, Tomilov A, Datta S, Allen S, O'Donnell R, Sears T, et al., Cortopassi G. 2020. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells. Pharmaceuticals (Basel) 13(12): 10.3390/ph13120419.
","pubmedId":"33255358","doi":""},{"reference":"Terland O, Flatmark T. 1999. Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. Neuropharmacology 38(6): 879-82.
","pubmedId":"10465691","doi":""},{"reference":"Therneau T. M., 2020 coxme: Mixed Effects Cox Models. R package version 2.2.16.
","pubmedId":"","doi":""},{"reference":"Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. 2003. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967): 620.
","pubmedId":"14668850","doi":""},{"reference":"Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M. 2014. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13(2): 206-15.
","pubmedId":"24134630","doi":""}],"title":"Caenorhabditis Intervention Testing Program: the mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans
","reviews":[{"reviewer":{"displayName":"Collin Ewald"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"a71ef1ca-2a77-4c98-bca4-e743597992e7","decision":"revise","abstract":"The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel putative mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans, following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan.
","acknowledgements":"We thank the members of the Phillips lab and all members of CITP for useful discussions.
","authors":[{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","writing_reviewEditing","writing_originalDraft"],"email":"ejohns10@uoregon.edu","firstName":"Erik","lastName":"Johnson","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","formalAnalysis","writing_reviewEditing","visualization"],"email":"csedore@uoregon.edu","firstName":"Christine A.","lastName":"Sedore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["writing_reviewEditing","resources","project","investigation"],"email":"acoleman@uoregon.edu","firstName":"Anna L.","lastName":"Coleman-Hulbert","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0001-8090-551X"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"bdonken@dls.rutgers.edu","firstName":"Brian D.","lastName":"Onken","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8818-4497"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"va242@scarletmail.rutgers.edu","firstName":"Vijaya Madhuri","lastName":"Achanta","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"songy3@dls.rutgers.edu","firstName":"Yuhua","lastName":"Song","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of California Davis, Davis, California, USA"],"departments":["Department of Molecular Biosciences"],"credit":["conceptualization","writing_reviewEditing"],"email":"gcortopassi@ucdavis.edu","firstName":"Gino","lastName":"Cortopassi","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0003-2563-4133"},{"affiliations":["The Buck Institute for Research on Aging, Novato, California, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"glithgow@buckinstitute.org","firstName":"Gordon J.","lastName":"Lithgow","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8953-3043"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"driscoll@dls.rutgers.edu","firstName":"Monica","lastName":"Driscoll","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8751-7429"},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","supervision","writing_reviewEditing"],"email":"pphil@uoregon.edu","firstName":"Patrick C.","lastName":"Phillips","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":"","orcid":"0000-0001-7271-342X"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"This work was supported by funding from National Institutes of Health grants (U01 AG045844, U01 AG045864, U01 AG045829, and U24 AG056052).
","image":{"url":"https://portal.micropublication.org/uploads/e117fb3a1c705cabcc049d3a1c77f496.png"},"imageCaption":"(A) Survival curves for C. elegans strain N2 exposed to 0, 1, 3, 10, 30, and 100 µM cinnarizine (orange) or meclizine (green) starting on the first day of adulthood, measured in a single lab (University of Oregon). (B) The highest non-toxic dose for both compounds (3 µM) replicated across two labs (Oregon and Rutgers). Each dot represents the percent change in median lifespan of a single compound plate as compared to its specific control. The shape indicates the lab in which the replicate was tested (circles: Oregon; diamonds: Rutgers). The bars represent the mean and standard error of the mean. All statistical comparisons were made with a Cox proportional hazards (CPH) mixed-model using the coxme v.2.2-22 package in R. Asterisks represent p-values from the CPH model such that ****p<.0001, ***p<.001, **p<.01, and *p<.05.
","imageTitle":"Longevity of C. elegans under adult drug exposure
","methods":"For all experiments, C. elegans N2 worms were age-synchronized by timed egg-lays on standard 60 mm diameter Nematode Growth Media (NGM) plates and transferred at a density of 50 individuals per 35 mm treated plate in triplicate upon onset of adulthood (for control plates, there were six replicates of 50 animals each). Both cinnarizine and meclizine were dissolved in DMSO and diluted appropriately such that addition of 132.5 µl of solution to 35 mm diameter plates containing NGM with lawns of E. coli OP50-1 and 51 µm FUdR would generate the following final concentrations: 0 µM (control), 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. Final concentration of DMSO in all plates was 0.25%. Animals were maintained at 20 °C and 80% RH and moved to fresh plates on the first, second, and fifth day of adulthood, then once weekly afterward. Three times weekly, we observed animals for spontaneous movement or movement after gentle perturbation with a 0.2 mm diameter platinum wire. Death was scored as a lack of movement.
Statistical analyses were performed as previously described (Lucanic et al. 2017). In brief, survival was analyzed both with a generalized linear model using the lme4 package (version 1.1-35.5), and with a mixed-model Cox-Proportional Hazards (CPH) using the coxme package (version 2.2-22; Therneau 2020) in the R statistical language (R Core Team 2021; version 4.4.1). Compound effects were analyzed as a planned comparison between individuals exposed to compound (cinnarizine or meclizine) or vehicle control (DMSO) (multcomp package, version 1.4-26). The raw data can be accessed on the CITP Data Portal (citpaging.org/portal v2.1), and on figshare.com along with CITP SOPs and the R scripts used for analysis (https://doi.org/10.6084/m9.figshare.c.7561101).
","reagents":"Experiments were performed using C. elegans N2_PD1073 (Banse et al. 2019; Yoshimura et al. 2019) from the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). For chemical interventions, cinnarizine (Alfa Aesar CAS: 298-57-7) and meclizine (Millipore Sigma CAS: 1104-22-9) were obtained in solid form and dissolved in DMSO (Sigma-Aldrich).
","patternDescription":"The Caenorhabditis Intervention Testing Program (CITP) is a multi-institute research consortium with the aim of identifying compounds that robustly extend lifespan with reproducible effects across genetically diverse Caenorhabditis species and strains (Lucanic et al., 2017). Prioritization of compounds for testing is based on recommendations made by our scientific Access Panel and the CITP Steering Committee; nominations for compounds to test can be made by any individual, nonprofit, academic group, or business during the CITP’s annual call-for-submissions period (https://citpaging.org/submissions). Several factors, such as predicted or known interactions with established lifespan-regulating pathways, computational predictions for effects on lifespan or health-span (Coleman-Hulbert et al., 2019), or previous reports of life- or health-span extension in laboratory animals are considered when evaluating a compound for testing in the CITP pipeline.
Both cinnarizine and meclizine are piperazine-based antihistamines. Clinically, both are used in the treatment of nausea and vomiting associated with motion sickness and in the treatment of vestibular disorders such as vertigo (Pianese et al., 2002; Patel et al., 2011). Like the well-characterized lifespan-extending compound rapamycin, cinnarizine and meclizine were also both recently identified in a screen of more than 1600 human medicines targeting mTORC1-specific inhibitors (Allen et al., 2018). The mTOR kinase forms two complexes, mTORC1 and mTORC2, which are composed of discrete protein binding partners that are sensitive to distinct stimuli (Panwar et al., 2023). Numerous studies have found that genetic inhibition of mTORC1 or its downstream signaling pathways extends lifespan (Vellai et al., 2003; Kaeberlein et al., 2005; Lamming et al., 2013), whereas inhibition of mTORC2 has been associated with decreased lifespan in worms and mice (Lamming et al., 2012; Lamming et al., 2014). Both cinnarizine and meclizine were recently shown to bind to mTOR and significantly inhibit mTORC1, measured as phospho-S6 kinase inhibition, but not mTORC2, determined by the inability to inhibit phospho-Akt (Allen et al., 2018; Sandoval et al., 2020), raising the possibility that, like rapamycin, these novel mTORC1 inhibitors might also extend lifespan in model organisms, yet with fewer side effects than rapamycin. Of note, identification and classification of these compounds as mTOR inhibitors is inferred using human and mouse mTOR, and the specific inhibition of C. elegans mTOR/LET-363 is unknown, thus both compounds should be considered putative mTOR inhibitors in C. elegans. Regardless, mTOR is highly conserved in nematodes (Blackwell et al., 2019), and cinnarizine was shown to increase longevity in C. elegans (Ye et al., 2014). Additionally, the Mouse Intervention Testing Program (ITP) found that meclizine extends lifespan in male mice (Harrison et al., 2023). Cinnarizine and meclizine have a smaller size (369 g/mol and 391 g/mol, respectively) compared to rapamycin (914 g/mol). They are approved for use in humans (cinnarizine since 1955 and meclizine since 1953) and display a relatively mild profile of known side-effects (e.g. drowsiness and dry mouth) as compared to the more serious adverse immunosuppressive effects in patients treated with rapamycin (Kraig et al., 2017). Although cinnarizine has also been associated with drug-induced parkinsonism (Martí-Massó & Poza, 1998; Terland & Flatmark, 1999), we were interested in testing the longevity effects of both compounds in C. elegans.
Here, we tested whether cinnarizine and meclizine could reproducibly and robustly increase lifespan in C. elegans using our recently revised workflow. C. elegans N2 worms were assayed on five different concentrations of cinnarizine and meclizine at a single research site (University of Oregon). Both cinnarizine and meclizine had no effect on lifespan at the two lowest doses tested (1 µM and 3 µM, along with 10 µM for meclizine alone; Fig. 1A). Conversely, both compounds exerted a toxic effect at the higher concentrations tested (10, 30, and 100 µM for cinnarizine and 30 and 100 µM for meclizine), significantly shortening lifespan (Fig. 1A). Following the CITP protocol for null or negative results, the experiment was repeated at the highest non-toxic dose (3 µM) for both compounds at a second research site (Rutgers University); results from this assay demonstrated that 3 µM of meclizine at both the Rutgers and Oregon sites had no significant effect, while treatment with 3 µM of cinnarizine showed a significantly negative lifespan effect when the data from both sites were pooled (Fig. 1B).
Overall, our preliminary findings may seem surprising given the observed pro-longevity effects of the mTORC-1 inhibiting compound rapamycin in numerous model organisms (Mannick & Lamming, 2023). However, previous CITP studies on rapamycin also showed a null effect on lifespan in C. elegans underscoring the consistency of the current results (Banse et al., 2024). This fact, combined with results from other studies showing the ability of rapamycin to extend life in C. elegans, indicates that cinnarizine and meclizine’s potential ability to extend lifespan may be dependent on the specific protocols used, and further experimentation is likely warranted. Others in the field acknowledge the effect of assay conditions on outcomes of aging interventions, including those who previously reported a positive effect from cinnarizine on C. elegans lifespan (Ye et al., 2014). Given the aims of the CITP to identify compounds that robustly and reproducibly increase lifespan (with an effect size of 20% or more) following a standardized pipeline, and the fact that cinnarizine and meclizine showed null or negative lifespan effects using our protocol, further investigation under the CITP workflow was not pursued.
","references":[{"reference":"Allen SA, Tomilov A, Cortopassi GA. 2018. Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochem Pharmacol 155: 298-304.
","pubmedId":"30028993","doi":""},{"reference":"Banse SA, Lucanic M, Sedore CA, Coleman-Hulbert AL, Plummer WT, Chen E, et al., Phillips PC. 2019. Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions. Geroscience 41(6): 945-960.
","pubmedId":"31820364","doi":""},{"reference":"Banse SA, Sedore CA, Johnson E, Coleman-Hulbert AL, Onken B, Hall D, et al., Phillips PC. 2024. Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes. Geroscience 46(2): 2239-2251.
","pubmedId":"37923874","doi":""},{"reference":"Blackwell TK, Sewell AK, Wu Z, Han M. 2019. TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging. Genetics 213(2): 329-360.
","pubmedId":"31594908","doi":""},{"reference":"Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, et al., Miller RA. 2024. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. Geroscience 46(1): 795-816.
","pubmedId":"38041783","doi":""},{"reference":"Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, et al., Kennedy BK. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751): 1193-6.
","pubmedId":"16293764","doi":""},{"reference":"Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al., Kellogg DL Jr. 2018. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105: 53-69.
","pubmedId":"29408453","doi":""},{"reference":"Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al., Baur JA. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076): 1638-43.
","pubmedId":"22461615","doi":""},{"reference":"Lamming DW, Ye L, Sabatini DM, Baur JA. 2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 123(3): 980-9.
","pubmedId":"23454761","doi":""},{"reference":"Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, et al., Sabatini DM. 2014. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13(5): 911-7.
","pubmedId":"25059582","doi":""},{"reference":"Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al., Phillips PC. 2017. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nat Commun 8: 14256.
","pubmedId":"28220799","doi":""},{"reference":"Mannick JB, Lamming DW. 2023. Targeting the biology of aging with mTOR inhibitors. Nat Aging 3(6): 642-660.
","pubmedId":"37142830","doi":""},{"reference":"Martí-Massó JF, Poza JJ. 1998. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 13(3): 453-6.
","pubmedId":"9613736","doi":""},{"reference":"Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al., Garg M. 2023. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 8(1): 375.
","pubmedId":"37779156","doi":""},{"reference":"Patel PN, Ambizas EM. 2011. Meclizine: Safety and Efficacy in the Treatment and Prevention of Motion Sickness. Clinical Medicine Insights: Therapeutics 3: 10.4137/cmt.s6237.
","pubmedId":"","doi":"10.4137/CMT.S6237"},{"reference":"Pianese CP, Hidalgo LO, González RH, Madrid CE, Ponce JE, Ramírez AM, et al., F GV. 2002. New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational, double-blind study. Otol Neurotol 23(3): 357-63.
","pubmedId":"11981396","doi":""},{"reference":"R Core Team, 2021 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
","pubmedId":"","doi":""},{"reference":"Sandoval JA, Tomilov A, Datta S, Allen S, O'Donnell R, Sears T, et al., Cortopassi G. 2020. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells. Pharmaceuticals (Basel) 13(12): 10.3390/ph13120419.
","pubmedId":"33255358","doi":""},{"reference":"Terland O, Flatmark T. 1999. Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. Neuropharmacology 38(6): 879-82.
","pubmedId":"10465691","doi":""},{"reference":"Therneau T. M., 2020 coxme: Mixed Effects Cox Models. R package version 2.2.16.
","pubmedId":"","doi":""},{"reference":"Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. 2003. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967): 620.
","pubmedId":"14668850","doi":""},{"reference":"Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M. 2014. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13(2): 206-15.
","pubmedId":"24134630","doi":""}],"title":"Caenorhabditis Intervention Testing Program: the mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans
","reviews":[{"reviewer":{"displayName":"Collin Ewald"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"6926b92b-701c-4284-9133-cd7f30e2d61d","decision":"accept","abstract":"The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel putative mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans, following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan.
","acknowledgements":"We thank the members of the Phillips lab and all members of CITP for useful discussions, and the anonymous reviewer who helped to improve the clarity of this work.
","authors":[{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","writing_reviewEditing","writing_originalDraft"],"email":"ejohns10@uoregon.edu","firstName":"Erik","lastName":"Johnson","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","formalAnalysis","writing_reviewEditing","visualization"],"email":"csedore@uoregon.edu","firstName":"Christine A.","lastName":"Sedore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["writing_reviewEditing","resources","project","investigation"],"email":"acoleman@uoregon.edu","firstName":"Anna L.","lastName":"Coleman-Hulbert","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0001-8090-551X"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"bdonken@dls.rutgers.edu","firstName":"Brian D.","lastName":"Onken","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8818-4497"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"va242@scarletmail.rutgers.edu","firstName":"Vijaya Madhuri","lastName":"Achanta","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"songy3@dls.rutgers.edu","firstName":"Yuhua","lastName":"Song","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of California Davis, Davis, California, USA"],"departments":["Department of Molecular Biosciences"],"credit":["conceptualization","writing_reviewEditing"],"email":"gcortopassi@ucdavis.edu","firstName":"Gino","lastName":"Cortopassi","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0003-2563-4133"},{"affiliations":["The Buck Institute for Research on Aging, Novato, California, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"glithgow@buckinstitute.org","firstName":"Gordon J.","lastName":"Lithgow","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8953-3043"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"driscoll@dls.rutgers.edu","firstName":"Monica","lastName":"Driscoll","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8751-7429"},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","supervision","writing_reviewEditing"],"email":"pphil@uoregon.edu","firstName":"Patrick C.","lastName":"Phillips","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":"","orcid":"0000-0001-7271-342X"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"This work was supported by funding from National Institutes of Health grants (U01 AG045844, U01 AG045864, U01 AG045829, and U24 AG056052).
","image":{"url":"https://portal.micropublication.org/uploads/e117fb3a1c705cabcc049d3a1c77f496.png"},"imageCaption":"(A) Survival curves for C. elegans strain N2 exposed to 0, 1, 3, 10, 30, and 100 µM cinnarizine (orange) or meclizine (green) starting on the first day of adulthood, measured in a single lab (University of Oregon). (B) The highest non-toxic dose for both compounds (3 µM) replicated across two labs (Oregon and Rutgers). Each dot represents the percent change in median lifespan of a single compound plate as compared to its specific control. The shape indicates the lab in which the replicate was tested (circles: Oregon; diamonds: Rutgers). The bars represent the mean and standard error of the mean. All statistical comparisons were made with a Cox proportional hazards (CPH) mixed-model using the coxme v.2.2-22 package in R. Asterisks represent p-values from the CPH model such that ****p<.0001, ***p<.001, **p<.01, and *p<.05.
","imageTitle":"Longevity of C. elegans under adult drug exposure
","methods":"For all experiments, C. elegans N2 worms were age-synchronized by timed egg-lays on standard 60 mm diameter Nematode Growth Media (NGM) plates and transferred at a density of 50 individuals per 35 mm treated plate in triplicate upon onset of adulthood (for control plates, there were six replicates of 50 animals each). Both cinnarizine and meclizine were dissolved in DMSO and diluted appropriately such that addition of 132.5 µl of solution to 35 mm diameter plates containing NGM with lawns of E. coli OP50-1 and 51 µm FUdR would generate the following final concentrations: 0 µM (control), 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. Final concentration of DMSO in all plates was 0.25%. Animals were maintained at 20 °C and 80% RH and moved to fresh plates on the first, second, and fifth day of adulthood, then once weekly afterward. Three times weekly, we observed animals for spontaneous movement or movement after gentle perturbation with a 0.2 mm diameter platinum wire. Death was scored as a lack of movement.
Statistical analyses were performed as previously described (Lucanic et al. 2017). In brief, survival was analyzed both with a generalized linear model using the lme4 package (version 1.1-35.5), and with a mixed-model Cox-Proportional Hazards (CPH) using the coxme package (version 2.2-22; Therneau 2020) in the R statistical language (R Core Team 2021; version 4.4.1). Compound effects were analyzed as a planned comparison between individuals exposed to compound (cinnarizine or meclizine) or vehicle control (DMSO) (multcomp package, version 1.4-26). The raw data can be accessed on the CITP Data Portal (citpaging.org/portal v2.1), and on figshare.com along with CITP SOPs and the R scripts used for analysis (https://doi.org/10.6084/m9.figshare.c.7561101).
","reagents":"Experiments were performed using C. elegans N2_PD1073 (Banse et al. 2019; Yoshimura et al. 2019) from the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). For chemical interventions, cinnarizine (Alfa Aesar CAS: 298-57-7) and meclizine (Millipore Sigma CAS: 1104-22-9) were obtained in solid form and dissolved in DMSO (Sigma-Aldrich).
","patternDescription":"The Caenorhabditis Intervention Testing Program (CITP) is a multi-institute research consortium with the aim of identifying compounds that robustly extend lifespan with reproducible effects across genetically diverse Caenorhabditis species and strains (Lucanic et al., 2017). Prioritization of compounds for testing is based on recommendations made by our scientific Access Panel and the CITP Steering Committee; nominations for compounds to test can be made by any individual, nonprofit, academic group, or business during the CITP's annual call-for-submissions period (https://citpaging.org/submissions). Several factors, such as predicted or known interactions with established lifespan-regulating pathways, computational predictions for effects on lifespan or health-span (Coleman-Hulbert et al., 2019), or previous reports of life- or health-span extension in laboratory animals are considered when evaluating a compound for testing in the CITP pipeline.
Both cinnarizine and meclizine are piperazine-based antihistamines. Clinically, both are used in the treatment of nausea and vomiting associated with motion sickness and in the treatment of vestibular disorders such as vertigo (Pianese et al., 2002; Patel et al., 2011). Like the well-characterized lifespan-extending compound rapamycin, cinnarizine and meclizine were also both recently identified in a screen of more than 1600 human medicines targeting mTORC1-specific inhibitors (Allen et al., 2018). The mTOR kinase forms two complexes, mTORC1 and mTORC2, which are composed of discrete protein binding partners that are sensitive to distinct stimuli (Panwar et al., 2023). Numerous studies have found that genetic inhibition of mTORC1 or its downstream signaling pathways extends lifespan (Vellai et al., 2003; Kaeberlein et al., 2005; Lamming et al., 2013), whereas inhibition of mTORC2 has been associated with decreased lifespan in worms and mice (Lamming et al., 2012; Lamming et al., 2014). Both cinnarizine and meclizine were recently shown to bind to mTOR and significantly inhibit mTORC1, measured as phospho-S6 kinase inhibition, but not mTORC2, determined by the inability to inhibit phospho-Akt (Allen et al., 2018; Sandoval et al., 2020), raising the possibility that, like rapamycin, these novel mTORC1 inhibitors might also extend lifespan in model organisms, yet with fewer side effects than rapamycin. Of note, identification and classification of these compounds as mTOR inhibitors is inferred using human and mouse mTOR, and the specific inhibition of C. elegans mTOR/LET-363 is unknown, thus both compounds should be considered putative mTOR inhibitors in C. elegans. Regardless, mTOR is highly conserved in nematodes (Blackwell et al., 2019), and cinnarizine was shown to increase longevity in C. elegans (Ye et al., 2014). Additionally, the mouse Intervention Testing Program (ITP) found that meclizine extends lifespan in male mice (Harrison et al., 2023). Cinnarizine and meclizine have a smaller size (369 g/mol and 391 g/mol, respectively) compared to rapamycin (914 g/mol). They are approved for use in humans (cinnarizine since 1955 and meclizine since 1953) and display a relatively mild profile of known side-effects (e.g. drowsiness and dry mouth) as compared to the more serious adverse immunosuppressive effects in patients treated with rapamycin (Kraig et al., 2017). Although cinnarizine has also been associated with drug-induced parkinsonism (Martí-Massó & Poza, 1998; Terland & Flatmark, 1999), we were interested in testing the longevity effects of both compounds in C. elegans.
Here, we tested whether cinnarizine and meclizine could reproducibly and robustly increase lifespan in C. elegans using our recently revised workflow. C. elegans N2 worms were assayed on five different concentrations of cinnarizine and meclizine at a single research site (University of Oregon). Both cinnarizine and meclizine had no effect on lifespan at the two lowest doses tested (1 µM and 3 µM, along with 10 µM for meclizine alone; Fig. 1A). Conversely, both compounds exerted a toxic effect at the higher concentrations tested (10, 30, and 100 µM for cinnarizine and 30 and 100 µM for meclizine), significantly shortening lifespan (Fig. 1A). Following the CITP protocol for null or negative results, the experiment was repeated at the highest non-toxic dose (3 µM) for both compounds at a second research site (Rutgers University); results from this assay demonstrated that 3 µM of meclizine at both the Rutgers and Oregon sites had no significant effect, while treatment with 3 µM of cinnarizine showed a significantly negative lifespan effect when the data from both sites were pooled (Fig. 1B).
Overall, our preliminary findings may seem surprising given the observed pro-longevity effects of the mTORC-1 inhibiting compound rapamycin in numerous model organisms (Mannick & Lamming, 2023). However, previous CITP studies on rapamycin also showed a null effect on lifespan in C. elegans underscoring the consistency of the current results (Banse et al., 2024). This fact, combined with results from other studies showing the ability of rapamycin to extend life in C. elegans, indicates that cinnarizine and meclizine's potential ability to extend lifespan may be dependent on the specific protocols used, and further experimentation is likely warranted. The absence of lifespan extension here may indicate that mTOR inhibition does not confer pro-longevity effects in this context. Alternatively, the lack of an observed effect could reflect limited compound uptake and/or exposure in the target tissues, metabolism or efflux, or inadequate activity against mTOR in C. elegans. Others in the field acknowledge the effect of assay conditions on outcomes of aging interventions, including those who previously reported a positive effect from cinnarizine on C. elegans lifespan (Ye et al., 2014). Given the aims of the CITP to identify compounds that robustly and reproducibly increase lifespan (with an effect size of 20% or more) following a standardized pipeline, and the fact that cinnarizine and meclizine showed null or negative lifespan effects using our protocol, further investigation under the CITP workflow was not pursued.
","references":[{"reference":"Allen SA, Tomilov A, Cortopassi GA. 2018. Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochem Pharmacol 155: 298-304.
","pubmedId":"30028993","doi":""},{"reference":"Banse SA, Lucanic M, Sedore CA, Coleman-Hulbert AL, Plummer WT, Chen E, et al., Phillips PC. 2019. Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions. Geroscience 41(6): 945-960.
","pubmedId":"31820364","doi":""},{"reference":"Banse SA, Sedore CA, Johnson E, Coleman-Hulbert AL, Onken B, Hall D, et al., Phillips PC. 2024. Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes. Geroscience 46(2): 2239-2251.
","pubmedId":"37923874","doi":""},{"reference":"Blackwell TK, Sewell AK, Wu Z, Han M. 2019. TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging. Genetics 213(2): 329-360.
","pubmedId":"31594908","doi":""},{"reference":"Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, et al., Miller RA. 2024. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. Geroscience 46(1): 795-816.
","pubmedId":"38041783","doi":""},{"reference":"Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, et al., Kennedy BK. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751): 1193-6.
","pubmedId":"16293764","doi":""},{"reference":"Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al., Kellogg DL Jr. 2018. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105: 53-69.
","pubmedId":"29408453","doi":""},{"reference":"Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al., Baur JA. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076): 1638-43.
","pubmedId":"22461615","doi":""},{"reference":"Lamming DW, Ye L, Sabatini DM, Baur JA. 2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 123(3): 980-9.
","pubmedId":"23454761","doi":""},{"reference":"Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, et al., Sabatini DM. 2014. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13(5): 911-7.
","pubmedId":"25059582","doi":""},{"reference":"Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al., Phillips PC. 2017. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nat Commun 8: 14256.
","pubmedId":"28220799","doi":""},{"reference":"Mannick JB, Lamming DW. 2023. Targeting the biology of aging with mTOR inhibitors. Nat Aging 3(6): 642-660.
","pubmedId":"37142830","doi":""},{"reference":"Martí-Massó JF, Poza JJ. 1998. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 13(3): 453-6.
","pubmedId":"9613736","doi":""},{"reference":"Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al., Garg M. 2023. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 8(1): 375.
","pubmedId":"37779156","doi":""},{"reference":"Patel PN, Ambizas EM. 2011. Meclizine: Safety and Efficacy in the Treatment and Prevention of Motion Sickness. Clinical Medicine Insights: Therapeutics 3: 10.4137/cmt.s6237.
","pubmedId":"","doi":"10.4137/CMT.S6237"},{"reference":"Pianese CP, Hidalgo LO, González RH, Madrid CE, Ponce JE, Ramírez AM, et al., F GV. 2002. New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational, double-blind study. Otol Neurotol 23(3): 357-63.
","pubmedId":"11981396","doi":""},{"reference":"R Core Team, 2021 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
","pubmedId":"","doi":""},{"reference":"Sandoval JA, Tomilov A, Datta S, Allen S, O'Donnell R, Sears T, et al., Cortopassi G. 2020. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells. Pharmaceuticals (Basel) 13(12): 10.3390/ph13120419.
","pubmedId":"33255358","doi":""},{"reference":"Terland O, Flatmark T. 1999. Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. Neuropharmacology 38(6): 879-82.
","pubmedId":"10465691","doi":""},{"reference":"Therneau T. M., 2020 coxme: Mixed Effects Cox Models. R package version 2.2.16.
","pubmedId":"","doi":""},{"reference":"Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. 2003. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967): 620.
","pubmedId":"14668850","doi":""},{"reference":"Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M. 2014. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13(2): 206-15.
","pubmedId":"24134630","doi":""}],"title":"Caenorhabditis Intervention Testing Program: the putative mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1788896885073"}]},{"id":"9d9183e4-96dd-4c47-a4a6-64dc98f84f49","decision":"publish","abstract":"The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel putative mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans, following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan.
","acknowledgements":"We thank the members of the Phillips lab and all members of CITP for useful discussions, and the anonymous reviewer who helped to improve the clarity of this work.
","authors":[{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","writing_reviewEditing","writing_originalDraft"],"email":"ejohns10@uoregon.edu","firstName":"Erik","lastName":"Johnson","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["investigation","formalAnalysis","writing_reviewEditing","visualization"],"email":"csedore@uoregon.edu","firstName":"Christine A.","lastName":"Sedore","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":""},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["writing_reviewEditing","resources","project","investigation"],"email":"acoleman@uoregon.edu","firstName":"Anna L.","lastName":"Coleman-Hulbert","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0001-8090-551X"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"bdonken@dls.rutgers.edu","firstName":"Brian D.","lastName":"Onken","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8818-4497"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"va242@scarletmail.rutgers.edu","firstName":"Vijaya Madhuri","lastName":"Achanta","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["investigation","writing_reviewEditing"],"email":"songy3@dls.rutgers.edu","firstName":"Yuhua","lastName":"Song","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of California Davis, Davis, California, USA"],"departments":["Department of Molecular Biosciences"],"credit":["conceptualization","writing_reviewEditing"],"email":"gcortopassi@ucdavis.edu","firstName":"Gino","lastName":"Cortopassi","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0003-2563-4133"},{"affiliations":["The Buck Institute for Research on Aging, Novato, California, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"glithgow@buckinstitute.org","firstName":"Gordon J.","lastName":"Lithgow","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8953-3043"},{"affiliations":["Rutgers University, Piscataway, New Jersey, USA"],"departments":["Department of Molecular Biology and Biochemistry"],"credit":["fundingAcquisition","methodology","writing_reviewEditing"],"email":"driscoll@dls.rutgers.edu","firstName":"Monica","lastName":"Driscoll","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":"","orcid":"0000-0002-8751-7429"},{"affiliations":["Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon, USA"],"departments":[""],"credit":["fundingAcquisition","methodology","supervision","writing_reviewEditing"],"email":"pphil@uoregon.edu","firstName":"Patrick C.","lastName":"Phillips","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":"","orcid":"0000-0001-7271-342X"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"This work was supported by funding from National Institutes of Health grants (U01 AG045844, U01 AG045864, U01 AG045829, and U24 AG056052).
","image":{"url":"https://portal.micropublication.org/uploads/e117fb3a1c705cabcc049d3a1c77f496.png"},"imageCaption":"(A) Survival curves for C. elegans strain N2 exposed to 0, 1, 3, 10, 30, and 100 µM cinnarizine (orange) or meclizine (green) starting on the first day of adulthood, measured in a single lab (University of Oregon). (B) The highest non-toxic dose for both compounds (3 µM) replicated across two labs (Oregon and Rutgers). Each dot represents the percent change in median lifespan of a single compound plate as compared to its specific control. The shape indicates the lab in which the replicate was tested (circles: Oregon; diamonds: Rutgers). The bars represent the mean and standard error of the mean. All statistical comparisons were made with a Cox proportional hazards (CPH) mixed-model using the coxme v.2.2-22 package in R. Asterisks represent p-values from the CPH model such that ****p<.0001, ***p<.001, **p<.01, and *p<.05.
","imageTitle":"Longevity of C. elegans under adult drug exposure
","methods":"For all experiments, C. elegans N2 worms were age-synchronized by timed egg-lays on standard 60 mm diameter Nematode Growth Media (NGM) plates and transferred at a density of 50 individuals per 35 mm treated plate in triplicate upon onset of adulthood (for control plates, there were six replicates of 50 animals each). Both cinnarizine and meclizine were dissolved in DMSO and diluted appropriately such that addition of 132.5 µl of solution to 35 mm diameter plates containing NGM with lawns of E. coli OP50-1 and 51 µm FUdR would generate the following final concentrations: 0 µM (control), 1 µM, 3 µM, 10 µM, 30 µM, and 100 µM. Final concentration of DMSO in all plates was 0.25%. Animals were maintained at 20 °C and 80% RH and moved to fresh plates on the first, second, and fifth day of adulthood, then once weekly afterward. Three times weekly, we observed animals for spontaneous movement or movement after gentle perturbation with a 0.2 mm diameter platinum wire. Death was scored as a lack of movement.
Statistical analyses were performed as previously described (Lucanic et al. 2017). In brief, survival was analyzed both with a generalized linear model using the lme4 package (version 1.1-35.5), and with a mixed-model Cox proportional hazards (CPH) using the coxme package (version 2.2-22; Therneau 2020) in the R statistical language (R Core Team 2021; version 4.4.1). Compound effects were analyzed as a planned comparison between individuals exposed to compound (cinnarizine or meclizine) or vehicle control (DMSO) (multcomp package, version 1.4-26). The raw data can be accessed on the CITP Data Portal (citpaging.org/portal v2.1), and on figshare.com along with CITP SOPs and the R scripts used for analysis (https://doi.org/10.6084/m9.figshare.c.7561101).
","reagents":"Experiments were performed using C. elegans N2_PD1073 (Banse et al. 2019; Yoshimura et al. 2019) from the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). For chemical interventions, cinnarizine (Alfa Aesar CAS: 298-57-7) and meclizine (Millipore Sigma CAS: 1104-22-9) were obtained in solid form and dissolved in DMSO (Sigma-Aldrich).
","patternDescription":"The Caenorhabditis Intervention Testing Program (CITP) is a multi-institute research consortium with the aim of identifying compounds that robustly extend lifespan with reproducible effects across genetically diverse Caenorhabditis species and strains (Lucanic et al., 2017). Prioritization of compounds for testing is based on recommendations made by our scientific Access Panel and the CITP Steering Committee; nominations for compounds to test can be made by any individual, nonprofit, academic group, or business during the CITP's annual call-for-submissions period (https://citpaging.org/submissions). Several factors, such as predicted or known interactions with established lifespan-regulating pathways, computational predictions for effects on lifespan or health-span (Coleman-Hulbert et al., 2019), or previous reports of life- or health-span extension in laboratory animals are considered when evaluating a compound for testing in the CITP pipeline.
Both cinnarizine and meclizine are piperazine-based antihistamines. Clinically, both are used in the treatment of nausea and vomiting associated with motion sickness and in the treatment of vestibular disorders such as vertigo (Pianese et al., 2002; Patel et al., 2011). Like the well-characterized lifespan-extending compound rapamycin, cinnarizine and meclizine were also both recently identified in a screen of more than 1600 human medicines targeting mTORC1-specific inhibitors (Allen et al., 2018). The mTOR kinase forms two complexes, mTORC1 and mTORC2, which are composed of discrete protein binding partners that are sensitive to distinct stimuli (Panwar et al., 2023). Numerous studies have found that genetic inhibition of mTORC1 or its downstream signaling pathways extends lifespan (Vellai et al., 2003; Kaeberlein et al., 2005; Lamming et al., 2013), whereas inhibition of mTORC2 has been associated with decreased lifespan in worms and mice (Lamming et al., 2012; Lamming et al., 2014). Both cinnarizine and meclizine were recently shown to bind to mTOR and significantly inhibit mTORC1, measured as phospho-S6 kinase inhibition, but not mTORC2, determined by the inability to inhibit phospho-Akt (Allen et al., 2018; Sandoval et al., 2020), raising the possibility that, like rapamycin, these novel mTORC1 inhibitors might also extend lifespan in model organisms, yet with fewer side effects than rapamycin. Of note, identification and classification of these compounds as mTOR inhibitors is inferred using human and mouse mTOR, and the specific inhibition of C. elegans mTOR/LET-363 is unknown, thus both compounds should be considered putative mTOR inhibitors in C. elegans. Regardless, mTOR is highly conserved in nematodes (Blackwell et al., 2019), and cinnarizine was shown to increase longevity in C. elegans (Ye et al., 2014). Additionally, the mouse Intervention Testing Program (ITP) found that meclizine extends lifespan in male mice (Harrison et al., 2023). Cinnarizine and meclizine have a smaller size (369 g/mol and 391 g/mol, respectively) compared to rapamycin (914 g/mol). They are approved for use in humans (cinnarizine since 1955 and meclizine since 1953) and display a relatively mild profile of known side-effects (e.g. drowsiness and dry mouth) as compared to the more serious adverse immunosuppressive effects in patients treated with rapamycin (Kraig et al., 2017). Although cinnarizine has also been associated with drug-induced parkinsonism (Martí-Massó & Poza, 1998; Terland & Flatmark, 1999), we were interested in testing the longevity effects of both compounds in C. elegans.
Here, we tested whether cinnarizine and meclizine could reproducibly and robustly increase lifespan in C. elegans using our recently revised workflow. C. elegans N2 worms were assayed on five different concentrations of cinnarizine and meclizine at a single research site (University of Oregon). Both cinnarizine and meclizine had no effect on lifespan at the two lowest doses tested (1 µM and 3 µM, along with 10 µM for meclizine alone; Fig. 1A). Conversely, both compounds exerted a toxic effect at the higher concentrations tested (10, 30, and 100 µM for cinnarizine and 30 and 100 µM for meclizine), significantly shortening lifespan (Fig. 1A). Following the CITP protocol for null or negative results, the experiment was repeated at the highest non-toxic dose (3 µM) for both compounds at a second research site (Rutgers University); results from this assay demonstrated that 3 µM of meclizine at both the Rutgers and Oregon sites had no significant effect, while treatment with 3 µM of cinnarizine showed a significantly negative lifespan effect when the data from both sites were pooled (Fig. 1B).
Overall, our preliminary findings may seem surprising given the observed pro-longevity effects of the mTORC-1 inhibiting compound rapamycin in numerous model organisms (Mannick & Lamming, 2023). However, previous CITP studies on rapamycin also showed a null effect on lifespan in C. elegans (Banse et al., 2024) underscoring the consistency of the current results. This fact, combined with results from other studies showing the ability of rapamycin to extend life in C. elegans, indicates that cinnarizine and meclizine's potential ability to extend lifespan may be dependent on the specific protocols used, and further experimentation is likely warranted. The absence of lifespan extension here may indicate that mTOR inhibition does not confer pro-longevity effects in this context. Alternatively, the lack of an observed effect could reflect limited compound uptake and/or exposure in the target tissues, metabolism or efflux, or inadequate activity against mTOR in C. elegans. Others in the field acknowledge the effect of assay conditions on outcomes of aging interventions, including those who previously reported a positive effect from cinnarizine on C. elegans lifespan (Ye et al., 2014). Given the aims of the CITP to identify compounds that robustly and reproducibly increase lifespan (with an effect size of 20% or more) following a standardized pipeline, and the fact that cinnarizine and meclizine showed null or negative lifespan effects using our protocol, further investigation under the CITP workflow was not pursued.
","references":[{"reference":"Allen SA, Tomilov A, Cortopassi GA. 2018. Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochem Pharmacol 155: 298-304.
","pubmedId":"30028993","doi":""},{"reference":"Banse SA, Lucanic M, Sedore CA, Coleman-Hulbert AL, Plummer WT, Chen E, et al., Phillips PC. 2019. Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions. Geroscience 41(6): 945-960.
","pubmedId":"31820364","doi":""},{"reference":"Banse SA, Sedore CA, Johnson E, Coleman-Hulbert AL, Onken B, Hall D, et al., Phillips PC. 2024. Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes. Geroscience 46(2): 2239-2251.
","pubmedId":"37923874","doi":""},{"reference":"Blackwell TK, Sewell AK, Wu Z, Han M. 2019. TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging. Genetics 213(2): 329-360.
","pubmedId":"31594908","doi":""},{"reference":"Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, et al., Miller RA. 2024. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. Geroscience 46(1): 795-816.
","pubmedId":"38041783","doi":""},{"reference":"Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, et al., Kennedy BK. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751): 1193-6.
","pubmedId":"16293764","doi":""},{"reference":"Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al., Kellogg DL Jr. 2018. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105: 53-69.
","pubmedId":"29408453","doi":""},{"reference":"Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al., Baur JA. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076): 1638-43.
","pubmedId":"22461615","doi":""},{"reference":"Lamming DW, Ye L, Sabatini DM, Baur JA. 2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 123(3): 980-9.
","pubmedId":"23454761","doi":""},{"reference":"Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, et al., Sabatini DM. 2014. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13(5): 911-7.
","pubmedId":"25059582","doi":""},{"reference":"Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al., Phillips PC. 2017. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nat Commun 8: 14256.
","pubmedId":"28220799","doi":""},{"reference":"Mannick JB, Lamming DW. 2023. Targeting the biology of aging with mTOR inhibitors. Nat Aging 3(6): 642-660.
","pubmedId":"37142830","doi":""},{"reference":"Martí-Massó JF, Poza JJ. 1998. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 13(3): 453-6.
","pubmedId":"9613736","doi":""},{"reference":"Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al., Garg M. 2023. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 8(1): 375.
","pubmedId":"37779156","doi":""},{"reference":"Patel PN, Ambizas EM. 2011. Meclizine: Safety and Efficacy in the Treatment and Prevention of Motion Sickness. Clinical Medicine Insights: Therapeutics 3: 10.4137/cmt.s6237.
","pubmedId":"","doi":"10.4137/CMT.S6237"},{"reference":"Pianese CP, Hidalgo LO, González RH, Madrid CE, Ponce JE, Ramírez AM, et al., F GV. 2002. New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational, double-blind study. Otol Neurotol 23(3): 357-63.
","pubmedId":"11981396","doi":""},{"reference":"R Core Team, 2021 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
","pubmedId":"","doi":""},{"reference":"Sandoval JA, Tomilov A, Datta S, Allen S, O'Donnell R, Sears T, et al., Cortopassi G. 2020. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells. Pharmaceuticals (Basel) 13(12): 10.3390/ph13120419.
","pubmedId":"33255358","doi":""},{"reference":"Terland O, Flatmark T. 1999. Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles. Neuropharmacology 38(6): 879-82.
","pubmedId":"10465691","doi":""},{"reference":"Therneau T. M., 2020 coxme: Mixed Effects Cox Models. R package version 2.2.16.
","pubmedId":"","doi":""},{"reference":"Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. 2003. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967): 620.
","pubmedId":"14668850","doi":""},{"reference":"Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M. 2014. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13(2): 206-15.
","pubmedId":"24134630","doi":""}],"title":"Caenorhabditis Intervention Testing Program: the putative mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]}]}},"species":{"species":[{"value":"acer saccharum","label":"Acer saccharum","imageSrc":"","imageAlt":"","mod":"TreeGenes","modLink":"https://treegenesdb.org","linkVariable":""},{"value":"achillea millefolium","label":"Achillea millefolium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"acinetobacter baylyi","label":"Acinetobacter baylyi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"actinobacteria bacterium","label":"Actinobacteria bacterium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adelges tsugae","label":"Adelges tsugae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adenocaulon chilense","label":"Adenocaulon chilense","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aedes japonicus","label":"Aedes japonicus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aegorhinus vitulus","label":"Aegorhinus vitulus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aerococcus","label":"Aerococcus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alaimidae","label":"Alaimidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"allobates femoralis","label":"Allobates femoralis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alnus glutinosa","label":"Alnus glutinosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alosa aestivalis","label":"Alosa aestivalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alosa pseudoharengus","label":"Alosa pseudoharengus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"alternaria alternata","label":"Alternaria alternata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"amynthas agrestis","label":"Amynthas Agrestis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ancylostoma caninum","label":"Ancylostoma caninum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ancylostoma ceylanicum","label":"Ancylostoma ceylanicum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anemone multifida","label":"Anemone multifida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anguilla rostrata","label":"Anguilla rostrata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anisakis simplex","label":"Anisakis simplex","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anomala albopilosa","label":"Anomala albopilosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anthomyiidae sp","label":"Anthomyiidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"anthomyiidae sp","label":"Anthomyiidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arabidopsis","label":"Arabidopsis","imageSrc":"arabidopsis.png","imageAlt":"Arabidopsis graphic by Zoe Zorn CC BY 4.0","mod":"TAIR","modLink":"https://arabidopsis.org","linkVariable":""},{"value":"architeuthis dux","label":"Architeuthis dux","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arion vulgaris","label":"Arion vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"armeria","label":"Armeria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"artemia","label":"Artemia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"arthrobacter sp.","label":"Arthrobacter sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ascaridia","label":"Ascaridia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ascaridia galli","label":"Ascaridia galli","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"asparagopsis taxiformis","label":"Asparagopsis taxiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"astatotilapia burtoni","label":"Astatotilapia burtoni","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"avena sativa","label":"Avena sativa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aves","label":"Aves","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus","label":"Bacillus (firmicutes)","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus cereus","label":"Bacillus cereus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus mycoides","label":"Bacillus mycoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus subtilis","label":"Bacillus subtilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus thuringiensis","label":"Bacillus thuringiensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus toyonensis","label":"Bacillus toyonensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacillus wiedmannii","label":"Bacillus wiedmannii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacteria","label":"Bacteria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bacteriophage","label":"Bacteriophage","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bactrocera","label":"Bactrocera sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"batrachospermum gelatinosum","label":"Batrachospermum gelatinosum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"betula lenta","label":"Betula lenta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"betula nigra","label":"Betula nigra","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombus dahlbohmii","label":"Bombus dahlbohmii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombus terrestris","label":"Bombus terrestris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bombyx mori","label":"Bombyx mori","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bos taurus","label":"Bos Taurus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brachygobius doriae","label":"Brachygobius doriae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brassica oleracea","label":"Brassica oleracea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brassica rapa","label":"Brassica rapa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"brugia malayi","label":"Brugia malayi","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"burkholderia thailandensis","label":"Burkholderia thailandensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"buttiauxella","label":"Buttiauxella","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caenorhabditis brenneri","label":"Caenorhabditis brenneri","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis briggsae","label":"Caenorhabditis briggsae","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"c. elegans","label":"Caenorhabditis elegans","imageSrc":"c-elegans.jpg","imageAlt":"C. elegans graphic by Zoe Zorn CC BY 4.0","mod":"WormBase","modLink":"https://wormbase.org","linkVariable":""},{"value":"caenorhabditis inopinata","label":"Caenorhabditis inopinata","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis japonica","label":"Caenorhabditis japonica","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis nigoni","label":"Caenorhabditis nigoni","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caenorhabditis remanei","label":"Caenorhabditis remanei","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"caenorhabditis tropicalis","label":"Caenorhabditis tropicalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calidifontibacillus","label":"Calidifontibacillus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calidifontibacillus erzuremensis","label":"Calidifontibacillus erzuremensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"calliphora sp","label":"Calliphora sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caltha sagittata","label":"Caltha sagittata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cambarus latimanus","label":"Cambarus latimanus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"candida albicans","label":"Candida albicans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"canis familiaris","label":"Canis familiaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cannabis sativa","label":"Cannabis sativa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caretta caretta","label":"Caretta caretta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cassiopea xamachana","label":"Cassiopea xamachana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"caulobacter vibrioides","label":"Caulobacter vibrioides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cephalopods","label":"Cephalopoda","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cerastium arvense","label":"Cerastium arvense","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ceriodaphnia","label":"Ceriodaphnia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ceroglossus suturalis","label":"Ceroglossus suturalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chaetoceros","label":"Chaetoceros","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chamaecrista fasciculata","label":"Chamaecrista fasciculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chilicola chalcidiformis","label":"Chilicola chalcidiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chitinimonas","label":"Chitinimonas","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chlamydomonas reinhardtii","label":"Chlamydomonas reinhardtii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chromobacterium","label":"Chromobacterium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chrysemys picta","label":"Chrysemys picta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"chrysoperla rufilabris","label":"Chrysoperla rufilabris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"citrus","label":"Citrus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"clavibacter sp.","label":"Clavibacter sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"colinus virginianus","label":"Colinus virginianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"crassostrea virginica","label":"Crassostrea virginica","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"crithidia fasciculata","label":"Crithidia fasciculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cutibacterium acnes","label":"Cutibacterium acnes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"cyanobacteria","label":"Cyanobacteria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"daphnia","label":"Daphnia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"daphnia pulex","label":"Daphnia pulex","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dermacoccus nishinomiyaensis","label":"Dermacoccus nishinomiyaensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"diabrotica virgifera","label":"Diabrotica virgifera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"diabrotica virgifera virgifera virus 1","label":"Diabrotica virgifera virgifera virus 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"d. discoideum","label":"Dictyostelium discoideum","imageSrc":"dicty.png","imageAlt":"D. discoideum","mod":"dictyBase","modLink":"http://dictybase.org","linkVariable":""},{"value":"diptera","label":"Diptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dotocryptus bellicosus","label":"Dotocryptus bellicosus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"drechmeria coniospora","label":"Drechmeria coniospora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"drosophila","label":"Drosophila","imageSrc":"drosophila.png","imageAlt":"Drosophila graphic by Zoe Zorn CC BY 4.0","mod":"FlyBase","modLink":"https://flybase.org/doi/","linkVariable":"doi"},{"value":"dryopteris campyloptera","label":"Dryopteris campyloptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dryopteris expansa","label":"Dryopteris expansa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dryopteris intermedia","label":"Dryopteris intermedia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"dugesia dorotocephala","label":"Dugesia dorotocephala","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"elasmobranchii","label":"Elasmobranchii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"embryophyta","label":"Embryophyta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enoploteuthis chunii","label":"Enoploteuthis chunii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enterobacter aerogenes","label":"Enterobacter aerogenes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"enterococcus raffinosus","label":"Enterococcus raffinosus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"epichloë coenophiala","label":"Epichloë coenophiala","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"equus caballus","label":"Equus caballus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erigeron sp","label":"Erigeron sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eristalis","label":"Eristalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eruca vesicaria","label":"Eruca vesicaria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erwinia carotovora","label":"Erwinia carotovora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"erythronium americanum","label":"Erythronium americanum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"escherichia coli","label":"Escherichia coli","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"eukaryota","label":"Eukaryotes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"felis catus","label":"Felis catus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"francisella novicida","label":"Francisella novicida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"francisella tularensis","label":"Francisella tularensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fraxinus americana","label":"Fraxinus americana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fucus distichus","label":"Fucus distichus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"fungi","label":"Fungi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gasteropelecus sp.","label":"Gasteropelecus sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"geranium sp","label":"Geranium sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"girardia","label":"Girardia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"glaucomys volans","label":"Glaucomys volans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"glycine max","label":"Glycine max","imageSrc":"","imageAlt":"","mod":"Soybase","modLink":"https://soybase.org","linkVariable":""},{"value":"glyptemys insculpta","label":"Glyptemys insculpta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gossypium hirsutum","label":"Gossypium hirsutum","imageSrc":"","imageAlt":"","mod":"CottonGen","modLink":"https://www.cottongen.org/","linkVariable":""},{"value":"gromphadorhina portentosa","label":"Gromphadorhina portentosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"gryllodes sigillatus","label":"Gryllodes sigillatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"haliotis rufescens","label":"Haliotis rufescens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hepacivirus hominis","label":"Hepatitis C Virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"herpes simplex virus type 1","label":"Herpes simplex virus type 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"human","label":"Human","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"human coronavirus oc43","label":"Human coronavirus OC43","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hydra vulgaris","label":"Hydra vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hydropsyche sp","label":"Hydropsyche sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hymenoptera","label":"Hymenoptera","imageSrc":"","imageAlt":"","mod":"Hymenoptera Genome Database","modLink":"https://hymenoptera.elsiklab.missouri.edu/","linkVariable":""},{"value":"hypochaeris radicata","label":"Hypochaeris radicata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"hypodynerus vespiformis","label":"Hypodynerus vespiformis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"iflaviridae","label":"Iflaviridae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"iflavuris","label":"Iflavirus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ipomoea hederacea","label":"Ipomoea hederacea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ischnomera","label":"Ischnomera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ischnomera ruficollis","label":"Ischnomera ruficollis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"julidochromis marlieri","label":"Julidochromis marlieri","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"juniperus virginiana","label":"Juniperus virginiana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"kluyveromyces marxianus","label":"Kluyveromyces marxianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"l. casei","label":"L. casei","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lacticaseibacillus casei","label":"Lacticaseibacillus casei","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lactobacillus","label":"Lactobacillus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"larentiinae sp","label":"Larentiinae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"laurus nobilis","label":"Laurus nobilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lepidoptera","label":"Lepidoptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"leucanthemum vulgare","label":"Leucanthemum vulgare","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ligilactobacillus","label":"Ligilactobacillus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ligilactobacillus salivarius","label":"Ligilactobacillus salivarius","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"limosilactobacillus","label":"Limosilactobacillus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"linepithema humile","label":"Linepithema humile","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"liometopum occidentale","label":"Liometopum occidentale","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lolium arundinaceum","label":"Lolium arundinaceum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lontra longicaudis","label":"Lontra longicaudis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lumbriculus variegatus","label":"Lumbriculus variegatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lumbricus terrestris","label":"Lumbricus terrestris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lupinus polyphyllus","label":"Lupinus polyphyllus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lycorma delicatula","label":"Lycorma delicatula","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"lynx rufus","label":"Lynx rufus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"magnaporthe oryzae","label":"Magnaporthe oryzae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mammalia","label":"Mammalia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"manihot esculenta","label":"Manihot esculenta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"medicago lupulina","label":"Medicago lupulina","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"meloidogyne","label":"Meloidogyne","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mimus polyglottos","label":"Mimus polyglottos","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"bryophyta","label":"Mosses","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mouse","label":"Mouse","imageSrc":"","imageAlt":"","mod":"MGI","modLink":"https://informatics.jax.org","linkVariable":""},{"value":"m. minutoides","label":"Mus minutoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"mycobacterium smegmatis","label":"Mycobacterium smegmatis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nakaseomyces glabratus","label":"Nakaseomyces glabratus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nauphoeta cinerea","label":"Nauphoeta cinerea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"neurospora","label":"Neurospora","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"n. benthamiana","label":"Nicotiana benthamiana","imageSrc":"","imageAlt":"","mod":"Solgenomics Network","modLink":"https://solgenomics.net/organism/Nicotiana_benthamiana/genome","linkVariable":""},{"value":"nicotiana tabacum","label":"Nicotiana tabacum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"noctuidae","label":"Noctuidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"noctuidae sp","label":"Noctuidae sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"nothobranchius furzeri","label":"Nothobranchius furzeri","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"onchocerca volvulus","label":"Onchocerca volvulus","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"orconectes virilis","label":"Orconectes virilis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ormia ochracea","label":"Ormia ochracea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"o. sativa","label":"Oryza sativa","imageSrc":"","imageAlt":"","mod":"Gramene","modLink":"https://www.gramene.org/","linkVariable":""},{"value":"other","label":"Other","imageSrc":"","imageAlt":"","mod":null,"modLink":null,"linkVariable":null},{"value":"oxalis enneaphylla","label":"Oxalis enneaphylla","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paenarthrobacter nicotinovorans","label":"Paenarthrobacter nicotinovorans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paenarthrobacter nicotinovorans","label":"Paenarthrobacter nicotinovorans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pantoea","label":"Pantoea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pantoea agglomerans","label":"Pantoea agglomerans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"papaver sp","label":"Papaver sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"paramecium bursaria","label":"Paramecium bursaria","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"partitiviridae","label":"Partitiviridae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pelodiscus sinensis","label":"Pelodiscus sinensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"perezia recurvata","label":"Perezia recurvata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"petromyzon marinus","label":"Petromyzon marinus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis","label":"Photinus pyralis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis associated partiti-like virus","label":"Photinus pyralis associated partiti-like virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"photinus pyralis iflavirus 1","label":"Photinus pyralis iflavirus 1","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"physcomitrium patens","label":"Physcomitrium patens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pinus strobus","label":"Pinus strobus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pinus taeda","label":"Pinus taeda","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"platycheirus","label":"Platycheirus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"plectus sambesii","label":"Plectus sambesii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pogonomyrmex occidentalis","label":"Pogonomyrmex occidentalis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"poncirus trifoliata","label":"Poncirus trifoliata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"populus deltoides","label":"Populus deltoides","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"potato virus y","label":"Potato virus Y","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"primula magellanica","label":"Primula magellanica","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pristionchus pacificus","label":"Pristionchus pacificus","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"prunus persica","label":"Prunus persica","imageSrc":"","imageAlt":"","mod":"Genome Database for Rosaceae","modLink":"https://www.rosaceae.org/","linkVariable":""},{"value":"psalmopoeus iriminia","label":"Psalmopoeus iriminia","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudanabaena sp.","label":"Pseudanabaena sp.","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas","label":"Pseudomonas","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas aeruginosa","label":"Pseudomonas aeruginosa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas glycinae","label":"Pseudomonas glycinae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas putida","label":"Pseudomonas putida","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pseudomonas syringae","label":"Pseudomonas syringae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"pterophyllum scalare","label":"Pterophyllum scalare","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"python regius","label":"Python regius","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"quercus macrocarpa","label":"Quercus macrocarpa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ralstonia solanacearum","label":"Ralstonia solanacearum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ranitomeya imitator","label":"Ranitomeya imitator","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ranunculus peduncularis","label":"Ranunculus peduncularis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"rat","label":"Rat","imageSrc":"","imageAlt":"","mod":"RGD","modLink":"https://rgd.mcw.edu","linkVariable":""},{"value":"rheinheimera","label":"Rheinheimera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ribes rubrum","label":"Ribes rubrum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"sars-cov-2","label":"SARS-CoV-2","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. cerevisiae","label":"Saccharomyces cerevisiae","imageSrc":"yeast.png","imageAlt":"Yeast graphic by Zoe Zorn CC BY 4.0","mod":"SGD","modLink":"https://yeastgenome.org","linkVariable":""},{"value":"saccharomyces paradoxus","label":"Saccharomyces paradoxus ","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. uvarum","label":"Saccharomyces uvarum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"schistosoma","label":"Schistosoma","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"schizosaccharomyces japonicus","label":"Schizosaccharomyces japonicus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. pombe","label":"Schizosaccharomyces pombe","imageSrc":"pombe.png","imageAlt":"Pombe graphic by Zoe Zorn © Caltech","mod":"PomBase","modLink":"https://www.pombase.org/reference/PMID:","linkVariable":"pmId"},{"value":"schmidtea mediterranea","label":"Schmidtea mediterranea","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"senecio sp","label":"Senecio sp","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"simocephalus","label":"Simocephalus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"siraitia grosvenorii","label":"Siraitia grosvenorii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"solanum lycopersicum","label":"Solanum lycopersicum","imageSrc":"","imageAlt":"","mod":"Solgenomics Network","modLink":"https://solgenomics.net/organism/1/view/","linkVariable":""},{"value":"sorghum","label":"Sorghum","imageSrc":"","imageAlt":"","mod":"SorghumBase","modLink":"https://www.sorghumbase.org","linkVariable":""},{"value":"spiroplasma eriocheiris","label":"Spiroplasma eriocheiris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"staphylococcus aureus","label":"Staphylococcus aureus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"staphylococcus epidermidis","label":"Staphylococcus epidermidis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"steinernema carpocapsae","label":"Steinernema carpocapsae","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"https://wormbase.org","linkVariable":""},{"value":"steinernema hermaphroditum","label":"Steinernema hermaphroditum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"stenotrophomonas geniculata","label":"Stenotrophomonas geniculata","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"stewartia floidana","label":"Stewartia floridana","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"streptococcus gordonii ","label":"Streptococcus gordonii ","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"streptococcus mutans","label":"Streptococcus mutans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":" streptococcus pneumoniae","label":"Streptococcus pneumoniae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"s. purpuratus","label":"Strongylocentrotus purpuratus","imageSrc":"","imageAlt":"","mod":"Echinobase","modLink":"https://www.echinobase.org","linkVariable":""},{"value":"strongyloides ratti","label":"Strongyloides ratti","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"sulfolobus","label":"Sulfolobus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"symphoricarpos albus","label":"Symphoricarpos albus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"syncirsodes","label":"Syncirsodes","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"synechococcus elongatus","label":"Synechococcus elongatus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"syrphidae","label":"Syrphidae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tarantobelus jeffdanielsi","label":"Tarantobelus jeffdanielsi","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"taraxacum officinale","label":"Taraxacum officinale","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tatochila theodice","label":"Tatochila theodice","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tetrahymena","label":"Tetrahymena","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tetramorium immigrans","label":"Tetramorium immigrans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tomato brown rugose fruit virus","label":"ToBRFV","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trachemys scripta","label":"Trachemys scripta","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tribolium castaneum","label":"Tribolium castaneum","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trichoptera","label":"Trichoptera","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trichuris muris","label":"Trichuris muris","imageSrc":"","imageAlt":"","mod":"WormBase","modLink":"www.wormbase.org","linkVariable":""},{"value":"trifolium repens","label":"Trifolium repens","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"trypoxylus dichotomus","label":"Trypoxylus dichotomus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"tsuga canadensis","label":"Tsuga canadensis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"ulva expansa","label":"Ulva expansa","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"universal","label":"Universal","imageSrc":"","imageAlt":"","mod":null,"modLink":null,"linkVariable":null},{"value":"vargula hilgendorfii","label":"Vargula hilgendorfii","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"vespula vulgaris","label":"Vespula vulgaris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"virus","label":"Virus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"watasenia scintillans","label":"Watasenia scintillans","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"wolbachia pipientis","label":"Wolbachia pipientis","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"xenopus","label":"Xenopus","imageSrc":"xenopus.png","imageAlt":"Xenopus graphic by Zoe Zorn CC BY 4.0","mod":"XenBase","modLink":"https://xenbase.org","linkVariable":""},{"value":"xenorhabdus griffiniae","label":"Xenorhabdus griffiniae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"yramea cytheris","label":"Yramea cytheris","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"zaprionus indianus","label":"Zaprionus indianus","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"zea mays","label":"Zea mays","imageSrc":"","imageAlt":"","mod":"MaizeGDB","modLink":"https://www.maizegdb.org","linkVariable":""},{"value":"zebrafish","label":"Zebrafish","imageSrc":"zebrafish.png","imageAlt":"Zebrafish graphic by Zoe Zorn CC BY 4.0","mod":"ZFIN","modLink":"https://zfin.org","linkVariable":""}]}},"pageContext":{"id":"df841411-1d52-4511-a13e-cf974a511640","citedBy":[],"parsedCsv":{"csvHeader":[],"csvData":[]}}}, "staticQueryHashes": ["2114697108"]}