A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate
Open accessAbstract
Video abstract Aging is a complex process that affects multiple organs. Modeling aging and age-related diseases in the lab is challenging because classical vertebrate models have relatively long lifespans. Here, we develop the first platform for rapid exploration of age-dependent traits and diseases in vertebrates, using the naturally short-lived African turquoise killifish. We provide an integrative genomic and genome-editing toolkit in this organism using our de-novo-assembled genome and the CRISPR/Cas9 technology. We mutate many genes encompassing the hallmarks of aging, and for a subset, we produce stable lines within 2-3 months. As a proof of principle, we show that fish deficient for the protein subunit of telomerase exhibit the fastest onset of telomere-related pathologies among vertebrates. We further demonstrate the feasibility of creating specific genetic variants. This genome-to-phenotype platform represents a unique resource for studying vertebrate aging and disease in a high-throughput manner and for investigating candidates arising from human genome-wide studies.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Similar observations of decreased fertilization and developmental potential with short telomeres have been made in zebrafish and killifish.
“Similar observations have been made in zebrafish and killifish186,187.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [187]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease
Rhinn, H., Fujita, R., Qiang, L., Cheng, R., Lee, J. H., & Abeliovich, A. (2013) · Nature · doi:10.1038/nature12415 · Cited by 144 · see citing works
RetractedMEGA6: Molecular Evolutionary Genetics Analysis version 6.0.
Tamura, K., Stecher, G., Peterson, D., Filipski, A., & Kumar, S. (2013) · Molecular biology and evolution · doi:10.1093/molbev/mst197 · Cited by 41,174 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116 · see citing works
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
Trapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 11,930 · see citing works
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711 · see citing works
Development and Applications of CRISPR-Cas9 for Genome Engineering
Hsu, P. D., Lander, E. S., & Zhang, F. (2014) · Cell · doi:10.1016/j.cell.2014.05.010 · Cited by 5,762 · see citing works
Genome Regulation by Long Noncoding RNAs
Rinn, J. L., & Chang, H. Y. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-051410-092902 · Cited by 4,011 · see citing works
Efficient genome editing in zebrafish using a CRISPR-Cas system
Hwang, W. Y., Fu, Y., Reyon, D., Maeder, M. L., Tsai, S. Q., Sander, J. D., Peterson, R. T., Yeh, J.-R. J., & Joung, J. K. (2013) · Nature Biotechnology · doi:10.1038/nbt.2501 · Cited by 2,937 · see citing works
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739 · see citing works
Holt, C., & Yandell, M. D. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-491 · Cited by 2,042 · see citing works
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831 · see citing works
Identifying ChIP-seq enrichment using MACS
Feng, J., Liu, T., Qin, B., Zhang, Y., & Liu, X. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.101 · Cited by 1,805 · see citing works
The genomic basis of adaptive evolution in threespine sticklebacks
Jones, F. C., Grabherr, M. G., Chan, Y. F., Russell, P. H., Mauceli, E., Johnson, J., Swofford, R., Pirun, M., Zody, M. C., White, S. J., et al. (2012) · Nature · doi:10.1038/nature10944 · Cited by 1,747 · see citing works
Oases:robustde novoRNA-seq assembly across the dynamic range of expression levels
Schulz, M. H., Zerbino, D. R., Vingron, M., & Birney, E. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts094 · Cited by 1,423 · see citing works
Essential role of mouse telomerase in highly proliferative organs
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998) · Nature · doi:10.1038/33345 · Cited by 1,270 · cited 5× · see citing works
“As the TERTD8/D8 turquoise killifish model exhibits phenotypes in the first generation (as opposed to several generations in laboratory mice [Lee et al., 1998]) and within 2 months (as opposed to 6–8 months in zebrafish [Anchelin et al., 2013; Henriques et al., 2013]), it is currently the fastest…”
InfluentialEfficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system
Jao, L.-E., Wente, S. R., & Chen, W. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1308335110 · Cited by 1,261 · see citing works
CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing
Montague, T. G., Cruz, J. M. B. S., Gagnon, J. A., Church, G. M., & Valen, E. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku410 · Cited by 1,203 · see citing works
Genetic engineering of human pluripotent cells using TALE nucleases
Hockemeyer, D. F., Wang, H., Kiani, S., Lai, C. S., Gao, Q., Cassady, J. P., Cost, G. J., Zhang, L., Santiago, Y., Miller, J. C., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1927 · Cited by 1,129 · see citing works
In vivo genome editing using a high-efficiency TALEN system
Bedell, V. M., Wang, Y., Campbell, J. M., Poshusta, T. L., Starker, C. G., Krug, R. G., Tan, W. S., Penheiter, S. G., Ma, A. C. H., Leung, A. Y. H., et al. (2012) · Nature · doi:10.1038/nature11537 · Cited by 914 · see citing works
Gagnon, J. A., Valen, E., Thyme, S. B., Huang, P., Ahkmetova, L., Pauli, A., Montague, T. G., Zimmerman, S., Richter, C., & Schier, A. F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098186 · Cited by 861 · see citing works
Telomeres and telomerase in cancer
Artandi, S. E., & DePinho, R. A. (2010) · Carcinogenesis · doi:10.1093/carcin/bgp268 · Cited by 823 · see citing works
Self-citationH3K4me3 breadth is linked to cell identity and transcriptional consistency
Benayoun, B. A., Pollina, E. A., Ucar, D., Mahmoudi, S., Karra, K., Wong, E. D., Devarajan, K., Daugherty, A. C., Kundaje, A. B., Mancini, E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.027 · Cited by 536 · see citing works
Self-citationTăcutu, R., Craig, T., Budovsky, A., Wuttke, D., Lehmann, G., Toren, D., Cósta, J., Fraifeld, V. E., & de Magalhães, J. P. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1155 · Cited by 516 · see citing works
Cancer in dyskeratosis congenita
Alter, B. P., Giri, N., Savage, S. A., & Rosenberg, P. S. (2009) · Blood · doi:10.1182/blood-2008-12-192880 · Cited by 478 · see citing works
Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodsky, R. A., Hawkins, A., Griffin, C. A., Eshleman, J. R., Cohen, A. R., Chakravarti, A., Hamosh, A., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508124102 · Cited by 452 · see citing works
Syndromes of Telomere Shortening
Armanios, M. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082908-150046 · Cited by 317 · see citing works
Short Telomeres, even in the Presence of Telomerase, Limit Tissue Renewal Capacity
Hao, L.-Y., Armanios, M., Strong, M. A., Karim, B., Feldser, D. M., Huso, D., & Greider, C. W. (2005) · Cell · doi:10.1016/j.cell.2005.11.020 · Cited by 302 · see citing works
TPP1 OB-Fold Domain Controls Telomere Maintenance by Recruiting Telomerase to Chromosome Ends
Zhong, F. L., Batista, L. F. Z., Freund, A., Pech, M. F., Venteicher, A. S., & Artandi, S. E. (2012) · Cell · doi:10.1016/j.cell.2012.07.012 · Cited by 295 · see citing works
Self-citationSavage, S. A., & Alter, B. P. (2009) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2009.01.003 · Cited by 262 · see citing works
Annual fishes of the genus Nothobranchius as a model system for aging research
Genade, T., Benedetti, M., Tozzini, E. T., Roncaglia, P., Valenzano, D. R., Cattaneo, A., & Cellerino, A. (2005) · Aging Cell · doi:10.1111/j.1474-9726.2005.00165.x · Cited by 238 · see citing works
Self-citationPodlevsky, J. D., Bley, C. J., Omana, R. V., Qi, X., & Chen, J. J. ‐. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm700 · Cited by 235 · see citing works
Comparative genetics of longevity and cancer: insights from long-lived rodents
Gorbunova, V. A., Seluanov, A., Zhang, Z., Gladyshev, V. N., & Vijg, J. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3728 · Cited by 234 · see citing works
Beyond the zebrafish: diverse fish species for modeling human disease
Schartl, M. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.012245 · Cited by 214 · see citing works
Telomere length behaves as biomarker of somatic redundancy rather than biological age
Boonekamp, J. J., Simons, M. J. P., Hemerik, L., & Verhulst, S. (2013) · Aging Cell · doi:10.1111/acel.12050 · Cited by 209 · see citing works
Hussain, S. P. (1995) · Lung Cancer · doi:10.1016/0169-5002(95)90160-4 · Cited by 206 · see citing works
Parry, E. M., Alder, J. K., Qi, X., Chen, J. J.-L., & Armanios, M. (2011) · Blood · doi:10.1182/blood-2010-11-322149 · Cited by 194 · see citing works
Valenzano, D. R., Tozzini, E. T., Cattaneo, A., et al. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00212.x · Cited by 192 · see citing works
Self-citationGomes, N. M. V., Shay, J. W., & Wright, W. E. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.031 · Cited by 186 · see citing works
Tozzini, E. T., Valenzano, D. R., Benedetti, M., Roncaglia, P., Cattaneo, A., Domenici, L., & Cellerino, A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003866 · Cited by 184 · see citing works
Self-citationThere's more to life than rats and flies
Bolker, J. A. (2012) · Nature · doi:10.1038/491031a · Cited by 167 · see citing works
Hartmann, N., Reichwald, K., Lechel, A., Graf, M., Kirschner, J., Dorn, A., Tozzini, E. T., Wellner, J., Platzer, M., Rudolph, K. L., et al. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.01.003 · Cited by 146 · see citing works
Cicco, E. D., Tozzini, E. T., Rossi, G., & Cellerino, A. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.10.011 · Cited by 139 · see citing works
Telomerase Is Required for Zebrafish Lifespan
Henriques, C. M., Carneiro, M. C., Tenente, I. M., Jacinto, A., & Ferreira, M. G. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003214 · Cited by 133 · see citing works
Tozzini, E. T., Lefrançois, C., Domenici, P., et al. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00455.x · Cited by 123 · see citing works
Premature aging in telomerase-deficient zebrafish
Anchelin, M., Alcaraz-Pérez, F., Martínez, C. M., Bernabé-García, M., Mulero, V., & Cayuela, M. L. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011635 · Cited by 114 · see citing works
Blood Collection for Biochemical Analysis in Adult Zebrafish
Pedroso, G. L., Hammes, T. O., Escobar, T. D. C., et al. (2012) · Journal of Visualized Experiments · doi:10.3791/3865 · Cited by 110 · see citing works
Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis
Harel, I., Maezawa, Y., Avraham, R., Rinon, A., Ma, H., Cross, J. W., Leviatan, N., Hegesh, J. T., Roy, A., Jacob‐Hirsch, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208690109 · Cited by 110 · see citing works
Self-citationValenzano, D. R., Sharp, S. C., & Brunet, A. (2011) · G3 Genes Genomes Genetics · doi:10.1534/g3.111.001271 · Cited by 94 · see citing works
Self-citationReichwald, K., Lauber, C., Nanda, I., Kirschner, J., Hartmann, N., Schories, S., Gausmann, U., Taudien, S., Schilhabel, M. B., Szafranski, K., et al. (2009) · Genome biology · doi:10.1186/gb-2009-10-2-r16 · Cited by 94 · see citing works
Kirschner, J., Weber, D., Neuschl, C., Franke, A., Böttger, M., Zielke, L. G., Powalsky, E., Groth, M., Shagin, D. A., Petzold, A., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00780.x · Cited by 83 · see citing works
Bessler, M., Wilson, D. B., & Mason, P. J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.05.019 · Cited by 81 · see citing works
Fernald, R. D. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062111-150520 · Cited by 78 · see citing works
Valenzano, D. R., Kirschner, J., Kamber, R. A., Zhang, E., Weber, D., Cellerino, A., Englert, C., Platzer, M., Reichwald, K., & Brunet, A. (2009) · Genetics · doi:10.1534/genetics.109.108670 · Cited by 73 · see citing works
Self-citationUncoupling of Longevity and Telomere Length in C. elegans
Raı́ces, M., Maruyama, H., Dillin, A. G., & Karlseder, J. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010030 · Cited by 69 · see citing works
Hartmann, N., & Englert, C. (2012) · Developmental Dynamics · doi:10.1002/dvdy.23789 · Cited by 68 · see citing works
Petzold, A., Reichwald, K., Groth, M., Taudien, S., Hartmann, N., Priebe, S., Shagin, D. A., Englert, C., & Platzer, M. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-185 · Cited by 60 · see citing works
Genetic Mouse Models of Neurodegenerative Diseases
Trancikova, A. K., Ramonet, D., & Moore, D. J. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-384878-9.00012-1 · Cited by 46 · see citing works
Cats, "Rats," and Bats: The Comparative Biology of Aging in the 21st Century
Austad, S. N. (2010) · Integrative and Comparative Biology · doi:10.1093/icb/icq131 · Cited by 39 · see citing works
Blood Collection for Biochemical Analysis in Adult Zebrafish
Pedroso, G. L., Hammes, T. O., Escobar, T. D. C., et al. (2012) · Journal of Visualized Experiments · doi:10.3791/3865-v · Cited by 37 · see citing works
Understanding telomere diseases through analysis of patient-derived iPS cells
Batista, L. F. Z., & Artandi, S. E. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.07.006 · Cited by 33 · see citing works
Self-citationGenetics of proliferative aging
Zucchero, T. M., & Ahmed, S. C. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.06.057 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Blackburn, E. H., Epel, E. S., & Lin, J. (2015) · Science · doi:10.1126/science.aab3389 · Cited by 1,596 · see citing works
Epigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · see citing works
Pal, S., & Tyler, J. K. (2016) · Science Advances · doi:10.1126/sciadv.1600584 · Cited by 860 · see citing works
Telomere dysfunction in ageing and age-related diseases
Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00842-x · Cited by 754 · see citing works
Telomeres: history, health, and hallmarks of aging
Chakravarti, D., LaBella, K. A., & DePinho, R. A. (2021) · Cell · doi:10.1016/j.cell.2020.12.028 · Cited by 637 · see citing works
Regulation of life span by the gut microbiota in the short-lived African turquoise killifish
Smith, P., Willemsen, D., Popkes, M., Metge, F., Gandiwa, E., Reichard, M., & Valenzano, D. R. (2017) · eLife · doi:10.7554/elife.27014 · Cited by 423 · see citing works
Self-citationThe Genetics of Aging: A Vertebrate Perspective
Singh, P. P., Demmitt, B. A., Nath, R. D., & Brunet, A. (2019) · Cell · doi:10.1016/j.cell.2019.02.038 · Cited by 259 · see citing works
Self-citationKelmer Sacramento, E., Kirkpatrick, J. M., Mazzetto, M., Baumgart, M., Bartolome, A., Di Sanzo, S., Caterino, C., Sanguanini, M., Papaevgeniou, N., Lefaki, M., et al. (2020) · Molecular Systems Biology · doi:10.15252/msb.20209596 · Cited by 236 · see citing works
Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates
Wang, W., Hu, C.-K., Zeng, A., Alegre, D., Hu, D., Gotting, K., Ortega Granillo, A., Wang, Y., Robb, S., Schnittker, R., et al. (2020) · Science · doi:10.1126/science.aaz3090 · Cited by 210 · see citing works
Self-citationThe Geroscience Hypothesis: Is It Possible to Change the Rate of Aging?
Austad, S. N. (2016) · Advances in Geroscience · doi:10.1007/978-3-319-23246-1_1 · Cited by 43 · see citing works
- Authors
- Harel, I., Benayoun, B. A., Machado, B., Singh, P. P., Hu, C.-K., Pech, M. F., Valenzano, D. R., Zhang, E., Sharp, S. C., Artandi, S. E., & Brunet, A.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- Brunet, Anne
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 1013-1026
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4344913
- OpenAlex
- W1966737051
- Cited by
- 232
- References
- 63
- Citations by year
- 2026: 20 · 2025: 14 · 2024: 17 · 2023: 27 · 2022: 15 · 2021: 20 · 2020: 18 · 2019: 17 · 2018: 16 · 2017: 21 · 2016: 23 · 2015: 24
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (DP1AG044848)
- National Cancer Institute (T32CA009302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- aging, age-related diseases, African turquoise killifish, genome assembly, CRISPR/Cas9 genome editing, telomerase, telomere shortening, hallmarks of aging
- MeSH terms
- Aging, Animals, Base Sequence, DNA-Directed DNA Polymerase, Female, Genetic Techniques, Humans, Killifishes, Male, Molecular Sequence Data, Vertebrates, Telomerase, Models, Animal, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
