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Peer-reviewedCC BY-NC-NDNature Communications

An antagonistically pleiotropic gene regulates vertebrate growth, maturity, and lifespan

  • Eitan Moses1
  • Marva Bergman1,2
  • Tehila Atlan1
  • Elizabeth Duxbury3,4
  • Roman Franěk1,5
  • Omer Ben Dor1
  • Henrik von Chrzanowski1
  • Enas R. Abu‐Zhayia6
  • Nabieh Ayoub6
  • Shay Kinreich1
  • Ido Ben‐Ami2
  • Alexei A. Maklakov4
1 more authors
  • Itamar Harel7
7 affiliations
  1. 1Department of Genetics, The Silberman Institute, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel
  2. 2Department of Obstetrics & Gynecology, Shaare Zedek Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
  3. 3Department of Zoology, University of Cambridge, Cambridge, UK
  4. 4School of Biological Sciences, University of East Anglia, Norwich, UK
  5. 5University of South Bohemia in Ceske Budejovice, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany, Czech Republic
  6. 6Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel
  7. 7Department of Genetics, The Silberman Institute, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel. [email protected]
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Abstract

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly from causal genetic experiments. Here, combining genetic perturbation with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri), we identify vestigial-like 3 (vgll3), previously linked by GWAS to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects. Selective disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner. Transcriptomic and cellular analyses indicated increased cell division, corroborated in vivo by elevated germline and intestinal stem-cell proliferation. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit a shortened lifespan. Thus, we identify vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.

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Cite

BibTeXRIS
BibTeX
@article{moses2026antagonistically,
  title = {{An antagonistically pleiotropic gene regulates vertebrate growth, maturity, and lifespan}},
  author = {Eitan Moses and Marva Bergman and Tehila Atlan and Elizabeth Duxbury and Roman Franěk and Omer Ben Dor and Henrik von Chrzanowski and Enas R. Abu‐Zhayia and Nabieh Ayoub and Shay Kinreich and Ido Ben‐Ami and Alexei A. Maklakov and Itamar Harel},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-72381-0},
  url = {https://doi.org/10.1038/s41467-026-72381-0},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - An antagonistically pleiotropic gene regulates vertebrate growth, maturity, and lifespan
AU  - Eitan Moses
AU  - Marva Bergman
AU  - Tehila Atlan
AU  - Elizabeth Duxbury
AU  - Roman Franěk
AU  - Omer Ben Dor
AU  - Henrik von Chrzanowski
AU  - Enas R. Abu‐Zhayia
AU  - Nabieh Ayoub
AU  - Shay Kinreich
AU  - Ido Ben‐Ami
AU  - Alexei A. Maklakov
AU  - Itamar Harel
PY  - 2026
DA  - 2026/06/02
JO  - Nature Communications
DO  - 10.1038/s41467-026-72381-0
UR  - https://doi.org/10.1038/s41467-026-72381-0
AB  - The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly from causal genetic experiments. Here, combining genetic perturbation with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri), we identify vestigial-like 3 (vgll3), previously linked by GWAS to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects. Selective disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner. Transcriptomic and cellular analyses indicated increased cell division, corroborated in vivo by elevated germline and intestinal stem-cell proliferation. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit a shortened lifespan. Thus, we identify vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.
SN  - 2041-1723
ER  -