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<p>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 (<i>Nothobranchius furzeri</i>), we identify <i>vestigial-like 3</i> (<i>vgll3</i>), previously linked by GWAS to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects. Selective disruption of <i>vgll3</i> 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 <i>rag2</i> models, and exhibit a shortened lifespan. Thus, we identify <i>vgll3</i> as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Eitan Moses,
  • Marva Bergman,
  • Tehila Atlan,
  • Elizabeth M. L. Duxbury,
  • Roman Franěk,
  • Omer Ben Dor,
  • Henrik von Chrzanowski,
  • Enas R. Abu-Zhayia,
  • Nabieh Ayoub,
  • Shay Kinreich,
  • Ido Ben-Ami,
  • Alexei A. Maklakov,
  • Itamar Harel

摘要

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.