An Antagonistically Pleiotropic Gene Regulates Vertebrate Growth, Maturity and Aging

Abstract The antagonistic pleiotropy theory of aging predicts functional trade-offs between early-life and late-life fitness. However, empirical evidence for these trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 ( vgll3 ), a transcription cofactor previously linked with age at maturity in humans and Atlantic salmon through GWAS studies, as an antagonistically pleiotropic gene in turquoise killifish ( Nothobranchius furzeri ). By disrupting two conserved vgll3 isoforms, we show that reduction of vgll3 , in an isoform- or dose-dependent manner, accelerated male growth and reproductive development. This indicates that vgll3 regulates sexual maturity. However, early-life benefits come at a late-life cost, as older mutant males with a disrupted long isoform develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit increased age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.