Selective disruption of vgll3 isoforms in turquoise killifish accelerates male growth and maturation but incurs late-life costs including melanoma-like tumors and shortened lifespan, identifying vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.
Key Findings
Results
Disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner in turquoise killifish.
The study used genetic perturbation combined with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri).
The effect on growth and maturation was dose-dependent, suggesting a quantitative relationship between vgll3 disruption and the phenotypic outcome.
The accelerated maturation phenotype was observed specifically in males.
vgll3 had previously been linked by GWAS to age at maturity in humans and male Atlantic salmon, providing cross-species relevance.
Results
vgll3 disruption increased cell division, as evidenced by elevated germline and intestinal stem-cell proliferation in vivo.
Transcriptomic and cellular analyses indicated increased cell division in vgll3 mutants.
Elevated proliferation was corroborated in vivo by measurements of germline stem-cell proliferation.
Intestinal stem-cell proliferation was also elevated in mutant animals.
These cellular findings provide a mechanistic link between vgll3 loss and accelerated growth and maturation.
Results
Early-life maturation acceleration in vgll3 mutants incurs a late-life cost linked to altered DNA damage response.
The late-life cost was mechanistically associated with alterations in the DNA damage response pathway.
This finding supports the antagonistic pleiotropy framework, where the same genetic change that benefits early life is harmful late in life.
The DNA damage response alteration was identified through transcriptomic and cellular analyses.
This represents a causal genetic demonstration of a trade-off between early-life fitness and late-life survival in a vertebrate.
Results
Older vgll3 mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models.
Melanoma-like tumors emerged in older mutant males, representing a specific late-life pathological outcome.
Tumor identity was validated by transplantation into immunodeficient rag2 model animals, confirming malignant and transplantable nature of the tumors.
The tumor development is consistent with the elevated cell proliferation observed earlier in life in these mutants.
The altered DNA damage response was implicated as a contributing mechanism to tumor development.
Results
vgll3 mutant males exhibit a shortened lifespan compared to controls.
Shortened lifespan was observed in mutant males as a late-life fitness cost.
This lifespan reduction is consistent with the antagonistic pleiotropy theory of aging, which predicts genetic trade-offs between early-life and late-life fitness.
The shortened lifespan was associated with both the development of melanoma-like tumors and altered DNA damage response.
The study used longitudinal phenotyping to track lifespan outcomes in the turquoise killifish, a species known for its short lifespan and utility as an aging model.
Results
vgll3 was identified as an antagonistically pleiotropic gene in vertebrates, providing causal genetic evidence for a growth-longevity trade-off.
The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness, but empirical evidence from causal genetic experiments in vertebrates had previously been scarce.
This study provides causal evidence through direct genetic perturbation rather than correlational or GWAS approaches alone.
vgll3 had been linked to age at maturity in humans and male Atlantic salmon by prior GWAS studies, suggesting conserved function across vertebrates.
The study identifies vgll3 as balancing early-life fitness against late-life mortality.
What This Means
This research suggests that a single gene called vgll3 controls a fundamental trade-off in animal biology: growing and maturing faster early in life comes at the cost of living shorter and developing cancer later in life. The scientists studied this in the turquoise killifish, a small fish used in aging research because it has a naturally short lifespan. When they disabled specific versions of the vgll3 gene, male fish grew faster and reached sexual maturity earlier — but as they aged, they developed melanoma-like skin tumors and died sooner than normal fish. The more copies of the gene were disrupted, the stronger these effects were, suggesting the gene acts like a dial controlling the pace of life.
The underlying biology involves cell division: fish with disrupted vgll3 had more actively dividing stem cells in their gut and reproductive organs, which likely drives faster growth and maturation. However, this increased cellular activity also appeared to compromise the cells' ability to repair DNA damage, which may explain why the fish later developed tumors. The tumors were confirmed to be genuinely cancerous by transplanting them into immune-deficient fish, where they continued to grow.
This matters because it provides one of the first direct genetic proofs — in a vertebrate animal — of a long-standing evolutionary theory called antagonistic pleiotropy, which proposes that aging exists partly because genes that help us reproduce and grow early in life also cause harm later. Interestingly, the same gene vgll3 has already been linked to the timing of puberty and sexual maturation in humans and Atlantic salmon through large population studies, raising the possibility that similar biological trade-offs between growth, maturity, and longevity may operate in humans as well.
Moses E, Bergman M, Atlan T, Duxbury E, Franěk R, Ben Dor O, et al.. (2026). An antagonistically pleiotropic gene regulates vertebrate growth, maturity, and lifespan.. Nature communications. https://doi.org/10.1038/s41467-026-72381-0