Beneficial Gene in Early Life Linked to Accelerated Aging and Cancer

Genes that provide advantages early in life may cause future harm.

A new study in African turquoise killifish has identified that mutations in the vgll3 gene accelerate growth and maturation but also reduce lifespan and increase cancer risk. 

Antagonistic pleiotropy 

The finding that a gene can have opposite effects at different ages supports the theory of antagonistic pleiotropy. 

“Antagonistic pleiotropy is one of the central evolutionary theories of aging,” Prof. Itamar Harel, an associate professor at The Hebrew University of Jerusalem who led the research, told Technology Networks.  

The theory suggests that genes that improve survival, growth, or fertility early in life may later contribute to disease risk or reduce lifespan. 

“Because natural selection is generally strongest before and during reproduction, such genes can be favored even if they contribute to late-life disease or mortality,” Harel explained. 

Population-based and experimental evolution studies have illustrated that slowing growth or reproductive programs can extend lifespan, and human genetic studies have identified alleles that are beneficial for reproduction but increase disease risk later in life. 

“What has often been missing is causal evidence in a vertebrate that a single gene can promote early-life performance while increasing late-life pathology,” said Harel. “That is the gap we wanted to address.” 

A focus on vgll3  

Through genome-wide association studies (GWAS), vgll3 had previously been linked to the timing of puberty, puberty-related traits, and other sexually dimorphic traits in humans, as well as the timing of maturation in other species. 

Age at puberty or maturation is strongly associated with lifespan—in general, long-lived species mature more slowly than short-lived species. 

“We became interested in vgll3 because it sits at a very interesting intersection between evolution, puberty, and sex differences,” said Harel. “Our goal was to test whether vgll3 is a causal regulator of maturation, and whether experimentally shifting maturation timing through this gene would have consequences for lifespan.” 

In African turquoise killifish, the researchers used CRISPR to mutate vgll3. They followed the animals throughout their lifespan to determine whether early-life benefits were accompanied by detrimental effects later in life. 

Vgll3 has two evolutionarily conserved isoforms, so mutations were made to exon 1 to perturb the function of the longer isoform and to exon 3 to affect both the long and short isoforms. 

“The outcome was more nuanced than a simple loss-of-function experiment,” said Harel. “Exon 1 homozygous mutants and exon 3 heterozygotes both showed accelerated male maturation, while exon 3 homozygotes showed a different trend, slowing down maturation. This suggested that vgll3 dosage and isoform composition can tune maturation timing.” 

Mutated vgll3 had opposite effects at different life stages 

Focusing on males with exon 1 vgll3 mutations, Harel and his colleagues observed faster maturation, increased body size and weight, increased gonadosomatic index, and increased germline and intestinal stem cell proliferation. 

“At the cellular level, mutant-derived cells showed increased proliferation and altered responses to DNA damage,” noted Harel. “Transcriptomic data pointed to changes in cell-cycle regulation, respiration, translation, reproduction, steroid hormone-related pathways, and DNA damage response.” 

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“The late-life cost was striking,” he added. “The vgll3 mutants had reduced lifespan, especially in males, and increased age-related mortality.” 

A comparison between young and old male killifish. Credit: Prof. Itamar Harel.

The vast majority of older male killifish with the exon 1 vgll3 mutation also developed melanoma-like growths that weren’t seen on wild-type killifish. By creating an immunodeficient killifish model and introducing the melanoma-like cells, Harel and his colleagues confirmed that the growths were tumors. 

“Mechanistically, we think vgll3 acts as a regulatory node linking growth, reproductive maturation, stem-cell proliferation, and genome maintenance,” Harel explained. “VGLL3 is a transcriptional cofactor, and previous work links it to Hippo/TEAD biology and DNA double-strand break repair.” 

“Our data suggest that accelerating growth and maturation through vgll3 disruption may push proliferative programs forward early in life, but at the cost of altered DNA damage responses and increased cancer risk later,” he said. “That is precisely the kind of age-opposed effect predicted by antagonistic pleiotropy.” 

What the findings mean for aging research 

“Our findings show that genes involved in development, growth, and maturation can have long-term consequences for disease risk and lifespan,” Harel said. “This helps connect puberty, sex differences, stem-cell activity, cancer, and aging into a single life-course framework.” 

While vgll3 has been linked to traits at key life stages in human genetic studies, GWAS alone cannot establish causality or the mechanisms through which vgll3 functions. 

The data from the killifish provide causal evidence that changes in vgll3 function shift maturation, growth, cancer susceptibility, and survival, and identify potential biological pathways that might mediate these changes. 

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The work also suggests that some age-related diseases reflect the biological processes that were useful earlier in life.  

“That perspective may help us interpret why risk differs between sexes, why developmental timing is associated with later health outcomes, and why pathways that stimulate growth or repair can become harmful if they remain active or are misregulated later in life,” said Harel. 

“A better mechanistic understanding may eventually allow us to preserve the beneficial physiological effects while uncoupling them from late-life costs, thereby promoting healthier aging” — Prof. Itamar Harel 

Next steps 

Harel outlined that there are several important next steps for this project. “First, we want to understand the molecular mechanism more deeply: which transcription factors work with vgll3 in different tissues, how isoform usage and dosage alter downstream programs, and how vgll3 affects DNA damage responses and tumor initiation.” 

Comprehensive genomic and transcriptomic characterization of the tumors that developed in vgll3 mutant killifish will also help distinguish how vgll3 contributes to oncogenesis.  

Furthermore, “we need to connect the laboratory findings to natural variation,” said Harel. “That means testing naturally occurring vgll3 variants and directly measuring fitness trade-offs in ecologically relevant settings.” 

“Finally, we would like to explore whether similar vgll3-dependent life-history logic applies across vertebrates, including in mammalian systems and human datasets.” 

Reference: Moses E, Bergman M, Atlan T, et al. An antagonistically pleiotropic gene regulates vertebrate growth, maturity, and lifespan. Nat Comm. 2026. doi: 10.1038/s41467-026-72381-0 

About the interviewee:

Prof. Itamar Harel is an aging biologist and geneticist at the Hebrew University of Jerusalem. His laboratory studies the genetic and evolutionary architecture of vertebrate aging, with a focus on the African turquoise killifish as a rapid vertebrate model for lifespan, life-history traits, metabolism, reproduction, DNA damage responses, cancer, and age-related disease. His work helped establish and expand the turquoise killifish as a genetically tractable model for aging biology and uses comparative, genetic, metabolic, single-cell, behavioral, and disease-modeling approaches to uncover conserved mechanisms that regulate healthspan and lifespan.