Genetic Aging Research: Evolutionary Tradeoff Between Vestigial-like 3 (VGLL3) and Longevity

How Nature Maintains Stability

Antagonistic pleiotropy is an evolutionary theory that describes how genes that were helpful to us when we were younger become harmful to us as we age. Simply put, genes that enhance early-life fitness are now responsible for later-life health risks. Despite the negative outcomes, it is believed that these genes still persist and were not weeded out by natural selection because their earlier advantages outweigh the later costs. The gene APOE4 is an example of this: in children, this gene is helpful for protecting against childhood infections. As we age, however, it becomes a key gene associated with Alzheimer’s disease. Vestigial-like 3 (VGLL3) is another gene believed to possess this same quality. Previously studied in experiments with Atlantic salmon, scientists were intrigued to investigate VGLL3’s relevance to genetic aging research.

CRISPR Gene Editing Effects

In a study published in Nature Communications, a collaborative group of international researchers examined VGLL3 in African turquoise killifish—a species commonly studied in aging research due to its short lifespan (i.e., 4–6 months) and its ability to undergo diapause, a state of suspended development that allows organisms to survive harsh environments. Prior studies have connected VGLL3 to the onset of puberty, hormone levels, and maturation, with limited research on this gene’s relationship with dementia.

In their research, scientists used CRISPR gene-editing technology to modify the VGLL3 gene in the killifish. Compared to the fish that were not genetically modified, those containing the edited gene grew much faster and reached sexual maturity more rapidly. Evolutionarily speaking, these are prized characteristics that lead to the propagation of the species and reproductive success in nature. Even though this may initially seem beneficial, there was a cost: those same genetically modified fish lived much shorter lives and developed age-related tumors, such as melanoma.

According to Professor Itamar Harel, this study demonstrates how there is always a tradeoff in nature to maintain balance. That tradeoff is that nature does not prioritize longevity; instead, it focuses on continuity. When the fish were younger, VGLL3 helped them grow and mature. However, that came at a fatal price: the same gene that helped them grow became responsible for accelerated aging and tumor formation, meaning the fish were likely accumulating damage while developing. Dr. Harel and his colleagues note that the next step is to determine whether it is possible to separate the early-life benefits of VGLL3 from the detrimental outcomes that emerge later in life.

Vertebrate Relevance

Like fish, humans also possess the VGLL3 gene. Therefore, researchers can study VGLL3 to see if it exerts similar effects in our population, furthering our understanding of aging, age-related diseases, and human development. In turn, this could help us develop better treatment models for cancer and promote healthier aging practices.

This study also provides stronger support for the theory of antagonistic pleiotropy. Although it is a widely accepted concept in life sciences, scientists have historically struggled to identify specific genes responsible for this tradeoff in vertebrates (i.e., animals with a backbone). With these new findings, scientists have concrete evidence backing this theory and a foundation to search for additional genes that follow the same principle.

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