There is no complete genetic explanation for why humans live longer than mice or why tortoises can live for a century. Looking for answers in long-lived animals’ genomes is tempting for researchers who want to figure out which genes extend lifespan.
“I want to live as long as possible,” said Stephen Treaster, a postdoctoral researcher at Boston Children’s Hospital. “I want to see what technology and society looks like in 1000 years, ideally”he said. Treaster used rockfish as an unlikely organism to explore the possibilities for longevity and uncovered two new pathways that appear connected to lifespan. He and his colleagues published their results in Science Advances (1).
For aging studies, researchers mostly use short-lived animals like mice, which live about three years, or Drosophila and Caenorhabditis elegans, which live for months or days (2–4). “To make them live 10, 15, 20 percent longer, it doesn't necessarily apply to our end of the aging spectrum,” said Treaster. “Evolution has already solved the aging problem. There are individual species that can live hundreds and hundreds of years. My approach is to look at these exceptionally long-lived models.”
Lifespan arises in different species from a complex network of genes and environmental interactions. Because of that complexity, it is difficult to look at the genetics of many model organisms and say for certain which genes contribute to that organism’s lifespan. Fortunately, a natural evolutionary experiment on longevity exists. Rockfish are a family of common marine fish with worldwide distribution. Some species of rockfish live as little as 10 years while others can reach ages of 200 years or more. Since the rockfish clade emerged a relatively recent eight million years ago, there hasn’t been time for rockfish to develop much genetic diversity.
The rockfish’s nascent lineage is an analyst’s advantage. The wide variety of lifespans that different rockfish lineages exhibit can easily be pinned to genetic differences. Just as important, rockfish lifespans do not correlate with environmental conditions such as temperature or water depth, the kind of confounding effects that might make a genetic link to longevity in other animals less clear.
By analyzing genes related to aging that seemed to be evolutionarily selected across a variety of different rockfish species with varying lifespans, Treaster identified two different genetic pathways that seem to have evolved along with changes in lifespan.
The first pathway controls insulin signaling. Scientists know that insulin signaling affects aging and metabolism from past studies in other model organisms. “On one hand, this is kind of a boring result,” said Treaster. On the other hand, however, the fact that insulin signaling reappeared when analyzing rockfish seems to confirm the group’s approach.
It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.
- Stephen Austad, University of Alabama
The other less well-known pathway they found is in the flavonoid signaling network. The flavonoid pathway is made up of proteins with activity modulated by flavonoid molecules, which are three-ring and 15-carbon structures common in plants (5).
“None of the previous mouse or fly studies have pointed to the flavonoid network,” said Steven Austad, an evolutionary biologist and aging researcher at the University of Alabama at Birmingham who was not involved in the study. “It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.”
While Treaster is excited about identifying a possible new genetic link to lifespan, he emphasized that how exactly flavonoid pathway genes affect lifespan is not known. “The next step is to play with these genes from rockfish to see if we can extend longevity in a conventional model. We're doing that right now. We are targeting these genes in zebrafish to see if we can extend lifespan,” said Treaster. If that work confirms that flavonoids do directly alter lifespan, then Treaster hopes that scientists interested in aging-related diseases may explore the pathway for potential drug targets.
Austad isn’t certain that identifying these genetic pathways to aging in fish will result in druggable targets in humans. He doubts that the insulin pathway, which has a demonstrated connection to longevity in flies and roundworms, can be connected to human lifespan. “The evidence that that's a major player in human aging is relatively sparse,” he said, noting that there haven’t been any human centenarians with identified novel mutations in the insulin signaling pathway.
Nevertheless, the publication gave him hope. “This flavonoid network — it's really a new thing and deserves investigation,” he said.
- Treaster, S. et al. Convergent genomics of longevity in rockfishes highlights the genetics of human life span variation. Sci Adv 9, eadd2743 (2023).
- Van Voorhies, W. A. & Ward, S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci USA 96, 11399–11403 (1999).
- Paaby, A. B. & Schmidt, P. S. Dissecting the genetics of longevity in Drosophila melanogaster. Fly 3, 29–38 (2009).
- Blüher, M., Kahn, B. B. & Kahn, C. R. Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue. Science 299, 572–574 (2003).
- Chen, L. et al. Intracellular signaling pathways of inflammation modulated by dietary flavonoids: The most recent evidence. Critical Reviews in Food Science and Nutrition 58, 2908–2924 (2018).