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Long-Lived Rockfish Genome Analysis Provides New Clues to Longevity

NEW YORK — Researchers have uncovered genes that may influence how long Pacific Ocean rockfish, which differ widely in lifespan, can live. The results could inform the understanding of human longevity and aging and lead to new treatment for age-related diseases.

Pacific Ocean rockfish encompass dozens of species with a wide range of lifespans. The calico rockfish Sebastes dallii, for instance, lives for just over a decade, while the rougheye rockfish S. aleutianus can live for more than 200 years. By sequencing 88 different rockfish species, a team led by Peter Sudmant at the University of California, Berkeley homed in on genes under selection in long-lived fish to better understand the genetic determinants of their lifespans.

As they reported Thursday in Science, they uncovered about 100 genes that affect longevity, some by their effects on body size and environmental adaptations and others that directly affect insulin signaling and immune response. In particular, they noted copy number expansions affecting the immune-modulating butyrophilin genes. Together, these findings point to biological pathways that affect longevity, possibly also in humans.

"There is an opportunity here to look in nature and see how natural adaptations have shaped lifespan and to think about how those same sorts of genes are acting in our own bodies," Sudmant said in a statement.

For their study, Sudmant and colleagues sequenced and assembled the genomes of 102 rockfish, representing 88 different species, mostly from Sebastes. At the same time, they generated transcriptome data from the brain and eye tissues of eight species and identified about 25,000 genes throughout the rockfish genomes.

Within these genomes, the researchers identified 772 genes under positive selection in the longest-lived and 873 genes under positive selection in the shortest-lived rockfish species. Those in the longest-lived fish were enriched for involvement in DNA replication, repair, and maintenance.

The researchers further homed in on a set of 91 genes significantly associated with lifespan among rockfish, including genes with roles in cell growth and DNA repair. But they noted that some of these genes influence lifespan by affecting body size and environmental adaptations. Both body size and living at a deeper ocean depth have themselves been tied to longer life, they noted.

Fifty-six genes, though, act independently of those factors, many of which are involved in insulin and glucose signaling, which are also known to affect lifespan.

"Six different members of the insulin signaling pathway are under selection in these fish," Sudmant said. "If you look at the textbooks, there are about nine or 10 core members of the pathway, so the majority of them are under selection in rockfish."

Following a genome-wide screen, the researchers additionally uncovered a cluster of nine genes with copy number changes that were associated with rockfish lifespan. Six of these genes were members of the butyrophilin gene family of immune regulators. This points to a possible role for immunoregulatory genes in increased lifespan in rockfish.

Sudmant added that inflammation has been tied to aging in humans, suggesting that the immunoregulatory genes they identified could also be potential targets to slow the effects of aging in people.

In a related commentary appearing in Science, Yuyang Lu, Andrei Seluanov, and Vera Gorbunova from the University of Rochester noted long-lived rockfish might be able to endure reduced inflammatory function as there are fewer microbes in the deep ocean waters than in shallower areas, though they pointed out that long-lived animals like bats also appear to downregulate inflammation.

"Comparative transcriptomics, proteomics, and metabolomics will reveal further layers of aging and longevity regulation," the trio added.

Sudmant and colleagues next plan to similarly examine the genomes of other long-lived organisms, including bats and primates, to identify additional longevity-linked genes.