URochester scientists link the whales' longevity to CIRBP, a DNA-repair protein that could one day help humans live longer.
As humans age, we become more vulnerable to cancer and other diseases. Bowhead whales, however, can live for up to 200 years while staying remarkably disease resistant.
How does one of the largest animals on Earth stay healthy for centuries? And could their biology hold clues to help humans live longer too?
New research from scientists at the University of Rochester and their collaborators suggests one answer lies in a protein called CIRBP. The protein plays a key role in repairing double-strand breaks in DNA, a type of genetic damage that can cause disease and shorten lifespan in a variety of species, including humans. In a study published in Nature, the researchers-including URochester biology professors Vera Gorbunova and Andrei Seluanov and first authors Denis Firsanov, a postdoctoral researcher, and Max Zacher, a graduate student in their lab-found that bowhead whales have much higher levels of CIRBP than other mammals. The findings offer a new clue to how humans might one day enhance DNA repair, better resist cancer, and slow the effects of aging.
"This research shows it is possible to live longer than the typical human lifespan," says Gorbunova, the Doris Johns Cherry Professor in the Departments of Biology and of Medicine, the director of the Upstate NY Comparative Biology of Aging Nathan Shock Center, and a researcher with the University of Rochester Medical Center's Rochester Aging Research (RoAR) Center and Wilmot Cancer Institute. "By studying the only warm-blooded mammal that outlives humans, our work provides information about the mechanisms that allow such extended lifespans, underscoring the importance of genome maintenance for longevity."
A cancer paradox
The "multi-stage model of cancer" is a widely accepted framework that explains how normal cells don't just turn into cancer cells in one step, Gorbunova says. Instead, cancer develops after multiple genetic mutations or "hits"-called oncogenic hits-accumulate in key genes that control cell growth, division, and DNA repair.
Most human cancers arise after a cell accumulates five to seven "hits." A person's inherited genes, the type of tissue involved, and environmental exposures can all influence how many hits it takes for cancer to emerge.
Given this multi-step model, one might expect that animals with more cells and longer lifespans would accumulate more hits and therefore face higher cancer risks. But that is not what scientists observe. This puzzle is known as Peto's Paradox. Large species don't have higher rates of cancer compared to smaller animals, even though they have far more cells dividing over many more years. The paradox suggests that larger species such as elephants and whales must have evolved additional mechanisms to prevent or repair cancerous mutations. Exactly what those mechanisms are has long vexed scientists.
"We first hypothesized that oncogenic hits might explain this, and a whale would need six or seven hits to make them more cancer-proof," Gorbunova says. But when the researchers tested how many mutations it takes for bowhead whale cells to turn cancerous, they discovered that bowhead whales actually need fewer hits than humans.
Instead, Gorbunova continues, "we found that whale cells are less likely to accumulate oncogenic hits in the first place."
CIRBP: The DNA repair protein
By combining genomic data with molecular biology experiments, the URochester researchers studied cells harvested from bowhead whale tissue and analyzed proteins involved in DNA repair, shedding light on the cellular mechanisms that help whales live exceptionally long, healthy lives. While several DNA repair proteins were more abundant in bowhead whales than in other mammalian species, one protein was particularly remarkable: CIRBP.
"There were some other proteins that were expressed in bowhead whales at slightly higher levels, but CIRBP stood out because it was present at 100-fold higher levels," Gorbunova says.
To further test CIRBP's abilities, the team added bowhead whale CIRBP to human cell cultures and fruit fly cells. In both cases, DNA repair improved, and, in fruit flies, it even extended their lifespan.
A 'chilling' discovery
Collaborating with scientists in Alaska who are investigating how animals adapt to cold, the researchers discovered another intriguing aspect of CIRBP.
"If we just lower the temperature a few degrees, cells make more CIRBP protein," Seluanov says. "What we don't yet know is what level of cold exposure would be needed to trigger that response in humans."
Gorbunova says the team is considering multiple ways to ramp up the protein in humans. And some approaches may involve people's everyday habits.
"Both boosting the body's existing CIRBP activity or introducing more of the protein may work," Gorbunova says. "Lifestyle changes-things like taking cold showers-might contribute too and might be worth exploring."
For now, these ideas are hypothetical, and the researchers caution that it's too early to know whether they would work in people.
The next step, Gorbunova says, is further testing CIRBP to better understand whether this bowhead whale-inspired defense could someday help humans resist cancer and other age-related diseases.
"There are different ways to improve genome maintenance and here we learn there is one unique way that evolved in bowhead whales where they dramatically increase the levels of this protein," Gorbunova says. "Now we have to see if we can develop strategies to upregulate the same pathway in humans."
