An unlikely, decadelong journey that began with the discovery of a rapidly aging mouse has led scientists to a protein that seems to protect animals from cancer and other scourges of old age—with no apparent downsides. There are still lots of mysteries about the protein, called BubR1, but the work offers clues about how protecting chromosomes can enhance health.
Cancer biologist Jan van Deursen at the Mayo Clinic in Rochester, Minnesota, and his colleagues were initially interested in studying a common feature of cancers, called aneuploidy. Aneuploid cells have too few or too many chromosomes. Nearly all cancer cells fall into this category, but it's not clear whether aneuploidy actually causes cancer. van Deursen, along with a then-graduate student, Darren Baker, engineered mice to produce less BubR1, a protein that helps cells segregate their chromosomes when they divide. When BubR1 is reduced, chromosomes can't properly separate into identical daughter cells, leaving some daughters with the wrong number of chromosomes. van Deursen, Baker, and their colleagues wanted to see whether these mice would develop cancer.
To their surprise, instead of tumor-filled mice, they wound up with animals that aged very quickly. "These mice were clearly very, very different than a normal mouse," says Baker, who now studies the biology of aging at the Mayo Clinic. Last year, they reported that removing old cells—that is, cells with a genetic marker indicating senescence—from these mice could help them stay healthier longer. Adding intrigue is an extremely rare human condition caused by mutations in the BubR1 gene. Patients with the disease, mosaic variegated aneuploidy syndrome, age prematurely and have an elevated risk of cancer. Too little BubR1 seems to be bad news.
Too much, on the other hand, might be a good thing. In work published today in Nature Cell Biology, the biologists report that genetically engineered mice that make extra BubR1 are less prone to cancer. For example, they found that when they exposed normal mice to a chemical that causes lung and skin tumors, all of them got cancer. But only 33% of those overexpressing BubR1 at high levels did. They also found that these animals developed fatal cancers much later than normal mice—after about 2 years, only 15% of the engineered mice had died of cancer, compared with roughly 40% of normal mice.
The animals that overexpressed BubR1 at high levels also lived 15% longer than controls, on average. And the mice looked veritably Olympian on a treadmill, running about twice as far—200 meters rather than 100 meters—as control animals. All of this left Baker, van Deursen, and their colleagues thinking that BuBR1's life-extending effects aren't due to only its ability to prevent cancer, although that's not yet certain.
A big question now is why having your chromosomes out of order might accelerate aging, says Wei Dai, a cell biologist at the New York University Langone Medical Center who's based in Tuxedo, New York. Although aneuploidy seems less than desirable, studies haven't been consistent about its effects on animals. "We found that when the aneuploidy level became low"—just like in van Deursen's healthy mice—"you had more tumorigenesis," not less, says Cristina Montagna, a molecular geneticist at Albert Einstein College of Medicine in the Bronx, New York. She and her colleague Jan Vijg are collaborating with van Deursen to study the brains of his BubR1 mice. One possibility is that both very low and very high aneuploidy can protect from cancer, perhaps because highly aneuploid cells are so damaged they don't have the ability to quickly divide.
Still, there's hope that van Deursen's group may have identified a new drug target to slow aging. "There [are] no negative consequences that he identified" to having more BubR1, says Paul Hasty, who studies aging and DNA repair at the University of Texas Health Science Center in San Antonio. "You need to figure out exactly what BubR1 is doing to achieve this desired effect," he adds, but this could be the first step on a long path toward new treatments that delay aging—and possibly prevent cancer.