Researchers 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. BuBR1’s life-extending effects aren’t due to only its ability to prevent cancer, although that’s not yet certain.
They may have identified a new drug target to slow aging with no identified negative consequences and possibly prevent cancer.
The BubR1 gene encodes for a mitotic regulator that ensures accurate segregation of chromosomes through its role in the mitotic checkpoint and the establishment of proper microtubule–kinetochore attachments. Germline mutations that reduce BubR1 abundance cause aneuploidy, shorten lifespan and induce premature ageing phenotypes and cancer in both humans and mice. A reduced BubR1 expression level is also a feature of chronological ageing, but whether this age-related decline has biological consequences is unknown. Using a transgenic approach in mice, we show that sustained high-level expression of BubR1 preserves genomic integrity and reduces tumorigenesis, even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras. We find that BubR1 overabundance exerts its protective effect by correcting mitotic checkpoint impairment and microtubule–kinetochore attachment defects. Furthermore, sustained high-level expression of BubR1 extends lifespan and delays age-related deterioration and aneuploidy in several tissues. Collectively, these data uncover a generalized function for BubR1 in counteracting defects that cause whole-chromosome instability and suggest that modulating BubR1 provides a unique opportunity to extend healthy lifespan.
SOURCES – Sciencemag, Nature Cell Biology