Accurate segregation of chromosomes during mitosis is essential for maintenance of genomic integrity. Errors in this process cause an abnormal chromosome content, known as aneuploidy, which is a hallmark of most human cancers. To test whether aneuploidy is a cause or a consequence of the malignant phenotype, we generated mice that express low levels of BubR1, a key component of a mitotic checkpoint that prevents chromosome missegregation by delaying anaphase onset until all chromosomes are properly attached to mitotic spindle microtubules. Although these BubR1 hypomorphic mice accumulate vast amounts of aneuploid cells, they are not prone to spontaneous tumors. However surprisingly, they exhibit a number of progeroid features, including reduced lifespan, cachectic dwarfism, lordokyphosis, sarcopenia, cataracts, craniofacial dysmorphisms, heart arrhythmias, arterial stiffening, loss of (subcutaneous) fat, and impaired wound healing. Furthermore, natural aging of wild-type mice is marked by decreased expression of BubR1 in several tissues. Combined, these observations suggest a role for BubR1 in regulating aging. The recent discovery of bi-allelic BubR1 mutations in patients with mosaic variegated aneuploidy (MVA) syndrome, a disorder characterized by aneuploidy, tumor predisposition and several progeroid features, further supports this idea.

An important question that needs to be addressed now is how BubR1 insufficiency triggers aging-related pathologies. Because the only discernable defect in BubR1 mutant mice is a high rate of chromosome missegregation, we initially speculated that aneuploidy might be the primary lesion causing premature aging. However, mice defective in mitotic checkpoint genes other than BubR1 do not develop progeroid features despite severe chromosome number instability, arguing that aneuploidy per se is not the driving force behind accelerated aging. This leads us to believe that BubR1 has a function outside the mitotic checkpoint that plays a critical role in the suppression of early-aging associated phenotypes. The overall objective of our studies will be to establish the mechanism by which BubR1 insufficiency causes aging-related disorders. As the majority of MVA syndrome patients with bi-allelic BubR1 mutations suffer a complete loss or severe reduction of BubR1 kinase activity, we speculate that the kinase activity of BubR1 plays a critical role in suppressing segmental progeria. We will test this idea by the use of mutant mice that lack this activity. If these mice indeed age prematurely, we will identify the molecules and the pathways that are targeted by BubR1ís kinase activity.