The discoveries came as the result of general investigations into possible genetic causes of cancer. In this case, it was discovered that this particular gene, called BubR1, governs production of a protein that modulates physical aging. The mice studied lacked normal levels of that protein and began to age prematurely.
"Darren Baker in our laboratory found that mutant mice with low amounts of BubR1 protein live five times shorter than normal mice. They also develop a variety of age-related disorders at a very young age," says lead investigator Jan van Deursen, Ph.D., of the Mayo Clinic Departments of Pediatric and Adolescent Medicine, and Biochemistry and Molecular Biology.
Dr. van Deursen says, "This prompted us to investigate whether BubR1 protein levels go down as normal mice age naturally -- which is indeed what we found. Based on these findings, we believe it is the decline of this protein with time that may trigger some of the physiological effects of aging."
Another Mayo investigator, Karthik Jeganathan, discovered that mice with low amounts of BubR1 protein are infertile and unable to distribute chromosomes properly when their germ cells divide. Abnormal numbers of chromosomes in germ cells are a hallmark of reproductive aging in humans, and the primary cause of increased still births and birth defects, such as Down syndrome, in women over 35 years of age. Says Dr. van Deursen, "Given the age-dependent decline in ovarian BubR1 in mice, it seems reasonable to assume that this protein may contribute to age-related infertility and certain birth defects in humans."
In collaboration with Mayo ophthalmologist J. Douglas Cameron, M.D., the researchers discovered that mice with low amounts of BubR1 also develop cataracts that are very similar to age-related cataracts in humans. About 20 to 25 percent of individuals at age 65 and older have cataracts of this type, and 1 million Americans undergo surgery to repair this aging-related disorder each year.
In addition to Dr. van Deursen, other Mayo Clinic scientists involved in the investigation were: Darren J. Baker; Karthik B. Jeganathan; J. Douglas Cameron, M.D.; Michael A. Thompson; Subhash Juneja; Alena Kopecka; Rajiv Kumar, M.D.; Robert B. Jenkins, M.D., Ph.D.; Piet C. de Groen, M.D.; and Patrick Roche, Ph.D. The research was supported by a grant from the National Institutes of Health.
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