It was 2002 and one of those serendipitous moments that occur in science was about to happened in the lab of Dr. Jan van Deursen. He had been investigating possible causes of cancer when some unexpected, but very interesting results led him to try to answer a different question — What makes us age?

Dr. van Deursen had set out to study a protein called BubR1. This protein is a member of the mitotic checkpoint family, an intricate web of approximately 15 proteins that help regulate cell division. When the mitotic checkpoint proteins are functioning normally they help to ensure each cell has the correct number of chromosomes.

Because nearly 90 percent of cancer cells have an abnormal number of chromosomes, Dr. van Deursen wanted to find out if decreased levels of mitotic checkpoint proteins might increase the risk of developing cancer. To investigate this hypothesis, his laboratory team developed genetically modified mice that produced only 10 percent of the normal level of BubR1 protein.

Dr. van Deursen discovered that BubR1 deficient mice exposed to carcinogens, indeed, were more susceptible to developing cancerous tumors. In fact, they developed three-fold more tumors than normal mice. However, this was only part of the story.

An Unexpected Opportunity

In the early months of the experiment the team noticed that the BubR1 deficient mice looked different than normal mice. They were smaller, developed a curved spine and their eyes became clouded.

Some researchers may have overlooked these observations and focused only on the tumor data; some researchers may not have had the extensive network of expert collaborators required to find out what these observations signaled; and some would have been daunted by the lab time required to characterize the BubR1 deficient mice. It takes a great deal of time and effort to develop genetically modified mice, and once the mouse model is developed each experiment can take up to two years to complete. As aging-related diseases develop later in life, the normal control mice must be allowed reach an advanced age for proper comparison.

Care, patience and quiet determination are obvious van Deursen traits. Even outside of the lab, he is not easily deterred from a goal. For example, even on subzero mornings, he rides his bicycle to work. "With the proper clothing, it isn't so bad," he says.

With this same determination and attention to detail, he set about assembling a team to investigate the BubR1 deficient mice. "It is a great experience to be doing research at Mayo Clinic," Dr. van Deursen emphatically states, "where there are many expert specialists to collaborate with."

What the Team Found — BubR1 Helps to Govern Physical Aging

The work to characterize the BubR1 deficient mice required a team of more than twenty people. Although only few of them are mentioned by name in this article, each collaborator brought a unique area of specialized focus and technical expertise.

Dr. van Deursen credits Darren Baker, a member of his laboratory team with the initial discovery that BubR1 deficient mice age prematurely. In fact, they age four to five times faster than normal mice.

"We were getting all sorts of phenotypes in our mice and we weren't sure why," explains Baker. "So we began doing literature searches, looking for similarities with what people had reported before. When we found them, we discovered that most had been characterized as signs of early aging. That's when we started looking more closely at our mice and doing more extensive aging-related analyses."

This discovery led the team to measure BubR1 protein in normal mice at different ages, and they discovered that BubR1 protein declines with age in normal mice. In fact, the levels of BubR1 in normal mice during the last quarter of life are as low as in genetically modified BubR1 deficient mice. This age-related decrease in BubR1 protein levels was detected in heart, brain, skeletal muscle, spleen, testis and ovarian tissues.

Douglas J. Cameron, M.D., a Mayo Clinic ophthalmologist, performed the analysis that verified progressive cataract development in BubR1 deficient mice. Karthik Jeganathan, a graduate student, demonstrated BubR1 levels decrease with age in testis and ovary. The decreased BubR1 levels correlate with abnormal chromosome numbers in sperm and eggs (oocytes). These findings suggest the decline in BubR1 may be a contributing factor in age-related infertility and specific birth defects. Zvonimir Katusic, M.D., Ph.D., Director of the Mayo Vascular Biology Laboratory, brought to the team extensive experience in evaluating both the structural and biochemical properties of blood vessels. Research findings discovered in the Vascular Biology Laboratory demonstrated BubR1 deficient mice have aging-associated changes in the aorta and carotid arteries that can lead to hardening of the arteries (atherosclerosis) and stroke. Joseph Poduslo, Ph.D., Head of the Mayo Molecular Neurobiology Laboratory, helped determine that cerebral gliosis, an indicator of age-related cerebral degeneration, was highly accelerated in BubR1 deficient mice. Andre Terzic, M.D., Ph.D., Mayo Cardiovascular Research Laboratory, was instrumental in analyzing muscle tissue from the BubR1 deficient mice and in demonstrating a loss of muscle mass (atrophy) and degeneration of the muscle fibers.

BubR1 deficient mice also exhibit weight loss, loss of subcutaneous fat, thin skin, impaired wound healing and curvature of the spine in the upper back (kyphosis) when compared to normal mice. "The BubR1 deficient mice develop a variety of age-related disorders at a young age," says Dr. van Deursen.

Translating Findings to Human Aging

The aging-related disorders found in the BubR1 deficient mice are common in humans, and include cataracts, cardiovascular disease leading to heart attack and stroke, and muscle wasting. More than 90 percent of people over the age of 65 have at least one cataract, and in the United States, each year more than two million cataract surgeries are performed to restore lost vision. More than 2 million Americans have a cardiac rhythm problem called atrial fibrillation that can negatively affect quality of life and cause death. Approximately 80 percent of these cardiac rhythm problems occur in people age 65 or older. Loss of muscle mass and strength contributes to muscle weakness, which leads to frailty, falls and other injuries. Because it is difficult for elderly adults to regain muscle strength, healing and recovery are more difficult once injury occurs. Muscle wasting also may cause kyphosis. While many people associate kyphosis with osteoporosis, it is more commonly caused by muscle atrophy.

Dr. van Deursen points out, "The goal is not about extending the human lifespan, but to find ways to help elders maintain their independence and quality of life." The hope is that these interventions may help to slow the development of aging-related diseases and help physicians better treat aging-related disorders such as cataracts, cardiovascular disease and muscle atrophy. Dr. van Deursen's research is funded by the National Institutes of Health and the Robert and Arlene Kogod Program on Aging at Mayo Clinic.