I visited Dr. Craig Atwood at his Laboratory of Endocrinology, Aging and Disease at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin last week. To get to Dr. Atwood's office, I navigated through the hospital's maze of dark hallways and waiting rooms filled with American flags, flickering televisions and mostly older male patients. It seemed an unlikely setting for a discussion of Dr. Atwood's paper "Living and Dying for Sex: A Theory of Aging Based on the Modulation of Cell Cycle Signaling by Reproductive Hormones."
Co-authored by Dr. Richard Bowen of Voyager Pharmaceutical Corporation, "Living and Dying for Sex" was published in Gerontology in 2004. The paper lays out a new theory on aging, along with supporting data. I wanted to talk with Dr. Atwood because he believes this theory is relevant to the cerebral amyloid angiopathy and Alzheimer's that caused Dad's dementia and death.
An endocrinologist by training, Dr. Atwood is now Research Director of the Wisconsin Alzheimer's Institute at the University of Wisconsin School of Medicine and Public Health. Many Alzheimer's researchers focus on the pathology of the brain, including the plaques and tangles that are part of the official diagnosis of Alzheimer's. But as an endocrinologist, Dr. Atwood studies hormones, the glands that produce them, and their role in the body. Maybe this is why he sees things a little differently.
"This all started when a patient mentioned to Dr. Bowen that her husband's Alzheimer's disease hadn't worsened after he was placed on leuprolide acetate for the treatment of his prostate cancer," Dr. Atwood explained. "Leuprolide acetate decreases the levels of reproductive hormones in the blood. This, along with similar anecdotal reports, led us to focus on the hormones that regulate reproduction, including estrogen, testosterone, luteinizing hormone and follicle-stimulating hormone, as possible factors in Alzheimer's disease."
Craig S. Atwood, Ph.D.
"Throughout our reproductive lives, our reproductive hormones are in balance, but at mid-life (during menopause in women and andropause in men), the levels and balance of these hormones change," Dr. Atwood continued. "Estrogen and testosterone levels go down, and we know from previously published research that levles of luteinizing hormone and follicle-stimulating hormone go up during this time. We think that as estrogen and testosterone levels decrease, the pituitary gland increases production of these other hormones in an attempt to maintain fertility. This attempt to maintain fertility is good for the species, of course, but we think it's bad for the individual. It effectively removes post-reproductive individuals from the population."
Why might these normal hormone changes have been bad for my father or for any other "post-reproductive individual"? "The answer lies in the cell cycle," Dr. Atwood said, pointing to a poster about the cycle on his office wall. Cell division allows an organism to grow, and to repair and renew tissue. The process in which the chromosomes in a cell are replicated and the cell divides into two new cells is called the cell cycle.
In adults, brain cells or neurons don't normally go through the cell cycle. This may be because they develop extensions called axons and dendrites for transmitting information to other brain cells. Dr. Atwood explained that if you think of these axons and dendrites as hardwired into the brain's network, you can see that cell division would greatly disrupt brain function.
But in the 1990's, researchers found evidence that Alzheimer's patients' brain cells had been trying to replicate their chromosomes and divide. It may be this misguided attempt to re-enter the cell cycle that is causing the cells to die. Scientists don't know for sure why these brain cells are trying to divide, or exactly how the attempted division could cause cell death.
Given that a drug suppressing the reproductive hormones seemed to halt the progression of Alzhiemer's disease in some patients, Dr. Atwood theorized that imblanced or dysregulated reproductive hormones are somehow involved in signaling brain cells to divide. There are a lot of luteinizing hormone receptors in human brains, and researchers have found the same receptors in areas of rats' brains that correspond to the parts of the human brain typically affected by Alzheimer's. These observations indicate that luteinizing hormone could play a role in signaling those brain cells to divide.
To sum it all up, Drs. Atwood and Bowen think that mid-life changes in sex hormones signal normally stable neurons, or brain cells, to divide. According to their theory, the neurons' attempts to replicate chromosomes and divide goes awry somehow, resulting in cell death. This could be the underlying cause of Alzheimer's and similar diseases.
Research is underway in Dr. Atwood's lab to test this theory, and to develop Alzheimer's treatments based on these findings. He and his colleagues have already shown that leuprolide improves memory and decreases beta amyloid deposits in mice bred to have Alzheimer's disease. In addition to these efforts in the lab, Voyager Pharmaceutical Corporation is recruiting patients in the United States, Canada and South America for a Phase III trial of leuprolide acetate in 555 patients with mild or moderate Alzheimer's disease.
In future posts, I'll try to summarize how Dr. Atwood's theory may explain aging in general, and why he believes the beta amyloid protein deposits seen in Alzheimer's and cerebral amyloid angiopathy are protective, not harmful.