The theory suggests that very reactive chemicals, called "free radicals," can be damaging to the body at the cellular level. Those reactive chemicals can take part in unnecessary chemical reactions that can damage the cell components, including DNA. Some researchers believe that free radicals could contribute to or hasten heart disease, cancer, and other age-related diseases. The theory also suggests that if the body could be protected from those free radicals, then age-related diseases could be tamed and organisms – and ultimately people – may be able to live longer.
Scientists have previously been able to extend the lifespan of mice in lab experiments by managing their diets and reducing their caloric intake. Another method relied on the restriction of a growth factor, but a side effect was that the mice suffered from dwarfism. However, neither of those methods of elongating the mouse lifespan was clearly connected to the free-radical theory of aging.
A group of scientists led by Dr. Peter Rabinovitch, professor of pathology at the UW School of Medicine, examined a method that was closely connected to the free-radical theory. He and his colleagues focused their study on catalase, an enzyme in the body that helps convert hydrogen peroxide into water and oxygen. Hydrogen peroxide is a waste product of metabolism and it can be a the precursor of free radicals that can damage the cell. The damage can in turn lead to more flaws in the cell's chemical processes, making a vicious cycle that leads to more free radicals, more cellular damage, and so on.
The researchers studied mice with a genetic variation that made them produce more human catalase, the enzyme that breaks down hydrogen peroxide. They targeted delivery of the catalase to different areas of the cell: the cytoplasm, where catalase normally goes to decompose hydrogen peroxide; the nucleus, the DNA-containing "control center" for the cell; and the mitochondrion, the cell's power plant that converts organic matter into energy.
They compared the different groups of mice to a control group and found that increased production of catalase could affect the mouse lifespan. The mice with higher catalase levels in the mitochondria, dubbed the MCAT group, had about a 20 percent increase in average and maximum lifespan, or about four and a half months. The mice with increased catalase levels in the nucleus and cytoplasm saw only modest increases in lifespan. These results fit with the theory that mitochondria can be an important source of free radicals created as a byproduct of energy production. Removing hydrogen peroxide "at the source" seems to be the most effective strategy for enhancing lifespan, Rabinovitch said.
The scientists also found that the mitochondrion-targeted catalase mice had healthier heart muscle tissue, indicating that the catalase helped protect from age-related heart problems seen in wild-type mice. The MCAT mitochondria also had fewer mutations, and the MCAT nuclear DNA had fewer oxidized components.
"This study is very supportive of the free-radical theory of aging," said Rabinovitch. "It shows the significance of free radicals, and of reactive oxygen species in particular, in the aging process."
This study and others that are able to extend animal lifespan beyond the normal limits are very powerful in that they most clearly demonstrate the important steps and pathways in the aging process, Rabinovitch said. By identifying these steps and pathways, scientists could pave the way for future development of drugs or other treatments that protect the body from free radicals and possibly some age-related conditions.
"People used to only focus on specific age-related diseases, because it was believed that the aging process itself could not be affected," Rabinovitch explained. "What we're realizing now is that by intervening in the underlying aging process, we may be able to produce very significant increases in 'healthspan,' or healthy lifespan."
The study was funded by the National Institute on Aging. In addition to other researchers from the UW School of Medicine, the project also included researchers from the University of California, Irvine, and the University of Texas Health Sciences Center at San Antonio.