GAINESVILLE, Fla. --- A University of Florida study has found that mutations in the mitochondria caused by obesity and lack of exercise -- not oxidative stress from free radicals -- may be a key factor in the aging process.
The study, published in this Friday's issue of Science magazine, finds that accumulation of mitochondrial mutations that promote apoptosis, or programmed cell death, may be a central mechanism driving aging and may be unrelated to the release of free radicals, previously thought to cause aging. This may be because of an accumulation of DNA mutations in the mitochondria, the cellular powerhouse that converts food to energy.
Results from the study may lead to more effective methods to prevent aging and stress the importance of a healthy lifestyle, said Christiaan Leeuwenburgh, an associate professor in the department of aging and geriatric research in the College of Medicine and contributing author of the study. He estimated that average maximum human lifespan could be increased from the current 70 years to more than 100 years with exercise and a proper diet.
"All the therapies have been targeted to reduce the free radical production in the mitochondria, and now it looks like that doesn't make complete sense," he said.
By breeding mice with the inability to detect and repair mistakes in the DNA replication process, researchers discovered there was no increase in oxidative stress despite an increased mutational load. However, there was a significant increase in apoptosis, said Leeuwenburgh.
In mammals, uncorrected mistakes can cause genetic disorders, aging or even death, said doctoral student Asimina Hiona, who was instrumental in the biochemical analysis of free radicals and apoptosis in the study. In the mutated mice, that ability was impaired so the cells could not repair themselves.
The finding disproves the previously believed mitochondrial "vicious cycle" theory of aging, which states that increases in mitochondrial mutations increase oxidative damage, which is one cause of aging.
"It was previously believed that the more mitochondrial mutations you have, the more free radicals you're going to produce," said Leeuwenburgh. "But that's one thing this paper shows, that that's not necessarily the case."
The mice used in the study were bred by Thomas Prolla, an associate professor and lead investigator of the paper, and Greg Kujoth, an assistant scientist, both of the genetics department at the University of Wisconsin.
"Mice with accelerated aging may be a useful system to discover compounds that improve function in aging individuals and perhaps retard or prevent some of the diseases associated with aging," Prolla said.
The researchers discovered that on average, the mutant mice lived a third as long as normal mice. At just nine months of age, they experienced significant loss of hair, hearing, bone mass, intestinal lining and overall weight, conditions similar to those of an aging human. Unaltered, the same mice normally live 30 to 32 months.
Also, no programmed cell death was observed between mutant and control mice at 3 months of age. However, by the time the mice reached 9 months, significant levels of programmed cell death were found in the testes, heart, thymus and other organs.
Although the mice were considered a "good model" of aging, they lacked a chronic inflammatory component which can cause cardiovascular disease, Alzheimer's and other health problems that affect individuals as they age. Chronic inflammation is associated with the increased production of free radicals produced by other sources, such as white blood cells.
"As we get old, we become stiff and have pains and processes that have inflammation," Leeuwenburgh said. He added that inflammation may be prevented by maintaining an ideal body weight through caloric restriction and exercise.
If people practice a healthy lifestyle, then stem-cell therapy, nanotechnology and special exercise and dietary interventions will be even more beneficial, he said.
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