In the first study to look specifically at the effects of life-long calorie-restricted diets on brain cells, University of Florida researchers determined certain proteins linked to cell death that naturally increase with age were significantly reduced in the brains of rats whose calories were limited.
More important, they found the levels of a beneficial protein known to provide potent protection against neuron death were twice as high in older rats whose calories were restricted by 40 percent.
The findings could have significant implications not only for alleviating the memory loss and other mental declines that accompany normal aging, but also for a host of disorders related to excessive loss of brain cells, such as Alzheimer's and Parkinson's diseases, which together afflict an estimated 4 million people in the United States.
"In normal aging, there's a variety of factors that could alter the internal environment of the cell and make it more prone to die. We would like to stop this," said Christiaan Leeuwenburgh, director of the Biochemistry of Aging Laboratory at UF's College of Health and Human Performance. "Cells in neurons, muscle and heart have very low regenerative capacity, so obviously you don't want to lose a lot of them."
The findings of his study, supported by grants from the National Institutes of Health and the National Institute of Aging, are expected to be published Jan. 2 in the online edition of the journal of the Federation of American Societies for Experimental Biology.
The mechanisms of aging are complex, but as time passes, neurons of the brain and central nervous system are thought to be increasingly susceptible to apoptosis, a genetically programmed series of events leading to cell death. Apoptosis can occur as a normal process to destroy old cells so new ones can be made, or due to disease, infection, damaged DNA or other maladies.
Based on decades of research in several species showing calorie restriction not only boosted life span and general health but also increased mental capacity, Leeuwenburgh and UF postdoctoral student Rajani Shelke set out to determine if cutting calories also protected aging neurons.
Understanding the reasons calorie restriction increases certain neuroprotective proteins is important so that some day researchers may be able to develop therapies to repair cells harmed in the disease process or target genes to release additional amounts of these proteins to ensure healthy life, said Leeuwenburgh, who also is affiliated with UF's Institute on Aging.
Mitochondria - the cells' energy-producing centers - can be damaged by free radicals or through calcium imbalances and other processes during normal aging or as a result of disease. When that happens they release proteins, most notably cytochrome c, that initiate cell death.
Using standard tests, Leeuwenburgh measured the levels of cytochrome c and other indicators of apoptosis in the cytosolic fraction of the frontal cortexes - areas important in learning and memory - of three groups of rats: 12- and 26-month-old animals given unlimited food and water, and a group of 26-month-old rats given 40 percent fewer calories than those in the unrestricted groups. The animals in the last group received food that was more nutritionally dense to ensure they weren't malnourished, a key concern about calorie-restricted diets, Leeuwenburgh said.
The researchers found that cytochrome c, a natural protein that is harmless until mitochondria become damaged, increased with age in the normally nourished animals. In the 26-month-old, calorie-restricted rats, however, the protein did not increase; instead, it remained at the level of the young rats.
A novel protein the researchers focused on was ARC - or apoptosis repressor with a caspase recruitment domain. They discovered that while this beneficial protein, known to prevent the release of cytochrome c and other destructive substances, dropped 60 percent with age in the freely fed rats, levels of it increased over time in the older calorie-restricted animals. These rats showed 40 percent more ARC than in the young animals and 80 percent more than the older unrestricted animals.
The study also found that specific DNA fragmentation, another indicator of apoptosis, more than doubled in the unrestricted animals over time, but were 36 percent less in the calorie-restricted rats.
Additional proteins called tumor necrosis factor and caspases 2 and 8 - dormant proteins that become destructive when activated by the onset of apoptosis - also increased with age in the normally fed animals but were relatively unchanged in those that had been restricted, the researchers found.
In the future, Leeuwenburgh will explore other pathways that may play roles in neuron death. "It's a big puzzle, and we're slowing putting the pieces of the puzzle together, so to speak," he said.
While there are still many questions and major Western lifestyle obstacles to overcome, calorie restriction provides significant health benefits, even if started later in life, he said.
"We're not going to do it right away to improve our memories; we're going to do it probably in general for the first reasons, which would be to prevent cardiovascular disease and cancer," said Leeuwenburgh, who is physically active and has moderately restricted his own calorie intake for a decade. "And maybe it also has a protective effect - and it's very suggestive in this study that it does - on brain function."
Noting the results are preliminary and that many questions remain unanswered, Mark Mattson, chief of the National Institute on Aging's neurosciences laboratory, said, "The authors have made a new and potentially important finding concerning the mechanism whereby caloric restriction retards the aging process." If their discovery is valid, he said, "the authors' finding reveals a novel aging pathway that could be targeted by other dietary manipulations or drugs."
Source: Christiaan Leeuwenburgh
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