Diet Of Walnuts, Blueberries Improve Cognition; May Help Maintain Brain Function

Scientists are confirming that this age-old adage is worth following. And new studies show that diet may have implications for those who suffer from certain brain ailments.

Diets containing two percent, six percent, or nine percent walnuts, when given to old rats, were found to reverse several parameters of brain aging, as well as age-related motor and cognitive deficits, says James Joseph, PhD, of the U.S. Department of Agriculture Human Nutrition Research Center at Tufts University in Boston.

In previous research, Joseph and his colleagues showed that old rats maintained for two months on diets containing two percent high antioxidant strawberry or blueberry extracts exhibited reversals of age-related deficits in the way that neurons function and in motor and cognitive behavior. In the brain, antioxidant molecules wage war against molecules known as free radicals, which can harm brain cells and brain function. The present research extends these findings and shows that walnuts can have a similar effect.

Walnuts contain alpha-linolenic acid (ALA), an essential omega-3 fatty acid, and other polyphenols that act as antioxidants and may actually block the signals produced by free radicals that can later produce compounds that would increase inflammation. Findings from the studies by Joseph and his colleague Barbara Shukitt-Hale, PhD, show for the first time that shorter chain fatty acids found in plants, such as walnuts, may have beneficial effects on cognition similar to those from long chain fatty acids derived from animal sources, which have been reported previously.

A six percent diet is equivalent to a person eating 1 ounce of walnuts each day, which is the recommended amount to reduce harmful low-density lipoprotein, or LDL, cholesterol, while a nine percent diet is equivalent to people eating 1.5 ounces of walnuts per day. "Importantly," Joseph says, "this information, coupled with our previous studies, shows that the addition of walnuts, berries, and grape juice to the diet may increase 'health span' in aging and provide a 'longevity dividend' or economic benefit for slowing the aging process by reducing the incidence and delaying the onset of debilitating degenerative disease."

Joseph and his colleagues are currently assessing whether increased neurogenesis or alterations in stress signaling, or both, may be involved in the mechanisms through which the walnut diets could be producing their effects. Ongoing research suggests that walnuts involve more than the mere "quenching" of free radicals and may in fact involve direct effects on blocking the deleterious "stress signals" generated by the oxidative stressors. "The beneficial effects of walnuts also may be the direct result of enhancements of signals which mediate such important functions as neuronal communication and the growth of new neurons," says Joseph.

A great deal of data suggests that the deficits associated with aging, for example, Alzheimer's disease and cardiovascular diseases, arise as a result of an increasing inability of the aging organism to protect itself against inflammation and oxidative stress, providing fertile ground for the development of neurodegenerative diseases. "The good news," Joseph says, "is that it appears that compounds found in fruits and vegetables -- and, as we have shown in our research, walnuts -- may provide the necessary protection to prevent the demise of cognitive and motor function in aging."

Other research shows that walnut extract may play a role toward developing novel treatments for Alzheimer's. Amyloid-ß plaques are the primary physiological hallmark of Alzheimer's. The presence of the enzyme acetylcholinesterase within these plaques has been confirmed, and the enzyme has been shown to induce plaque formation.

Modern Alzheimer's drugs typically target either acetylcholinesterase activity or plaque formation, but do not simultaneously inhibit both. "Therefore, they only have limited success in slowing the progression of the disease," says Gina Wilson, of Baldwin-Wallace College in Berea, Ohio. Wilson and her colleagues have discovered through the use of strictly chemical techniques in the absence of living cells that walnut extract and two of its major components, gallic and ellagic acids, act as "dual-inhibitors" of the enzyme acetylcholinesterase. Chemical techniques included enzyme kinetics and colorimetric analyses of congo red, a dye that binds to amyloid-ß aggregates. It was found that gallic and ellagic acids not only inhibit the site of acetylcholinesterase associated with amyloid-ß protein aggregation, but will also inhibit the site of acetylcholinesterase responsible for the breakdown of acetylcholine.

"Initially, we confirmed earlier results showing that walnut extract inhibits amyloid-ß protein aggregation in the presence of acetylcholinesterase and breaks apart preformed aggregates," says Wilson. "However, the new findings have not been presented elsewhere or replicated by other laboratories, to the best of our knowledge." Wilson's research is the first set of data to demonstrate inhibition of acetylcholine breakdown by walnut extract and to isolate specific chemicals from that extract, gallic and ellagic acids, responsible for the observed dual-inhibition. The research is the first to suggest that ellagic acid, and possibly gallic acid, can break up preformed aggregates.

While exact replications are needed, Wilson and her colleagues plan to extend their research to live animals. They plan to inject rats with an amyloid-ß protein fragments that will aggregate in their brains. Experimental animals will then be treated with either chemical. This will allow for measurements of brain acetylcholinesterase activity, plaque formation, and oxidative damage. Additionally, this procedure will provide comparisons of cognitive-behavioral data between treated and untreated groups.

Acetylcholine is a brain chemical particularly important for learning and memory. Levels of acetylcholine found in the brains of Alzheimer's patients are significantly depleted. However, this is not the sole event responsible for progression of the disease. Abnormal amyloid-ß proteins aggregate and form what are known as plaques, another key feature found in the brains of Alzheimer's sufferers. Amyloid-ß plaques have also been linked to the memory impairments and cognitive decline associated with the disease. Acetylcholinesterase is an integral part of these plaques and accelerates plaque formation.

"It is important," Wilson says, "to investigate 'dual-inhibitors' of acetylcholinesterase in efforts to develop more efficient pharmacological treatments for Alzheimer's disease."

Another avenue of research regarding a link between diet and the brain shows that blueberries contain compounds that can reduce inflammation in the central nervous system. Inflammation in the central nervous system is known to be a key issue in the progression of neurodegeneration, and dietary intake of blueberries has been shown to alleviate cognitive decline associated with disease and aging.

Thomas Kuhn, PhD, of the University of Alaska, Fairbanks, and his colleagues have discovered that Alaska wild bog blueberries contain compounds that efficiently interfere with inflammatory processes in the central nervous system.

The study conducted in Kuhn's lab revealed an interaction between compounds in Alaska blueberries and a specific protein molecule in neuronal cells that reduces detrimental effects of inflammation. Understanding the interaction of these compounds could lead to the development of new drug therapies that would diminish inflammation of the brain and spinal cord.

While the health benefits of fruits and vegetables are largely attributed to polyphenols, molecules with strong antioxidant potential, Kuhn says that, surprisingly, the compounds in Alaska blueberries discovered in their study are neither antioxidants nor polyphenols, yet rather serve as specific inhibitors.

Using a cell-based model of nueroinflammation, Kuhn's lab exposed neuronal cells to tumor necrosis factor alpha (TNFa), a pivotal factor mediating inflammation in the brain and spinal cord. Exposure of neuronal cells to TNFa rapidly stimulates a cascade of reactions, which ultimately leads to the death of neuronal cells. The application of Alaska blueberry extracts to neuronal cells effectively prevented the degeneration of neuronal cells exposed to TNFa.

"Expanding our knowledge of natural products' health benefits and their molecular targets in the nervous system would improve preventative measures and potentially reveal new therapeutic strategies to alleviate inflammation in the brain and spinal cord," says Kuhn. Inflammation in the brain and spinal cord accompanies most chronic degenerative diseases such as Alzheimer's, Parkinson's, ALS, or multiple sclerosis, or acute injuries including stroke and trauma. Moreover, inflammation is highly prevalent in psychiatric disorders such as depression and autism and in the normal aging process.

In other recent studies, Ron Mervis, PhD, of the Center for Aging and Brain Repair at the University of South Florida College of Medicine in Tampa, Fla., who collaborated with Joseph and Shukitt-Hale, has discovered that supplementing the diet of old rats with blueberries for a relatively short period (8 weeks), resulted in maintenance and rejuvenation of brain circuitry. These results, using a small amount of blueberry extract, two percent, to supplement a standard rat diet, are the first to show that a dietary intervention, specifically blueberries, can not only protect against the loss of dendritic branching and dendritic spines (e.g., synapses) seen in aged animals, but can result in neuroplastic enhancement of brain circuitry such that it looks like a much younger brain.

Mervis explains that age-related oxidation and inflammation in the brain can damage neurons. He notes that blueberries also contain various chemical compounds-flavonoids-which have strong antioxidant and anti-inflammatory activities.

"These benefits, along with other indirect mechanisms, may help to minimize, or reverse, the age-related breakdown of communication between neurons," says Mervis, "and optimize brain function in the old rat." A two percent blueberry extract is equivalent to a human having about half a cup of blueberries added to their daily diet.

The decrease in the amount of dendritic branching, or atrophy, of neurons and loss of synapses on the branches in the aging mammalian brain is correlated with memory loss and cognitive dysfunction. Dendrites, which receive and process incoming information from other neurons, comprise about 95 percent of the surface area of the cell, and the vast majority of the synapses are on dendritic spines. Therefore, Joseph says, "analysis of dendritic branching and dendritic spines can accurately reflect the integrity of brain circuits and neuronal communication."

Previous research showed that blueberry-enriched diets fed to aging rats reversed age-related declines in cognitive function. The current data show that a diet supplemented with blueberry extract should be able to protect against the loss of dendritic branching and dendritic spines-in other words, Joseph says, the blueberry supplement diet "would enhance the neuronal circuitry back to the status associated with a younger brain."

While these parameters have not been investigated in humans, it is known that individuals who consume a diet high in fruits and vegetables are less likely to develop some of the neurodegenerative diseases associated with aging and may not exhibit declines in motor and cognitive function that are as great as those seen in people whose consumption is less.