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We have all learned a great deal about how our diet can reduce risks associated with heart disease and cancer. This should come as no surprise. Those diseases have dominated our health concerns (and research) for much of the past half century. The dietary advice did not come as a complete surprise, either. It seems that our mothers were on the right track when they said, “Finish your fruits and vegetables. They’re good for you!” The same advice now appears almost daily in health reports.
Sometime in the 1980s, however, Americans began to turn their attention to the diseases of older age, especially Alzheimer’s. Certainly this attention was not to the exclusion of worries about the other killer diseases, but an afﬂiction that results in the inexorable destruction of the mind and personality—and doubles in incidence with every decade of life after our 50s—did arrest our attention. Alzheimer’s, like many of the gravest diseases of old age, is a brain disease that entails a gradual failure that we term neurodegeneration. Will diet turn out to be part of the explanation? Until very recently, scientists had barely asked that question, and, apart from the effects of certain vitamin deﬁciencies, we had known little about the possible role of nutrition in preventing neurodegenerative illnesses.
The ﬁrst question we must ask is why the aging human brain is apparently such fertile ground for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Even in normal, non-diseased brains, we can observe with aging a gradual decrease in communication among neurons. The micronutrients, such as vitamins, that research has shown to be crucial in prenatal and postnatal brain development do little to prevent the deleterious effects of aging—or the incidence of neurodegenerative diseases. What, then, stokes the ﬁres of aging in the brain? And can nutrition help to quench them?
The Age Connection
Asked to characterize an old person, many of us would mention (in addition to gray hair and wrinkles) difﬁculty in moving or in remembering things. Research shows that, on average, we undergo considerable declines in both motor and cognitive function as we age. Changes in motor function can include decreases in balance, muscle strength, and coordination, whereas cognitive declines are observed in tasks that require, for example, the use of spatial learning and memory. Both types of deﬁcits occur in animals as well as in humans.
Age-related deﬁcits in both movement and spatial orientation seem to result from alterations in an area of the brain known as the striatum, which exhibits profound neurodegenerative changes with age, including alterations in the important chemical messenger (or neurotransmitter) dopamine. The striatum’s receptor cells for dopamine and another neurotransmitter, muscarine, appear to be especially vulnerable and develop a loss of sensitivity to stimulation. Similarly, the cerebellum, another of the brain’s movement-control areas, shows alterations in both structure and function, as well as changes in norepinephrine receptors, as we age. When we turn to memory deﬁcits of aging, they appear to occur primarily in secondary memory systems, the ones that store newly acquired information. Among these areas, for example, the brain’s hippocampus probably mediates our learning about place, and the prefrontal cortex is critical to acquiring the rules that govern performance on particular tasks.
Until recently, many studies had suggested that these age-related deﬁcits might result from loss of neuronal cells in the aged brain. But more recent and sophisticated cell-counting techniques (called “unbiased stereology”) have revealed that there is actually very little loss of brain cells in the cerebellum or striatum, or elsewhere, as a function of aging alone. Of course, such losses are seen in diseases such as Alzheimer’s and Parkinson’s.
But if, in normal aging, cells are not being lost in areas that mediate motor and memory function, what might be responsible for the alterations? Research over the past several years points to two possible factors:
- losses of sensitivity in the receptors for neurotransmitters and their associated second messengers (molecules that help move the signal further along into the neuron) and resulting declines in calcium activation, and
- alterations in complicated age- and calcium-sensitive signaling agents associated with memory, especially with converting short-term memories to long-term memories.
To simplify what might be going on here, we could say that old neurons, like some long-married couples, do not talk to each other as much anymore—some communication is lost. These deﬁcits in neuronal communication could result, in turn, in declines in motor and cognitive competence. Think of this as trying to make a call on your cell phone. The phone illuminates, you dial the number, but you receive a message that says “call failed.” The fault probably does not lie with your phone but with the ability to communicate the signal to a tower, to a satellite, and so on until the signal reaches the next phone. If there is a defect in any part of the “signaling pathway,” the call fails. Think of the recent TV commercial showing someone moving around and asking repeatedly, “Can you hear me now?” This happens innumerable times in the older brain.
Oxidative Stress and Inflammation
To explore the possible causes of these pervasive losses of neuronal signaling and the resulting behavior problems in aging individuals, we must begin more than half a century ago. In the 1950s, Denham Harmon, M.D., theorized that we age because of an increasing inability to protect against damage from very reactive molecules called free radicals. Free radicals are formed from sunlight, metabolizing food, air pollution, radiation, and numerous other sources. They are a bit like a large, friendly dog with muddy paws that wants to bond with you, except that you are wearing a white suit that will be ruined by the contact. Free radicals always want to bond with our membranes and other tissues, but in doing so will damage them. The damage, which is called “oxidative stress,” can be observed externally in signs of aging such as wrinkles and cataracts.
For much of our lives, we are well protected against the ravages of oxidative stress, but, as we age, both protection and repair are reduced, even as our sensitivity to the insult increases. Brain tissue taken from aged animals is more sensitive to the application of oxidative stressors than similar tissue taken from young animals. Studies have indicated that the brain can be particularly vulnerable to oxidative stress, because the brain at rest uses 10 percent of the body’s oxygen and during mental activity up to 50 percent.
As though that were not bad enough, oxidative stress has an evil twin: inﬂammation. Recent evidence suggests that inﬂammation in the central nervous system also plays an important role in aging. By middle age, indicators of inﬂammation have already increased in the brain. In older age, an inﬂammatory agent called tumor necrosis factor alpha (TNF) is produced in higher amounts than are seen in younger brains. Other studies report increases in TNF and a second inﬂammatory agent, interleukin-6 (IL-6), in aged mice and humans. In fact, it has been suggested that a process known as the up-regulation of C-reactive protein, which is associated with increased inﬂammatory activity in the cardiovascular system, might be one factor in biologic aging. This protein has been implicated in heart disease, and it appears that heart disease and Alzheimer’s disease can occur in concert in aged individuals, with the cardiovascular disease exacerbating the cognitive dysfunction of Alzheimer’s.
We have dwelt on some technicalities of oxidative stress because it appears to be of paramount importance in Alzheimer’s disease, where several studies have shown increased oxidative stress and damage to proteins. The prevailing view is that amyloid beta—a peptide that is responsible for producing one of the hallmarks of the Alzheimer’s brain, neuritic plaques—is capable of causing oxygen radical formation, thus inducing oxidative stress and leading ultimately to cell death. But now a complication enters the picture: It appears that oxidative stress could also happen before the development of neuritic plaques in the Alzheimer’s brain. Investigation of the sources of oxidative stress, and in what order they appear in Alzheimer’s disease, continues apace.
Another parallel with discoveries about oxidative stress is the increased sensitivity to inﬂammation as we age. Studies show, for example, that old rats are more sensitive to brain injuries caused by neurotoxins that increase mediators of inﬂammation such as cytokines (an effect found in the hippocampus). The effects of such increases in inﬂammatory reactions might act in concert with oxidative stress to initiate declines in neuronal function or declines in interactions between neurons and other brain cells. Like oxidative stress, inﬂammation seems to intensify the pathogenic processes that give rise to Alzheimer’s disease.
The Fire that Cooks the Soup
An old tale tells of hungry soldiers who entered a village, foraging for food. After asking several villagers for handouts and being turned down, the soldiers conceived a plan. At the center of the village they made a ﬁre and began to heat a large kettle with stones and water. The curious villagers soon approached and asked what they were doing. The solders told them that they were making stone soup. It was delicious, they told one fascinated villager, but it would be even better with some potatoes in it. The villager ran to get potatoes to put into the soup. The soldiers told another curious villager that the soup would be much better with carrots, which the villager ran to fetch. Soon the soldiers had a pot of vegetable soup.
In a similar manner, we have been told that amyloid beta is both necessary and sufﬁcient for the development of Alzheimer’s disease (the stones, as it were). It appears, however, that amyloid beta is but one ingredient in this “soup.” Other, genetic factors (such as abnormal processing of a protein called tau that produces the characteristic tangles seen in the brains of AD patients) and increases in indicators of oxidative stress and inﬂammation all suggest that—like the soup made by the soldiers but with vegetables from the villagers—multiple factors contribute to this disease. Not the least of these contributors is aging, which provides the environment in which the other factors are expressed or “cooked.”
Although the moral of the stone soup story usually has to do with cooperation and the importance of each individual contribution, without the ﬁre, even with all of the ingredients present, the soldiers would have been eating cold soup or cold water with vegetables. In our present example, aging is the ﬁre. Although inﬂammation and oxidative stress are important ingredients, aging provides the major impetus for development of a variety of conditions, from diabetes and cardiovascular disease to cancer and age-related neurodegenerative diseases. Obviously, it would be prudent to seek ways to quench the ﬁres of aging, since without that ﬁre the aberrant genes will not be able to initiate the neurodegenerative processes.
Can We Quench the Fire with Supplements?
One approach to protecting or improving brain functioning might be to alter the environment in which neurons exist by reducing the effect of oxidative and inﬂammatory stressors. One way to accomplish this reduction is by changes in what we eat. The diet we have come to associate with healthy aging (a diet that emphasizes fruits and vegetables and is low in saturated fats from red meat and other sources) has already been shown to reduce the risk of developing diseases such as diabetes that involve oxidative stress and inﬂammation. Many people now take anti-oxidant supplements, including vitamins E and C and ginkgo biloba. A detailed review of these dietary supplements is beyond the scope of this article, but a few of them stand out with regard to their potential beneﬁts for the aging brain.
One widely studied antioxidant with respect to brain aging is vitamin E. Results have been mixed. It appears that vitamin E does play a beneﬁcial role in the maintenance of good health, and studies have demonstrated that vitamin E deﬁciency leads to increased levels of brain damage from oxidative stress. In one study, for example, Harbans Lal, Ph.D., and colleagues at the University of North Texas chronically deprived both young and aged rats of vitamin E to induce nutrition-related characteristics of central nervous system aging. Vitamin E-deﬁcient animals had higher levels of lipofuscin (known as the “age pigment”) and an indicator of oxidative stress in the hippocampus than did rats of the same age that had sufﬁcient vitamin E, suggesting that the effects of vitamin E deﬁciency were additive to the effects of aging alone. Another study of vitamin E deﬁciency showed increased evidence of oxidative stress, and brain tissue taken from the affected animals was more sensitive to the induction of oxidative stress.
If a deﬁciency of vitamin E hurts, does supplementation help? Apparently so. Vitamin E supplements have been associated with a reduction in oxidative stress. For example, hypoxia (depriving cells of oxygen) can increase the levels of oxidative injury in animals, but studies show that supplements reduce this effect. Interestingly, it also appears that vitamin E supplements offer some protection against inﬂammation, because reductions were observed in an inﬂammatory marker, interleukin-1 beta (Il-1), in cortical tissue from young and aged rats that received these supplements. More importantly, it appears that to some extent these beneﬁcial effects of vitamin E translate into beneﬁts for motor and cognitive functions, helping to prevent their decline with age. Because the studies found beneﬁcial effects of vitamin E supplements at all ages and in patients with neurodegenerative disease, they are encouraging, but there is still a great deal we simply do not know, such as the optimal source, dose, and age to initiate supplementation.
Although vitamin C has been studied for many years, there is still no agreement on a minimum daily requirement. What we do know is that vitamin C seems to have beneﬁts for cognitive function in aging, beneﬁts that might depend on its ability to protect blood vessels, presumably through its antioxidant effects. As we know, the blood vessels are involved in diseases such as Alzheimer’s, and studies have shown that cognitive performance in the elderly might be affected by vitamin C. For example, M.
Paleologos, M.D., and associates from the University of New South Wales demonstrated that, after adjusting for factors such as age, sex, smoking, and education, the consumption of vitamin C supplements was inversely related to cognitive impairment assessed with the Mini Mental State Examination. The higher the consumption of vitamin C, the lower the cognitive impairment.
Other studies have shown that vitamin C can protect against cognitive impairment both directly and through the prevention of cerebrovascular disease and stroke. In addition, it has been postulated that vitamin C can work directly in the brain by improving the degradation of modiﬁed proteins. In other words, vitamin C may enable the brain to eliminate these damaged or modiﬁed proteins.
Ginkgo biloba is an herbal supplement made from leaves of the ginkgo tree. Unlike single antioxidants, such as vitamin C, it is a mixture of complicated compounds called ﬂavonoids and terpenes, which can be powerful antioxidants and anti-inﬂammatory agents. Ginkgo biloba has been shown to block the effects of exposure to oxidative stress-inducing agents in several types of neurons in laboratory cultures. In addition, an abundance of experiments in both animals and humans show that the standard formulation of ginkgo biloba, called Egb 761, improves aspects of cognitive function in aging. It might have some positive effects in Alzheimer’s disease, but results of studies thus far have been mixed. In one controlled study, which examined ginkgo biloba’s effects on Alzheimer’s-type dementia, a three-month treatment seemed to yield signiﬁcant improvement in some measures of cognitive function but not in others.
One possible pivotal discovery was made in several studies: When only some components were used (for example, only the ﬂavonoids), protection against oxidative stress was signiﬁcantly reduced. Could this ﬁnding point to a more general conclusion: that stronger effects are achieved when the antioxidants in our diet are combined? But if so, what foods, and in what combination?
Diet for an Aging Brain
Recent research suggests that the right ingredients for these higher-effect combinations are found in fruits and vegetables. In other words, what might be beneﬁcial for your heart also might help your brain. Plants, including those that we use as food, synthesize a vast array of chemical compounds not involved in the plant’s own primary metabolism. These so-called “secondary compounds” serve several functions that ultimately enhance the plant’s survival, and research suggests that they might be responsible for the many beneﬁcial effects of fruits and vegetables on our biologic activities. Antioxidant and anti-inﬂammatory effects are two of the most important.
One type of these naturally occurring substances is called polyphenolic compounds, which are found in many fruits and vegetables. We are learning that these compounds can affect neuronal communication directly, enabling neurons to “talk to each other” more effectively. This process might be critical to the positive effects of antioxidants on cognitive and motor behavior.
Scientists have known for some time how diet affects cognitive function in the developing brain, but new research indicates signiﬁcant, positive correlations between a higher intake of fruits and vegetables by older adults and their scores on tests of cognitive ability. At ﬁrst, scientists explained these correlations by saying that the vitamins in fruits and vegetables might provide protective antioxidants. Now, however, researchers have established that the polyphenolic compounds in those foods contribute substantially to overall dietary intake of antioxidants but have other beneﬁts, as well. Upward of 4,000 polyphenolic compounds are widely found in fruits, vegetables, nuts, seeds, and grains. Some have antioxidant, anti-allergic, anti-inﬂammatory, antiviral, antiproliferative (prevents cell proliferation) or anticarcinogenic effects.
ORAC can serve as one guide to which foods you might want to include in your diet. If an ORAC source is unavailable, you can “let color be your guide,” since many of the foods that have a great deal of color are also very high in antioxidant activity.
But how do you choose? If you are standing in a supermarket produce section, how do you tell which of the myriad fruits and vegetables will optimize health? Seeking an answer, at least with respect to antioxidant activity, Guohua Cao and Richard Cutler developed a procedure called the oxygen radical absorbance capacity (ORAC) assay. By using this procedure, one can ascertain the total antioxidant activity of any fruit or vegetable. A few years later, Ronald Prior, Ph.D., along with Cao, automated the procedure and began testing various vegetables, fruits, and fruit juices. The ORAC rankings of berries such as blueberries, cranberries (a botanical “cousin” of the blueberry), and strawberries were among the highest, while apples and bananas were among the lowest. As with most tests, however, this one alone does not bequeath “goodness” or “badness” on a particular fruit or vegetable. Apples, for example, while low in ORAC, appear to have potent anticarcinogenic properties. Nonetheless, ORAC scores, as shown in the chart on the following page, can serve as one guide to which foods you might want to include in your diet. If an ORAC score is unavailable, you can “let color be your guide,” since many of the foods that have a great deal of color are also very high in antioxidant activity. In that case, do not forget that white—for example, of garlic and onions—is also a color.
We will focus on the effects of blueberries on the brain, because some of the discoveries are very promising. But as our knowledge grows, it is quite likely that many other compounds in fruits, vegetables, and other foods will reveal important secrets for health.
The Prodigious Blueberry
Armed with ORAC rankings, our laboratory at Tufts University tested the effects on aged rats (19 months old) of eight weeks of dietary supplementation with extracts of two of the fruits highest in ORAC: blueberries and strawberries. Nineteen months is elderly for a rat, so when the supplements were started, the rats were already showing deﬁcits in both cognitive and motor behaviors. The experimental group received extracts that amounted to about 2 percent of their diet, which is equivalent to an adult human eating a pint of strawberries or a cup of blueberries a day. Age-matched rats in the control group received no special supplements. We discovered that the supplemented diet was effective in reversing age-related deﬁcits on several measurements of types of neuronal and cognitive behavioral activity. Most striking, however, was that the blueberry-supplemented diet—but not the strawberry-supplemented diet—also improved performance on two tests of motor behavior.
Because this study fed the rats the blueberry supplements as part of a puriﬁed, deﬁned diet, and because we know that no one regularly eats such a diet, a second study looked at effects of blueberry supplements as part of a diet of natural ingredients. The same beneﬁts for motor and cognitive function were achieved, and we also discovered that both wild and cultivated blueberries produced similar beneﬁts.
What accounts for these remarkable effects? When the brain tissue of the rats was examined for indications of levels of oxidative stress, the animals fed the supplements had signiﬁcantly lower levels of indicators than did control animals. On further examination, though, the magnitude of this difference seemed insufﬁcient to account for the remarkable behavioral effects that we saw in the blueberry-supplemented animals. We have since ascertained that the brain tissue of the blueberry-supplemented animals showed greater protection against both oxidative and inﬂammatory stressors.
As exciting as were these discoveries, it was apparent that the antioxidant/antiinﬂammatory protection offered by fruit and vegetable extracts was only the tip of the proverbial iceberg. To yield the surprising reversals in motor and cognitive deﬁcits that we observed in the animals, it seemed that there would have to be other beneﬁts being provided by the supplements, especially those containing the blueberries—beneﬁts that were acting in concert with the antioxidant and anti-inﬂammatory effects. So we next wanted to ﬁnd out if it was the myriad interactions among the various phytochemicals present in the blueberries that were directly affecting the behavior of the aged animals. This hunch now appears to be true.
In a recent experiment, we showed that the larger the number (not the absolute quantities, which are too small to assess at this point) of phytochemicals called anthocyanins that were found in the cortex of animals that received the blueberry supplements, the fewer errors these animals made on a cognitive performance test using a maze. Anthocyanins (from the Greek words anthos, “ﬂower,” and kyanos, “dark blue”) are a particular class of phytochemicals found throughout the plant kingdom: for example, in foods such as cherries, plums, red currants, blueberries, and strawberries. Anthocyanins are what make roses red and violets blue. There are more than 300 of these pigments, 70 of which are found in fruits—and as many as 40 in blueberries. Assuming that at least some anthocyanins can enter the brain, what could they be doing there (in addition to their antioxidant and anti-inﬂammatory effects) that would enhance the behaviors that we observed?
The answer brings us back to the changes in neuronal communication, reviewed earlier, that may be occurring in the aged brain. We know that neurotransmitter receptors lose their sensitivity to stimulation as we age. This loss is both a central effect (occurring in the brain’s striatum) and a peripheral effect (occurring in organs such as the heart). In the studies described earlier, the old rats that were fed the blueberry-supplemented diet showed enhancements in two important areas that provide further clues to the link between the supplemented diet and the beneﬁts we observed. The ﬁrst clue was an increased sensitivity in a particular kind of receptor in the striatum called the muscarinic receptor. These receptors play a key role in mediating motor and cognitive behavior, in aspects of blood ﬂow, and in processing something called the amyloid precursor protein, which is important in regulating the formation of amyloid beta peptide in Alzheimer’s disease. It also appears that blueberry supplements increased the coupling and uncoupling of the muscarinic receptor to a regulatory protein called a G protein, a process that shows declines in both aging and Alzheimer’s disease.
The second enhancement found in the rats on the blueberry-supplemented diet was improved transport of calcium. Calcium transport in neurons is critical to their functioning, and with age neurons from areas such as the hippocampus lose their ability to clear or buffer calcium after stimulation. We can, therefore, see how, by improving both calcium transport and the functioning of the muscarinic receptors, blueberry supplements can actually increase neuronal communication directly.
Diet and Alzheimer’s Disease
More evidence for an increase in neuronal communication comes from a recent study in which we used mice bred to be models of human Alzheimer’s disease. These animals have genetic mutations that promote production of amyloid beta and, therefore, the hallmark plaques seen in the brains of Alzheimer’s patients. Beginning at four months of age, the mice were given supplements of blueberry extract for eight months, just as we had done earlier with the old rats. At 12 months of age, the mice were tested for their performance in a maze. Those mice that received the supplements responded as well as the controls (mice without Alzheimer’s), and much better then the “Alzheimer’s” mice fed the normal diet. Examination of the brains of the mice revealed no differences between the supplemented and non-supplemented Alzheimer’s mice in the number of plaques. What we seemed to be seeing was a dichotomy between plaque density and behavior, since the behavior did not decline in the blueberry-supplemented mutant mice but did show decrements in the mutant mice maintained on the control diet. As pointed out earlier, amyloid beta-induced plaques are only one aspect of Alzheimer’s disease, not a necessary and sufﬁcient condition for the loss of cognitive function.
Further analyses revealed that the blueberry supplements had enhanced neuronal communication in the brains of the Alzheimer’s-model mice by increasing the activity of a family of molecules (called MAP kinases) involved in signaling pathways in learning and memory, especially conversion of short-term to long-term memory. The interesting discovery is that blueberry supplements seemed to enhance not only the activities of those kinases but also the signaling in certain receptors. This enhancement might be what contributed to the effects on behavior that were observed: that is, that the Alzheimer’s-model mice showed no worse cognitive effects of aging than did the control, non-Alzheimer mice.
One other aspect of communication in the brain seemed to be affected by blueberry supplements: neuronal plasticity. Dramatic experiments by Fred Gage, Ph.D., and his colleagues at the Salk Institute for Biological Studies have shown that the brain continues to make new neurons (a process called neurogenesis) even into old age, but, as we might have suspected, at a much slower rate. Experiments in our laboratory by Gemma Casadesus, Ph.D., suggested that old animals receiving blueberry supplements exhibited increased neurogenesis in the brain’s dentate gyrus (a memory-control area). These increases in neurogenesis appear to translate into fewer errors on maze tests of cognition.
More is going on here than we yet understand. It would be reasonable to speculate that the antioxidant/anti-inﬂammatory activities of blueberries (and other foods) enable the brain cells to function more efﬁciently, accounting for increases in neuronal signaling (communication), but blueberries also improve behavior in young animals in which, presumably, natural oxidant/inﬂammatory protection mechanisms are still at peak efﬁciency.
Coming Full Circle
Experiments suggesting that certain fruits and vegetables can affect signaling and neuronal communication—directly and powerfully— give us reason for the ﬁrst time to hope that as we age nutrition may be useful for more than preventing disorders associated with malnutrition or building up the enfeebled to withstand surgery. A readily accessible diet effective in boosting neuronal function could give all of us more control over how our brains deal with the changes of aging. Diet might even become our ally in resisting the ravages of Alzheimer’s and Parkinson’s diseases, making existing conventional treatments more effective.
Do we stand on the threshold of an entirely new way of thinking about nutrition and the health of the aging brain? Consider that we know from very early books of the Bible that people were exhorted to include in their diets items such as leeks, garlic, pomegranates, wine, and nuts. All have potent antioxidant/anti-inﬂammatory activities, and, for those containing polyphenolics, possible beneﬁts for signaling processes in the brain.
There is a joke now circulating at conferences of scientists who study nutrition. Its author is unknown:
The “New” Millennium
2000 BC: “Here, eat this root.”
1000 BC: “That root is heathen. Here, say this prayer.”
1850 AD: “That prayer is superstition. Here, drink this potion.”
1940 AD: “That potion is snake oil. Here, swallow this pill.”
1985 AD: “That pill is ineffective. Here take this antibiotic.”
2004 AD: “That antibiotic doesn’t work anymore. Here, eat this root.”