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When it comes to brain protection, there is nothing quite like blueberries,” according to James Joseph, PhD, lead scientist in the Laboratory of Neuroscience at the USDA Human Nutrition Research Center on Aging at Tufts University. “Call the blueberry the brain berry,” says Dr. Joseph.1

Dr. Joseph’s claim was made with the publication of his landmark blueberry research. It has since been bolstered by animal studies demonstrating that daily consumption of modest amounts of blueberries dramatically slows impairments in memory and motor coordination that normally accompany aging. Moreover, a wealth of exciting new research clearly establishes that in addition to promoting brain health, this long-prized native North American fruit—whether consumed fresh, frozen, canned, or as an extract—may confer a range of diverse health benefits.

After testing 24 varieties of fresh fruit, 23 vegetables, 16 herbs and spices, 10 different nuts, and 4 dried fruits, the US Department of Agriculture determined that blueberries scored highest overall in total antioxidant capacity per serving. As most health-conscious adults are aware by now, antioxidants are vital in countering free radicals, the harmful byproducts of cellular metabolism that can contribute to cancer and other age-related diseases.2

Separate studies show that blueberries may help to lower blood cholesterol,3 promote urinary tract health, and reduce the risk of urinary infections.4,5 Studies in Europe have documented the relationship between consumption of bilberries (the blueberry’s close European cousin) and eye health, highlighting the berries’ ability to improve night vision, halt cataract progression, and protect against glaucoma.6 New studies also support blueberries’ ability to reduce age-associated lipid peroxidation,7 a contributor to cardiovascular disease, and to suppress the growth of several types of cancer cells,8,9 suggesting that blueberry phytochemicals may well play a future role in human cancer treatment. And you can add to the manifold health benefits of blueberries at least one more reason to eat them daily: virtually everyone agrees that they are delicious.

When the Plymouth colonists arrived in what is now Massachusetts, native American inhabitants shared with them the blue-tinged fruit of a low woody shrub whose calyx forms a delicate five-point star. For centuries, native American cultures had consumed “star berries” not only as food but also as medicine, drinking blueberry juice to relieve coughs, brewing a tea from blueberry leaves as a tonic, and eating fresh, dried berries to sharpen their vision.10

Blueberries and bilberries belong to the genus Vaccinium, which includes more than 450 plants grown in all parts of the world. Members of the Vaccinium genus possessing the darkest-colored fruits appear to provide the greatest health benefits, a fact that scientists attribute to the compounds that give the plants their dark pigmentation. These bioflavonoids include anthocyanins and their precursor, proanthocyanidins, both of which are voracious scavengers of free radicals.11,12 Research demonstrates that blueberry consumption boosts serum antioxidant status in humans.13 Elevated antioxidant levels in the body may protect against damage to cells and cellular components, thus helping to reduce the risk of many chronic degenerative diseases.13

How Blueberries Combat Brain Aging

In Dr. Joseph’s groundbreaking work at Tufts, 19-month-old laboratory rats—the equivalent of 60- to 65-year-old humans—were fed dried blueberry extract at a dose the investigators calibrated to be the human equivalent of one-half cup of blueberries per day. Three other groups of rats received spinach extract, strawberry extract, or a control diet. After eight weeks on the regimen, the investigators evaluated the rats—now equivalent in age to 70- to 75-year-old humans—using various tests of memory function.

Compared to a control group fed only a standardized diet, each of the three supplemented groups performed at least marginally better on memory and learning tests.14 In tests of neuromotor function, however, the blueberry-fed rats significantly outperformed the other groups. These rats were much better able to walk the length of a narrow rod and balance on an accelerating rotating rod compared to the other groups. This was indeed a stunning finding, as scientists have for some time tended to accept as established fact that age-related neuromotor dysfunction is irreversible. Dr. Joseph’s findings appear to flatly contradict this notion. Blueberry extract, he discovered, was clearly capable of reversing this particular aging process as no other agent had ever been demonstrated to do. Dr. Joseph concluded:

“This is the first study that has shown that dietary supplementation with fruit and vegetable extracts that are high in phyto-nutrient antioxidants can actually reverse some of the aging-relatedneuronal/behavioral dysfunction.” 14

Dr. Joseph’s blueberry-supplemented rats also demonstrated improved learning and memory skills as they navigated mazes and found—and then remembered—the location of an underwater platform on which they could rest from swimming. When Dr. Joseph and his colleagues examined the brain tissues of these rats in vitro, they found that dopamine levels were much higher than in the brains of rats in the other groups. Dopamine is an essential neurotransmitter that enables smooth, controlled movements as well as efficient memory, attention, and problem-solving function. Dr. Joseph speculated that blueberry extract might also increase brain cell membrane fluidity while reducing levels of inflammatory compounds, thus slowing the brain’s normal aging process.14

To other researchers, Dr. Joseph’s study seemed especially promising in its implications for aging humans. Older adults tend to fall or stumble—sometimes with catastrophic consequences—because their brains become less adept at monitoring and modulating swaying motion, as conduction of neural signals in the brain slows with aging. Older people likewise tend to suffer memory loss and an inability to learn new behaviors in ways that can starkly limit their ability to lead productive, satisfying lives. “People are told once you’re old, there’s nothing you can do,” noted Dr. Joseph’s colleague and study coauthor Dr. Barbara Shukitt-Hale. “That might not be true.”15

New Studies Confirm Brain Benefits

Dr. Joseph’s findings not only spurred scientific research into the health properties of blueberries, but also greatly increased public awareness of this remarkable fruit. Five important new studies support and expand on Dr. Joseph’s original research.

In a 2005 article published in the journal Neurobiology of Aging, Rachel Galli and her colleagues, also based at Tufts, reported discovering a specific mechanism by which blueberries help reverse the neurological aging process.16 The Galli study—which included Drs. Joseph and Shukitt-Hale as co-investigators—sought to measure the heat-shock protein response in the brains of both young and aged rats supplemented with blueberry extract compared to a control group of aged rats. A protective mechanism produced in the brains of most animals (and humans), heat-shock proteins fight free radicals and inflammation-inducing agents, acting similarly to antioxidants to support healthy brain tissues. As people age, however, their ability to generate heat-shock proteins in sufficient quantity declines,17 sometimes dramatically. The Tufts researchers sought to determine whether blueberries could help restore the heat-shock protein response in rats.16

After 10 weeks, the scientists subjected brain tissues from the rats to an inflammatory challenge and then measured the subsequent heat-shock protein response. As presumed, the brains of young rats that had consumed blueberries produced a strong heat-shock protein response, unlike the brains of the aged rats that did not consume blueberry extract. The significant finding, however, was that the brains of aged rats fed blueberries were as successful at initiating the heat-shock protein response as the brains of young rats. The blueberry extract proved capable of entirely restoring the heat-shock protein response in the test animals, suggesting that blueberries may protect against neurodegenerative processes associated with aging.16

Last year, the journal Nutritional Neuroscience published an important new study by scientists at the University of Barcelona. The Spanish researchers previously had demonstrated blueberries’ effectiveness in reversing age-related deficits in neuronal signaling. They now sought to determine whether the active phytochemicals that give blueberries their significant neurological benefits do indeed cross the blood-brain barrier. Examining the brains of rats that had been fed blueberry extract for 10 weeks, they were able to isolate blueberry-specific agents in the rats’ cerebellum, cortex, hippocampus, and striatum—brain areas that control memory and learning processes. Most striking, the scientists were able to correlate the presence of blueberry phytochemicals in the rat brain cortices they examined with improved cognitive performance in tests initiated at the end of the 10-week supplementation period.18

Blueberries may also prove capable of helping humans whose brains have been damaged by a loss of blood flow and the critical oxygen and nutrients it provides, a condition known as ischemia (one of the two principal causes of stroke). In a May 2005 study published in the journal Experimental Neurology, researchers documented how three groups of rats whose diets were supplemented with blueberries, spinach, and spirulina, respectively, all suffered less brain cell loss and were better able to recover lost function following artificially induced ischemia than rats in a non-supplemented control group. At autopsy, the scientists observed that the physical extent of ischemic damage to the brains of rats that had been fed the three supplements was significantly less than that suffered by the control group.19

Similarly, the Tufts scientists who have been in the forefront of blueberry research reported an additional study in the August 2005 issue of Neurobiology of Aging. In this study, they demonstrated that the auditory processing speed of aged rats supplemented with blueberries nearly matched the lightning-fast auditory processing speeds of young rats, while the speeds of a control group of non-supplemented aged rats were dramatically slower. According to the researchers, “These results suggest that the age-related changes in temporal processing speed in [the primary auditory cortex] may be reversed by dietary supplementation of blueberry phytochemicals.”20

Another recent study suggests that blueberries may have applications in the developing field of neural transplants, which many neuroscientists believe hold promise as a means of replacing vital brain structures destroyed or damaged by brain injury or degenerative disease. Unfortunately, the survival of transplanted tissue is often poor, especially in older recipients. When researchers gave blueberry supplements to middle-aged rats receiving neural implants, the growth of their hippocampal grafts was markedly more vigorous than that of identical grafts in a control group, and cellular organization was comparable to that in tissue grafted into young laboratory animals. Blueberries may someday play an important role in ensuring that surgically grafted tissues thrive in the new host, where they may help to restore lost motor and cognitive functions.21

Benefits for Other Body Systems

Blueberries’ benefits for neurological health and vigor are so well established as to make daily consumption of the fruit a “no-brainer” for virtually everyone. Moreover, new studies continue to confirm blueberries’ remarkable health-promoting effects in other areas of the human body.

For decades, researchers in Europe have documented evidence of the ability of bilberries to combat a range of eye disorders. During World War II, French researchers who examined bilberry extract’s effects in pilots found that bilberry helped improve nighttime visual acuity, adjustment to darkness, and recovery from glare.6 In another study, all eight patients with glaucoma who were given a single oral dose of bilberry extract demonstrated improvements based on electroretinography, a measure of electrical responsiveness of the retinal cells. Bilberry’s antioxidant properties may protect against glaucoma by supporting healthy intraocular pressure.6 In a clinical study, the combination of bilberry extract with vitamin E stopped the formation of senile cortical cataracts in 48 of 50 patients.6 Researchers believe that the anthocyanins and proanthocyanidins found in blueberries might similarly offer benefits for eye health.

In an article in the Journal of Agricultural and Food Chemistry in 2004, researchers announced that they had isolated three compounds in blueberries and other dark-pigmented berries known to lower cholesterol levels.22 In a follow-up study, one of the three phytochemicals—pterostilbene—showed a particularly potent effect in stimulating a receptor protein in cells that plays an important role in lowering cholesterol and other blood fats.3 “We are excited to learn that blueberries, which are already known to be rich in healthy compounds, may also be a potent weapon in the battle against obesity and heart disease,” lead author Agnes Rimando told members of the American Chemical Society.3,22,23

Blueberry juice or extract may help avert urinary tract infections commonly suffered by women. Scientists formerly hypothesized that dark-pigmented berries such as cranberry help fight infection through an antibacterial effect caused by the acidification of urine.4 Current research suggests that berries, including cranberry and blueberry, may fight bacterial urinary infections by preventing E. coli and other forms of bacteria from adhering to cells lining the walls of the urinary tract.4,5

Blueberries also may slow the growth of cancer cells. In 2001, University of Mississippi researchers conducting in-vitro tests found that blueberry and strawberry extracts were remarkably successful in slowing the growth of two aggressive cervical cancer cell lines and two fast-replicating breast cancer cell lines, with the blueberry extract performing best against the cervical cancer cells.8 Last year, a University of Georgia study similarly demonstrated blueberry extract’s ability to inhibit cell proliferation in two separate lines of colon cancer cells, reducing by more than 50% the rate at which the cells otherwise multiplied.9 Further studies are indicated to determine whether phytochemicals from dark-pigmented berries may affect very early growth of malignant cells in the bodies of humans as well.

NEW FINDINGS ON BLUEBERRIES

New research reported in peer-reviewed journals by scientists around the world confirms the wide range of health benefits attributed to blueberries, while pointing to promising new therapeutic applications:

• In a study published in the journal Nutritional Neuroscience,24 a blueberry-supplemented diet was found to greatly enhance the spatial memory of laboratory animals. When later studied in vitro, the animals’ brains demonstrated structural changes associated with an improved capacity for learning. Researchers believe the two findings are directly correlated.

• In a study reported in the Journal of Agricultural and Food Chemistry, cold-pressed blueberry, Marionberry, boysenberry, and red raspberry seed oils were evaluated for their fatty acid composition. The oils were found to contain antioxidants with a high capacity to absorb oxygen radicals, and were deemed potent sources of tocopherols, carotenoids, and natural antioxidants.25

• The Journal of Medicinal Food reported that in an in-vitro study of aortic tissue of young rats, wild blueberries incorporated in the diet positively affect the plasticity of vascular smooth muscle, but have no deleterious effect on membrane sensitivity. This finding suggests that blueberries may have applications in helping prevent heart disease and stroke in humans.26

• In a similar study published in the Journal of Nutritional Biochemistry, researchers demonstrated that in rat aortic tissue, compounds from berry extracts caused cell changes that may affect cellular signal transduction pathways and contribute to improved cardiovascular health.27

• Research published in the journal Neurobiology of Aging showed that nutritional antioxidants found in blueberries can reverse age-related declines in neuronal signal transduction as well as cognitive and motor deficits. The investigators speculated that blueberry supplementation may also help slow declines in brain function that accompany diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease.28

• In an in-vitro study published in Biochemistry and Cell Biology, 24 hours of exposure to extracts of blueberry antioxidants sharply reduced the production of matrix metalloproteinases—enzymes believed to play key roles in malignant tissue metastasis—in human prostate cancer cells. This led the researchers to postulate that blueberry supplementation may help prevent tumor metastasis.29

Conclusion

Although no studies to date have compared the relative efficacy of fresh blueberries versus frozen berries, canned berries, or berry extracts, each form of the fruit has been shown to contain the essential anthocyanins and proanthocyanidins that make blueberries one of the most exciting nutraceuticals being researched and consumed today. Blueberry extracts have the advantage of delivering the fruit’s phytochemicals in a simple, standardized dose, while consuming blueberries as food offers the benefit of flavor.

Regardless of how they are consumed, blueberries should be considered a mainstay of every healthy diet. This remarkable fruit, known for centuries for its medicinal properties, continues to prove itself in research laboratories around the world, demonstrating a wide array of dramatic, health-enhancing benefits.

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ld blueberries are a rich source of phytochemicals called polyphenols, which have been reported by a growing number of studies to exert a wide array of protective health benefits. A new study by researchers at the University of Maine adds to this growing body of evidence.

This new research, published today in the journal Applied Physiology, Nutrition, and Metabolism, shows that regular long-term wild blueberry diets may help improve or prevent pathologies associated with the metabolic syndrome, including cardiovascular disease and diabetes.

"The metabolic syndrome (MetS) is a group of risk factors characterized by obesity, hypertension, inflammation, dyslipidemia, glucose intolerance and insulin resistance, and endothelial dysfunction," explains Dr. Klimis-Zacas, a Professor of clinical nutrition at the University of Maine and a co-author of the study. "MetS affects an estimated 37% of adults in the US ." Many substances found in food have the potential to prevent MetS, thus reducing the need for medication and medical intervention.
"We have previously documented the cardiovascular benefits of a polyphenol-rich wild blueberry in a rat model with impaired vascular health and high blood pressure," says Klimis-Zacas. "Our new findings show that these benefits extend to the obese Zucker rat, a widely used model resembling human MetS."
"Endothelial dysfunction is a landmark characteristic of MetS, and the obese Zucker rat, an excellent model to study the MetS, is characterized by vascular dysfunction. The vascular wall of these animals shows an impaired response to vasorelaxation or vasoconstriction which affects blood flow and blood pressure regulation."

According to the study, wild blueberry consumption (2 cups per day, human equivalent) for 8 weeks was shown to regulate and improve the balance between relaxing and constricting factors in the vascular wall, improving blood flow and blood pressure regulation of obese Zucker rats with metabolic syndrome.
"Our recent findings reported elsewhere, documented that wild blueberries reduce chronic inflammation and improve the abnormal lipid profile and gene expression associated with the MetS." Thus, this new study shows even greater potential such that "by normalizing oxidative, inflammatory response and endothelial function, regular long-term wild blueberry diets may also help improve pathologies associated with the MetS."

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Pterostilbene is a stilbenoid chemically related to resveratrol. It belongs to the group of phytoalexins, agents produced by plants to fight infections.[1] Based on animal studies it is thought to exhibit anti-cancer, anti-hypercholesterolemia, anti-hypertriglyceridemia properties, as well as the ability to fight off and reverse cognitive decline. It is believed that the compound also has anti-diabetic properties, but so far very little has been studied on this issue.

Pterostilbene is found in blueberries and grapes. It is also found in age-old darakchasava, an ayurvedic medicine from India in which the main ingredient is dried Vitis vinifera berries.[2]

Lowering blood lipids and cholesterol[edit]

Studies that used animals fed on blueberry based diets found significant reduction in blood lipid count and cholesterol count. While lipids and cholesterol stored in the cells do not pose much harm, elevated lipid and cholesterol levels in the blood have been linked to heart disease and stroke. In the mentioned study blueberries were found to be more effective than ciprofibrate, a cholesterol-lowering drug predominantly used outside the United States.[10] According to the study pterostilbene binds to PPARs, breaking down the cholesterol.[11]

Diabetes[edit]

Similar to what has been discovered with the drug metformin, pterostilbene has been shown to lower blood glucose levels in rats by as much as 56 percent, while simultaneously raising insulin and hemoglobin levels to near normal levels.[12] Pterocarpus marsupium, a tree that contains high levels of pterostilbene in its heartwood, has also showed an anti-diabetic effect in humans, with 67% of participants in a clinical study obtaining control of their blood sugar levels after 12 weeks and an average drop of 32 mg/dl in fasting blood glucose levels.[13]

Pterostilbene was shown to be a Nrf2 activator and its potential role in the therapeutic intervention in combating pancreatic B-cell damage thereby improving diabetes management.[14]

Cognitive decline reversal[edit]

In a study of 40 19-month-old rats fed either a normal diet or a diet containing blueberry, strawberry, or spinach extracts, the rats that were fed blueberry extracts had a significant reversal in motor-skill decline due to aging as well as other cognitive impairments. All of the diets above, except the normal one, resulted in some reversal or reduction of cognitive decline but none greater than the blueberry group.[15] A similar study with blueberries in a group of adults exhibiting age-related memory decline demonstrated a significant improvement in memory tests after just 12 weeks of drinking blueberry juice.[16] A study out of Tufts University on pterostilbene supplementation in elderly rats showed that pterostilbene conferred significant memory improvement as well.[17] The authors theorized that the memory improvement may be due to pterostilbene's unique ability as an anti-oxidant to cross the blood-brain barrier and co-localize in the hippocampus (the brain's memory center) where it may offer protection against free radical damage.

Anticancer effects in rats[edit]

In 2002, Rimando and University of Illinois at Chicago collaborators found in experiments using rat mammary glands that pterostilbene possessed potent anti-oxidant characteristics and possible cancer-fighting properties at concentrations similar to resveratrol.[18]

Additional work by Rimando and collaborators revealed a possible mechanism for pterostilbene's purported anti-cancer properties. Using mice cells, they demonstrated that pterostilbene, as well as other analogs of resveratrol, potently inhibits cytochrome P450.[19]

Human studies[edit]

The first human clinical trial on the effect of pterostilbene on cholesterol and blood pressure was completed at the University of Mississippi in April 2012.[20] The safety data from the double-blind, randomized, placebo-controlled clinical study demonstrated that pterostilbene is safe in doses up to 250 mg/day.[21] Efficacy data from the clinical study was published on Sept. 12, 2012. A study showed that pterostilbene at high doses was associated with reduced blood pressure and minor weight loss.[22]

Toxicity[edit]

Pterostilbene is not known to be toxic to humans.[4] There is some anecdotal evidence that doses of 200–250 mg or more at once may induce temporary hypoglycemia in normal individuals.[citation needed]

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Boosting Anti-Cancer Immunity with Berries

For disease prevention and health maintenance, berries of all colors have “emerged as champions.” Research has focused mainly on cancer prevention and treatment. Studies show that the anticancer effects of berries are partially mediated through their abilities to counteract, reduce, and also repair damage resulting from oxidative stress and inflammation. Berries may also have many other positive effects, such as boosting detoxifying enzymes.

One of the more remarkable effects is that of blueberries on natural killer cell counts. Natural killer cells are part of our immune system’s rapid response team against cancer cells, eliminating cancer cells through the activation of cancer cell suicide via death receptors. They’re called natural killers because they don’t require activation by prior exposure. We don’t want to wait until our second tumor before our immune system starts fighting.

We have about two billion of these soldiers circulating in our blood stream at any one time, but we may be able to get a troop surge with blueberries. Researchers had athletes eat about a cup and a half of blueberries a day for six weeks to see if that would reduce the oxidative stress of long-distance running. They indeed saw a blunting of the spike in oxidant stress. But that’s not what sets that study apart.

The number of natural killer cells in the blood typically decreases after prolonged endurance exercise, dropping by half to only about one billion—that is, unless we’ve been eating lots of blueberries. In the video, Boosting Natural Killer Cell Activity, you can see a graph comparing natural killer cell numbers with and without blueberries. Those who ate blueberries retained close to the standard two billion cells. This is because six weeks of blueberries had doubled the resting number of natural killer cells up to over four billion. This has never before been demonstrated in humans. There was a study on goji berries, but despite a cup a day for a month, there was no significant change in the number of natural killers.

Another study, though, showed a significant increase in natural killer cell activity thanks to the spice cardamom. (Cardamom and blueberries—I never thought we’d be fighting cancer with blueberry muffins!) When researchers took some lymphoma cells in a petri dish and added cardamom, nothing happened. However, if we add some natural killer cells, about 5% of the cancer cells are wiped out. Add a little more cardamom, and our troops do better still. And then if we add more and more spice, then all of a sudden the natural killer cells are killing cancer like crazy—the same number of natural killer cells, but they’re now able to kill off ten times more cancer cells. While cardamom alone had no effect on cancer cells even at the highest dose, it seemed to enhance our natural killer cells’ killer instincts.

The same thing was found for black pepper: Black pepper alone, nothing, but when combined with natural killer cells, there seemed to be a boosting effect up to around 30 or 40% cancer cell clearance. If cardamom and black pepper are combined, they synergize and their individual effects are doubled. The researchers conclude that “Taken together, these data strongly suggest that black pepper and cardamom have the potential to markedly enhance the anti-cancer activity of natural killer cells.”

Exercise itself can improve immune function in general (See Preserving Immune Function in Athletes With Nutritional Yeast), but the blueberry finding, so far, is unique. The oxidative stress part of the story is told in Reducing Muscle Soreness With Berries.

It is true that the blueberry study was funded by the North American Blueberry Council and the North Carolina High-bush Blueberry Council. However, just because the study was funded by blueberry councils doesn’t necessarily mean the science is suspect, but we would want to see the study independently verified, especially one so dramatic.

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Blueberries are among a small number of foods that contain measurable amounts of oxalates, naturally-occurring substances found in plants, animals, and human beings. When oxalates become too concentrated in body fluids, they can crystallize and cause health problems. For this reason, individuals with already existing and untreated kidney or gallbladder problems may want to avoid eating blueberries. Laboratory studies have shown that oxalates may also interfere with absorption of calcium from the body. Yet, in every peer-reviewed research study we've seen, the ability of oxalates to lower calcium absorption is relatively small and definitely does not outweigh the ability of oxalate-containing foods to contribute calcium to the meal plan. If your digestive tract is healthy, and you do a good job of chewing and relaxing while you enjoy your meals, you will get significant benefits -including absorption of calcium-from calcium-rich foods plant foods that also contain oxalic acid. Ordinarily, a healthcare practitioner would not discourage a person focused on ensuring that they are meeting their calcium requirements from eating these nutrient-rich foods because of their oxalate content.

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Low oxalate food lists (even those given to patients from well-meaning doctors) can often be out-of-date and do not reflect the newer, more accurate techniques. For example, many people on a low oxalate diet are told not to eat blueberries or strawberries. You can’t surf the internet more than a few minutes without at least one oxalate food list or authority incorrectly telling you that berries are high oxalate (15 mg. oxalate or more per serving is usually considered high oxalate). I unfortunately gave up blueberries for almost 12 years thinking they were harming my body. But thanks to the dedication of many scientists (and the people who fund their research!), we now know that blueberries are low oxalate (4.0 mg. oxalate per half cup) and strawberries are medium oxalate (7.8 mg. per half cup). Hurray! I now eat lovely low oxalate blue berries almost every day.