In late 2010, the Life Sciences Research Organization (LSRO), Bethesda, Md., conducted a review of the scientific evidence on more than 35 food ingredients, dietary supplements and dietary factors to determine whether claims could be linked to the ingredients’ effects on mental energy.

For the purposes of the study, mental energy was defined as consisting of mood -- “transient feelings about the presence of fatigue or energy; motivation -- determination and enthusiasm; and cognition -- sustained attention and vigilance.” The organization published a review article on the data for four dietary constituents/supplements: Gingko biloba, omega-3 fatty acids, Panax ginseng and glucose.

These and other ingredients, and the foods, beverages and supplements made with them, are designed to not only sharpen mental abilities during youth, but also help ameliorate some of the symptoms associated with age-related cognitive decline, dementia and Alzheimer’s. Such ingredients are employed to support brain health along several tracks. They can act to stimulate mental activity and improve energy metabolism; improve circulation and act to reduce inflammation; and decrease cellular damage due to oxidative stress.

Published in “Do Specific Constituents and Supplements Affect Mental Energy?” in the December 2010 issue of Nutrition Reviews, LSRO’s conclusions were that gingko appears to affect mood and attention, and omega-3 polyunsaturated fatty acids could reduce the risk of cognitive decline.

It should be noted that the literature was inconsistent regarding the effects of ginseng on cognition, specifically. But, one possible reason for this discrepancy could be that the performance differences stem from the inconsistencies in the level of active ginsenosides in the extracts administered. Meanwhile, a variety of studies have explored the relationship between glucose and memory, but the results have been inconsistent.

Another key ingredient for cognition-directed products is cobalamin -- vitamin B12. Although more common in energizing beverages and other products (see “Drink Fast!” in this issue), recently published scientific review identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia.

While 17 studies reported on the efficacy of vitamin B12 therapy for these conditions, the authors also found that vitamin B12 levels in the subclinical, low-normal range were associated with Alzheimer’s disease, vascular dementia and Parkinson’s disease.

Alpha and Omega

More than 20,000 scientific papers have been published on omega-3 fatty acids and their beneficial effects on such physical conditions as sustaining healthy cholesterol levels, and improving neural development and function in infants and older adults. Not all fatty acids are created equal.

Omega-3 fatty acids (i.e., linolenic acid type) are derived from marine sources, walnuts and other seeds, while omega-6 fatty acids (i.e., linoleic acid type) are derived from vegetable oils (predominantly soybean oil), seeds and nuts. The average U.S. diet is low in omega-3s, with an unnecessary overabundance of omega-6 fats. However, omega-3 fatty acids are vital for brain health.

The brain is composed of about 60% lipids (based on dry weight), with omega-3 fatty acids making up about 60% of nerve cell membranes in the vicinity of the synapses where the cells communicate with each other. Omega oils are needed to build and maintain neural tissues. Research continues to establish omega oils as key nutrients for learning, cognition and even amelioration of emotional stresses and depression.

The two omega-3 fatty acids considered most important to health are DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) -- both metabolites of ALA. Because the metabolic conversion of ALA to these fatty acids is low, people need to obtain these fatty acids from dietary sources, such as fatty fish like salmon, herring, sardines, tuna and mackerel -- or from the fishes’ original sources. More on that later.

The market research group Frost & Sullivan forecasts that the DHA/EPA market is expected to grow to $2.8 billion by 2015, almost double its value from 2009. The Academy of Nutrition and Dietetics (formerly the American Dietetic Assn.) rec-ommends 500mg of EPA and DHA combined per day. However, most Americans only consume an average of 57mg DHA and 34mg EPA per day.

Findings in the Journal of Alzheimer’s Disease suggest that the antioxidants in walnuts and other Mediterranean foods could help counteract age-related cognitive decline and reduce incidence of neurodegenerative diseases (including, of course, Alzheimer’s).

The California Walnut Commission notes that walnuts are a nutrient-dense, whole food that not only provides antioxidants, but also alpha-linolenic acid (ALA), the plant-based omega-3 essential fatty acid. These nutrients offer anti-inflammatory properties and protect brain cells from oxidative damage. Other sources of ALA include chia seeds, flax, rapeseed (canola) and soybeans.

While some of the recent smaller, short-term, randomized trials of DHA and/or EPA supplementation have found positive effects on some aspects of cognition in older adults who were cognitively intact or had mild cognitive impairment, little effect was found in participants who already were afflicted with Alzheimer’s disease. Thus, larger, long-term trials in this area are needed.

Omegas from non-marine sources have been experiencing impressive growth in popularity as consumers reduce consumption of animal-based products and focus, too, on the negative impacts of overfishing and depletion of aquatic resources. The idea of “let’s eat what the fish eat to get their omega-3s” is driving a market in DHA from microalgae.

Algal-based DHA is virtually identical to high-quality fish oil. Extensive purification and deodorization leaves it with a neutral flavor profile and, along with microencapsulation, allows algal omegas to be employed in beverage applications, such as dairy, juices and other beverages. As with other lipid-based ingredients, these oils are susceptible to light, heat and the oxidizing effects of contact with minerals, such as iron, copper and zinc.

A Rising Decline
Alzheimer’s disease affects an estimated 5.2 million Americans and is currently the sixth-leading cause of death in the U. S., according to the Alzheimer’s Association’s “2013 Alzheimer’s Disease Facts and Figures” report. According to the report, while death rates have declined for most major diseases over the past 10 years -- including stroke, prostate cancer, breast cancer, heart disease and HIV -- deaths from Alzheimer’s disease have risen by an alarming 68%. By 2050, the number of people afflicted with Alzheimer’s over the age of 65 could triple.

Botanical Brain Boosters

Caffeine has several close relatives, theophylline and theobromine (present in tea and chocolate). As a natural constituent in coffee, caffeine is known to stimulate mental alertness and help a person focus on mentally challenging projects. Caffeine also is present in colas, guarana, energy drinks and increasingly popular yerba maté teas. The caffeine content in coffee varies, depending upon the brewing method and the bean-roasting process.

A typical cup of coffee contains between 100-175mg caffeine. In contrast, cola soft drinks contain between 10-50mg caffeine per 12oz. Beverages that rely on caffeine, such as Red Bull, have about 80mg per serving. Caffeine-containing pro-ducts are a staple at college campuses, mostly for their stimulant effect, but also for their ability to sharpen mental alertness.

Another plant-derived ingredient, vinpocetine, possesses a studied ability to help improve cognitive function and memory. Vinpocetine has been the subject of several published clinical invesigations involving more than 30,000 individuals. Derived from the Voacanga africana shrub or from periwinkle species, vinpocetine often is called the “smart nutrient,” for its ability to increase blood circulation through the brain. Vinpocetine is commonly used for enhancing memory, as well as for helping to prevent Alzheimer’s disease and other conditions that affect learning, memory and information-processing skills as people age. It also has been looked at for potential ability to protect the brain from damage caused by strokes.

One of the more interesting cognitive health ingredients to hit the market recently is an extract of Sceletium tortuosum, a medicinal plant with a long history of folkloric tradition in South Africa. The shrub-like plant is a member of the Mesembryathemaceae family and contains several psychoactive alkaloids, key of which is mesembrine, which is known to act as a selective serotonin reuptake inhibitor.

A related, secondary alkaloid in this botanical, mesembrenone, is also a serotonin reuptake inhibitor, as well as an inhibitor of phosphodiesterase enzymes, which gives it some vasodilatory ability. Phospho-diesterases also are key components of the cellular signal process, acting as relays, regulators and signal enhancers.

Pharmaceutical phospho-diesterases have been used for conditions ranging from hyper-tension and erectile dysfunction to dementia, depression and schizophrenia. The two compounds are believed to work synergistically for a dual mechanism of action that is “experiential” for stress relief, enhanced mood and improved cognitive function.

In several recent randomized, double-blind, parallel-group placebo-controlled trials of sceletium extract on healthy adults, doses of 8 and 25mg/day have been determined to be both safe and effective. While the ingredient can be used as a supplement, it has attained GRAS status and so is suitable for food and beverage applications.

 American ginseng extract (Panax quinquefolius) is used in traditional medicine to improve cognitive performance. This ingredient has a specific profile of the active phytocompounds called ginsenosides. In one randomized, double-blind, placebo-controlled crossover study, a proprietary form of American ginseng ginsenosides improved working memory and supported attention in healthy individuals.

A 200mg dose has been clinically proven to immediately and significantly increase attention accuracy, and both working memory speed and capacity were significantly enhanced. Moreover, at this dosage level, the Canadian Health Authorities have recently approved the following claims:

  • Helps to support cognitive function
  • Helps to support cognitive performance
  • Helps to support working memory

The phospholipid compound phosphatidylserine, derived from soy lecithin, is another promising new ingredient for brain performance. More than 3,000 published research papers and more than 60 clinical trials have established that phosphatidylserine can rejuvenate brain cell membranes and, thus, could strengthen memory; increase vigilance and attention; boost learning; and increase mental acuity. Human clinical studies have shown that phosphatidylserine could protect against symptoms of dementia, age-associated memory impairment (AAMI) and cognitive dysfunction.

Phosphatidylserine enables the brain cells to metabolize glucose and to release and bind with neurotransmitters, all of which is important to learning, memory and other cognitive functions.

Phosphatidylserine increases communication between cells in the brain by increasing the number of membrane receptor sites for receiving messages. Phosphatidylserine also modulates the fluidity of cell membranes -- essential to brain cells’ ability to send and receive chemical communication. Scientific studies demonstrate that phosphati-dylserine restores the brain’s supply and output of acetylcholine, the neurotransmitter so important to memory, and so may turn back the clock in an aging brain.

Stake A Claim
According to the Dietary Supplement Health Education Act (DSHEA) of 1994, manufacturers are prohibited from making disease-related claims that their products can treat, prevent or cure diseases. However, they are permitted to make structure-function claims about a given supplement in their marketing material. Dietary supplement manufacturers are required to submit a notification to the FDA no later than 30 days after the product goes to market; this notification must include the text of the claim (conventional foods do not require this notification). 
In certain instances, manufacturers are allowed to make an authorized health claim, provided it falls under one of the approved substance-disease relationships. 
The FDA has permitted two structure-function claims for the popular omega-3 fatty acids. Besides the verbiage stating, “may contribute to maintenance of heart health,” the permitted cognitive claim verbiage is “may contribute to maintenance of mental and visual function.” 
In 2003, FDA agreed to exercise enforcement discretion for two qualified health claims relating to the use of phosphatidylserine dietary supplements in the treatment of the disease states dementia and cognitive dysfunction. The phosphatidylserine must be of a very high purity level, and the product’s claim must specify the daily dietary intake necessary to achieve the claimed effect. The companies must agree to the placement of a legal disclaimer directly following their claims. 
The verbiage of the dementia claim and disclaimer is: “Consumption of phosphatidylserine may reduce the risk of dementia in the elderly. Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia in the elderly. FDA concludes that there is little scientific evidence supporting this claim.”
The cognitive dysfunction claim and disclaimer are: “Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly. Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly. FDA concludes that there is little scientific evidence supporting this claim.” 

Think Antioxidant Power

Current research points toward the accumulation of damage resulting from oxidative stress as a major cause of cognitive decline. Free radicals from both the environment and normal cellular respiration can steal electrons from the cells, causing permanent damage.

One of the hallmarks of aging diseases such as Alzheimer’s is reduced hippocampal function, caused in part by accumulative damage brought about by oxidative stressors. While antioxidants can help alleviate this cumulative damage, a large number of them are not bioavailable.

Some of the best antioxidants have hydroxyl groups that give them their functional potential. But, this also reduces their lipophilicity (oil-solubility). Oil-soluble compounds generally have higher potential for cellular uptake as they can get through the cell’s lipid bilayer easier than water-soluble compounds. The free hydroxyl groups also work against a compound, in that they are more likely to be metabolized by the liver before hydroxyl-free compounds.

The quinone compound Pyrroloquinoline quinone (PQQ) is a fairly new player in the antioxidant market. PQQ is a potent and focused antioxidant that enhances the functioning of cellular mitochondria and has been found to support heart health and cognitive function. While PQQ has been shown to promote memory, attention and cognition in laboratory animals, more well-controlled clinical studies remain to be done in humans.

Stilbenoid compounds called pterostilbenes are chemically related to the well-known antioxidant resveratrol. Pterostilbene is found in abundance in blueberries and grapes. It belongs to the group of phytoalexins -- agents produced by plants to fight infections.

Animal studies indicate pterostilbene could help fight off and reverse cognitive decline. Unlike most other antioxidants, pterostilbene has two methoxy groups (making it highly lipid-soluble) and a hydroxyl, antioxidant group. While its antioxidant potential might be considered lower compared to antioxidants with multiple hydroxyls, its better uptake makes it a more viable antioxidant ingredient.

A collaboration of scientists at Tufts University and the USDA research station at the University of Mississippi resulted in a published animal study showing that not only can pterostilbene protect cells against oxidative stress in vitro and in vivo, its use is significantly correlated to increased cognitive function.

The study demonstrated a level of neuroprotection brought about by pterostilbene that was not seen with other anti-oxidants, such as resveratrol. Overall, pterostilbene has been shown to possess superior biological activity; better oral bioavailability; and metabolizes more slowly.

Exploring magnesium chelates, specifically magnesium l-threonate, in published animal research has shown positive results for short- and long-term memory with increased levels of magnesium. According to the USDA Agricultural Research Service, as of 2009, only 32% of Americans meet the Dietary Reference Intakes for magnesium.

Healthy magnesium levels are believed to have the potential to help against forgetfulness, difficulty in focusing, decision-making and even spatial/visual recognition. Magnesium l-threonate compounds are available that have GRAS status and are suitable for food and beverage formulations, while demonstrating neutral taste and aroma and high solubility.

Ancient Medicine

Since ancient times, Ayurvedic practitioners in India have used the plant Bacopa monniera to manage various mental conditions. Several clinical studies have showed bacopa (containing triterpene glycosides called “bacosides”) to be a useful agent for renovating and revitalizing components of intellectual functions in children. It has also been reported to be effective in reducing anxiety levels in adults, improving brain function via enhancing memory and elevating mental performance.

In 2008, Calabrese, et al., conducted a randomized, double-blind, placebo-controlled trial to determine the effects of a standardized bacopa extract on cognitive performance, anxiety and depression in the elderly and concluded that, “B. monniera has potential for safely enhancing cognitive performance in the aging.” In 2011, Morgan and Stevens reported results of a randomized, placebo-controlled, double-blind trial indicating that “Bacopa significantly improved memory acquisition and retention in healthy older Australians.”

Another ancient medicine widely studied for its beneficial effects on human health is turmeric (Curcuma longa). Already known as a powerful anti-inflammatory and antioxidant, data from clinical trials indicate that curcuminoids “enhance in vitro amyloid-beta uptake by macrophages of Alzheimer’s disease patients.” Water-soluble curcumin extracts as a combination of curcuminoids (10-15%) and bacosides (≥ 25%) are newly available and act as complementary nutraceuticals for cognition improvement.

The many available and up-and-coming ingredients for cognitive health and enhancement present a wide variety of approaches to the mitigation of the mental health issues facing an aging population. With the need for such ingredients only increasing, it remains only for functional product R&D teams to remember to avail themselves of them.