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Jennifer Grebow is editor-in-chief of Nutritional Outlook.
Phospholipid brain-health dietary supplements can be the foundation of a healthy mind.
Phospholipid brain-health dietary supplements can be the foundation of a healthy mind.
Don’t let age fool you: the brain supplements market is young, but thriving. Look at the numbers. According to market researcher SPINS, combined mass-market and natural channel retail sales grew almost 18% in the past year, spanning everything from acetyl-L-carnitine and Ginkgo biloba to fish oil and omega-3 fatty acid DHA specifically, vitamin B12, DMAE, and vinpocetine. That means that while cognitive health supplement sales a year ago were close to $42 million, today they now stand at close to $50 million.* Clearly, consumers, ingredient developers, and scientists are gravitating to the idea of nutritional ingredients for a healthy mind.
There are many components of brain health. Some cognitive supplements target stress and mood. Others power brain cells with amino acids like acetyl-L-carnitine and glutamine. Botanicals like Gingko biloba and vinpocetine help promote circulation in the brain. Still other interest areas in the cognitive supplements market are addressing oxidation and inflammation.
Obviously, the brain’s structural health is key to such functions as memory and cognition, including mental energy, focus, and concentration. Maintaining structural integrity includes keeping brain cells healthy: ensuring cell walls remain fluid so that they can effectively regulate nutrients coming in and waste going out, and supporting signal-transmitting chemicals in the brain called neurotransmitters.
Lipids are a key component of the body’s cells overall. Phospholipids, a class of lipids, are especially crucial to the health of both cell membranes and neurotransmitters. Brain cell membranes are rich in two phospholipids in particular: phosphatidylserine (PS) and phosphatidylcholine (PC), with PC accounting for a larger percentage. Ensuring a steady supply of PS and PC through diet and supplementation can help in the fight to dissuade age-related cognitive decline and illnesses.
PC came to the fore in the 1980s as a key brain phospholipid and a crucial component of healthy brain cell membrane. PC supplements on the dietary supplements shelf are often broadly referred to as “lecithin,” because PC is the major phospholipid component of lecithin.
As Kira Schmid, ND, associate director of scientific affairs for dietary supplements brand Life Extension, explains,“Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues, composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids (e.g., PC, phosphatidylethanolamine, and phosphatidylinositol).”
Although lecithin products can be formulated to contain higher amounts of PC, many say that in general, lecithin supplements are not very bioavailable sources of PC. And, as Steve Holtby, president and CEO of contract manufacturer Soft Gel Technologies Inc. (Los Angeles), explains, “As a nutritional supplement, PC is hoarded by the liver. As a result, hardly any of it actually makes it to the brain. This is why there are no solid, repeatable clinical studies correlating PC use with cognitive improvement.”
Chase Hagerman, business development and marketing manager for ingredients firm Chemi Nutra (White Bear Lake, MN), adds, “Research has shown that PC is not nearly as effective as a cognition compound as is PS, another phospholipid component found in lecithin but in much smaller amounts. In fact, commercially, PS is produced in a complex processing procedure starting with PC.” (Read the latter half of this article for more on PS.)
Additionally, lecithin supplements are considered poor sources of choline, a nutrient of great interest in the cognitive sector.
What is choline? PC is a key donor of choline, which is often associated with the family of B vitamins. While not a phospholipid in and of itself, choline forms acetylcholine, the brain’s most important neurotransmitter responsible for regulating cognition and memory. (By contrast, PC may not be as effective at converting to acetylcholine after ingestion.) In 1998, the U.S. Institute of Medicine officially recognized choline as an essential nutrient, establishing an Adequate Intake Level of 550 mg/day for men and 425 mg/day for women and an Upper Tolerable Limit of 3500 mg/day.
In the diet, choline is obtained from soybeans, eggs, liver, beef, milk, and cruciferous vegetables. Various sources of choline are also sold in the dietary supplements market, including choline salts such as choline bitartrate and choline chloride, and choline citrate. Some sources may cross the blood-brain barrier better than others.
Of choline chloride and choline bitartrate, Chemi Nutra’s Hagerman states, “Here is where the science comes into play: a number of published research studies conclusively demonstrate that commonly used choline compounds like choline chloride and choline bitartrate do not affect brain function, as they are totally ineffective at crossing the blood-brain barrier.”
By contrast, two other choline donors-alpha-glycerylphosphorylcholine (A-GPC) and citicoline-arepromoted as being more bioavailable sources of choline.
In terms of A-GPC’s choline content and bioavailability, “A-GPC contains approximately 40% choline, on a weight basis, which is very potent,” Hagerman says. “And, more importantly, due to its electrical charge characteristic (polarity) in the tissues, A-GPC releases its ‘choline payload’ very effectively-much more so than PC supplements, which normally comprise between 14–35% PC.” Chemi Nutra supplies its soy-derived AlphaSize A-GPC ingredient.
Ingredients firm American Lecithin Co. (Oxford, CT) also describes A-GPC’s bioavailability, on its website for branded A-GPC ingredient Alcolec GPC. “Because Alcolec GPC lacks the hydrophobic fatty acids typical with PC, its enhanced bioavailability allows it to easily pass through the blood-brain barrier, raising blood and brain choline levels safely and efficiently.”
Hagerman says a number of studies support A-GPC’s bioavailability claims. There are also studies suggesting that A-GPC may even work “more swiftly and more completely” than citicoline, another bioavailable choline source (R Di Perri et al., Journal of International Medical Research, 1991; and L Frattola et al., Current Therapeutic Research, 1991).
A-GPC may also be easier to work with from a formulation standpoint, Hagerman says. By contrast, he says, a concern with PC when used as a dietary supplement ingredient is that high-PC phospholipids can be very gummy and can oxidize easily, creating “off” flavors in finished products and thus making for a short shelf life in finished products.
Ingredients supplier Enzymotec USA Inc. (Morristown, NJ) offers two forms of A-GPC: a soy-derived powder form, Sharp GPC, and a liquid form, Sharp GPC Active. Enzymotec USA’s CEO Elzaphan Hotam adds that this liquid form does not require the addition of any stabilizers, taste modifiers, or flow modifiers.
Cytidine 5-diphosphocholine (also known as citicoline or CDP-choline) is an intermediate compound that occurs when choline converts to PC. Before citicoline reaches the brain, it breaks down into choline and cytidine, which is another important nutrient. Each is transported separately into the blood and then into brain or other tissues. In older subjects especially, higher brain levels of cytidine have been shown to increase the levels of PC incorporated in brain cell membrane, explained SM Babb et al. in the journal Psychopharmacology (1996).
Kyowa Hakko USA (New York City) supplies the patented Cognizin brand of citicoline. The company calls the presence of cytidine in citicoline “the differentiator [that] makes citicoline the more advanced brain ingredient than choline alone.” The company says that Cognizin has been shown to support healthy brain metabolism as well as protect against free radical damage. It has also been shown to increase adenosine-5’-triphosphate (ATP), a key energy source for the brain. “Choline alone does not do this,” the firms says.
Kyowa Hakko USA recently saw the publication of Cognizin’s largest human trial to date, in the journal Food and Nutrition Sciences (June 2012). The 28-day study performed on 60 healthy middle-aged women, at doses of either 250 or 500 mg, showed improved performance with both doses during cognitive function tests. According to the study’s authors, “To our knowledge, this study is the first to examine the effects of low doses of citicoline on cognitive performance in healthy female adults.”
PS, the brain’s other main phospholipid, may be less abundant in the brain than PC, but more research is unveiling the importance of this phospholipid, especially for memory and concentration. “PC has been around for much longer in the industry than PS. PC can be found in almost every tissue and comprises the majority of phospholipids in almost every organism,” says Enzymotec USA’s Hotam. “PS, on the other hand, is much more rare and can be found in relatively higher concentrations in specialized tissues. For instance, its abundance in the brain is higher than in other organs, suggesting that it has an important role in the brain.”
Some describe PS as being crucial to the “docking port” for neurotransmitters like acetylcholine, helping to positively benefit neurotransmitter release and neurotransmitter receptor density. “Nerve cells, in particular, depend on healthy membrane function for normal neurotransmitter metabolism and nerve signal transmission,” says Hotam. “PS levels in these tissues ensure the membranes’ fluidity and structure, and hence, their function. Furthermore, maintaining brain PS levels has been associated with normal and efficient signal transduction processes, efficient glucose consumption, and other biological pathways that are crucial to ensure normal and healthy cognitive and mental functions.”
In the Western diet, PS intake is said to be around 130 mg/day. “PS can be found in small quantities in rye and other cereal grains, and in vegetables, legumes, and fruit juices,” says Chemi Nutra’s Hagerman. He adds that because the quantity of PS present in these forms is often small, supplementation can be beneficial.
Research on PS for cognitive health ramped up in the 1980s. To date, decades and dozens of randomized controlled trials have shown PS to aid memory, learning, mood, and stress. “Well over 3000 individuals have used PS in clinical settings,” Hagerman adds. In fact, PS is thus far the only cognitive health nutrient to have gained a qualified FDA health claim, which states that consumption of PS may reduce the risk of dementia or cognitive dysfunction in the elderly.
Chemi Nutra supplies its SerinAid brand of soy-derived PS. More recently, the company has expanded its research to study PS’s benefits on cognitive function during exercise. Benefits were shown in a 14-day, 18-subject, 400-mg dose study published in the Journal of the International Society of Sports Nutrition (October 2011). Earlier this year, the company gained a patent linking oral administration of PS with maintaining healthy testosterone levels in both exercising and non-exercising men.
Recent decades have marked an important shift in PS research. Where PS was once largely obtained from bovine brain tissue, today, thanks to the scare of bovine spongiform encephalopathy (BSE, or Mad Cow Disease), PS ingredients are primarily obtained from soy phospholipids and other sources.
Many say that the long history of benefits shown in bovine PS research cannot necessarily be assumed to apply to soy-derived PS. “Studies based on bovine-sourced PS cannot be directly related to those performed on soy-derived PS,” says Holtby of Soft Gel Technologies. The contract manufacturer, which specializes in softgel capsules, offers customers its Smart PS brand of highly stable PS, which the company sources from Enzymotec USA.
As it stands, there are several important chemical differences between soy- and bovine-derived PS. Enzymotec USA’s Hotam explains that the biggest difference is that bovine-derived (animal) PS contains approximately 8% omega-3 fatty acid DHA attached to its backbone, while soy-derived (plant) PS contains no DHA.
And omega-3 fatty acids such as DHA and EPA have been shown to benefit cognitive health. Dallas Clouatre, PhD, R&D consult for supplements firm Jarrow Formulas Inc. in Los Angeles, points to a University of California, Los Angeles, study that looked at the diets of more than 1500 middle-aged and older adults. (Jarrow Formulas offers its PhosphOmega supplement containing phospholipid-bound omega-3s.)
“[Researchers] discovered that those individuals with the highest blood levels of DHA and EPA omega-3 fatty acids performed better on tests of mental functioning and exhibited less age-related brain shrinkage. Using a new test based on red blood cells that reveals the amount of these omega-3 fatty acids that have been consumed over the last few months, the scientists determined that higher levels of omega-3 fatty acids translated into approximately two years’ difference in brain structural aging.”
Clouatre goes on to explain that low levels of omega-3 fatty acid DHA in red blood cells were associated with smaller brain volumes and with a “vascular” pattern of weaker cognitive performance. “The UCLA study seconded a number of other studies showing that DHA positively alters neuronal membrane properties and is protective of neuronal health.”
In fact, DHA, as well as omega-6 fatty acid arachidonic acid, is the most common fatty acid naturally attached to the phospholipids in the brain. Together, DHA and PS are said to help build the number of neurotransmitter sites in the brain, improving signal transfer.
Enzymotec USA offers two PS ingredients containing omega-3 fatty acids, including DHA: soy-derived Sharp-PS Silver and krill-derived Sharp-PS Gold. Hotam explains the difference between the two: while Sharp-PS Silver is mixed with DHA and EPA omega-3 triglycerides, Sharp-PS Gold’s DHA is actually attached to the backbone of the PS, forming a true PS-DHA conjugate, because a significant portion of the omega-3 fatty acids in krill is naturally bound to phospholipids.
“Studies demonstrate that when omega-3 fatty acids are attached to phospholipids, they reach the target organs, such as the brain, in a more efficient way,” Hotam says.
Hotam says that Sharp-PS Gold’s DHA-PS conjugate better resembles the PS found naturally in the human brain and in breast milk-forms in which DHA is conjugated to the backbone of the PS. “It is known that phospholipids in the brain are attached to DHA, so Sharp-PS Gold is the most similar to brain PS than any other PS product [and is] immediately recognized as being ‘body ready,’ with increased bioavailability of DHA to the brain,” he says. He adds that clinical studies performed by Enzymotec on Sharp-PS Gold have shown positive effects in both animals and humans.
Hotam also says that an animal-derived ingredient like krill-derived Sharp-PS Gold better mimics the chemical structure of bovine PS (8% DHA), meaning that there may be more of a correlation with the results of bovine studies. “Sharp-PS Gold is researched, developed, executed, and patented to the identically same profile,” he declares. (Enzymotec also offers OmegaCholine, which is a PC ingredient derived from fish biomass with DHA attached, because “we believe the market is ready for alternatives offering other forms of omega-3-bound phospholipids which are not necessarily krill-derived,” Hotam says.)
And, for those seeking PS from a source other than soy, soy-free PS ingredients have emerged. Enzymotec offers Sharp-PS Green, derived from sunflower. Hotam says that the chemical structure and fatty acid profile of sunflower is quite similar to soy’s.
Soft Gel Technologies also offers a sunflower alternative. “It is a good option for those with soy allergies, other concerns about soy, or aversions to genetic modification,” Holtby says.
In the cognitive supplements market, there is growing interest in combining certain phospholipid ingredients with other brain-enhancing nutrients.
Last year, the Dr. Mercola’s supplements brand introduced Krill-IQ, a dietary supplement featuring the following Enzymotec ingredients: Sharp-PS Gold conjugated with omega-3s EPA and DHA, Sharp-GPC Active, GPE (glycerophosphatidylethanolamine), and astaxanthin. “This synergistic formula brings together all these strong components into one, so instead of using several different cognitive health products, consumers can get very strong benefits using just a single product,” Hotam says.
Sharp-PS Gold is also an ingredient in Life Extension’s Cognitex dietary supplement line. “While PS has demonstrated impressive results in clinical trials, combining it enzymatically with DHA can improve its efficacy even more,” says Life Extension’s Schmid. Additionally, Cognitex products contain ingredients such as A-GPC. The company has published research demonstrating Cognitex’s benefits for memory and overall cognitive function.
Sharp-PS Gold is also in Jarrow Formulas’ BrainBoost supplement. And Jarrow combines these ingredients in its Neuro-Optimizer supplement: citicoline, PS, alpha-lipoic acid, acetyl-L-carnitine, L-glutamine, and taurine.
Interest is also growing in combining PS and another phospholipid, phosphatidic acid. “Phosphatidic acid has an indirect effect on cognition by helping to regulate levels of cortisol [a stress hormone] to create optimal levels of stress,” explains Dave Pihlcrantz, technical director for ingredients supplier GCI Nutrients (Foster City, CA). “There has been much research that indicates that there is generally an inverted relationship between cognition-learning ability, memory, etc.-and stress level.”
GCI Nutrients’ LipoSerine branded ingredient contains equal concentrations of phosphatidic acid and PS, both soy derived. “The biochemical relationship between PS and phosphatidic acid strongly suggests that they are synergistic in their action,” the company states. Clinical trials on LipoSerine have shown that the ingredient combo is more effective than PS alone.
Late last year, PS specialist Lipogen Ltd. (Haifa, Israel) granted exclusive commercial rights to its PS to ingredients supplier Lonza (Basel, Switzerland), for dietary supplements, medical food, food, and beverages. Subsequently, late last year, Lonza introduced the Memree line of soy-derived PS ingredients. In addition to Memree PS, the line includes MemreePlus, which is a patented combination of PS and phosphatidic acid. (Also related to cognitive health, Lonza recently introduced its DHAid algae-derived DHA ingredient line.)
“Phosphatidic acid has many different functions in the body,” explains Kevin Owen, PhD, Lonza’s Nafta head of technical marketing and scientific affairs. “Phosphatidic acid serves as a precursor for phospholipids, such as PS, and can influence cell membrane curvature.”
Owen describes the combination of phosphatidic acid and PS as “a double whammy: you get benefits for mental acuity and function, in addition to stress reduction through the reduction of cortisol. It combines stress reduction and cognitive support.”
Sales-wise, phospholipids have performed quite well. “Interest and sales for PS and AlphaSize A-GPC have boomed for us in the last year,” says Chemi Nutra’s Hagerman. In fact, he says Chemi Nutra is currently expanding its manufacturing facility “to accommodate the overwhelming success of A-GPC.” Enzymotec’s Hotam also reports that A-GPC and PS sales are especially strong.
SPINS numbers echo reports of steady growth. According to the market researcher, in the past year PC saw 6.4% growth in combined channels, while PS saw slightly smaller growth, at 3.7%. And while these ingredients may not be the number-one market leaders-look to Ginkgo biloba, DHA/fish oil products, and acetyl-L-carnitine for that-they consistently rank among the top-10 ingredients in the brain health market.
Phospholipids have lots of room for growth in cognitive health, with opportunities still untapped, says Hotam. “Phospholipid sales have been stable and solid through all these years. We believe the general public is still very much unaware of their true potential, especially when it comes to ingredients such as PS, which has qualified health claims and extensive research.”
And cognitive health supplements in general have a bright future. “For years, cognitive decline was considered inevitable, and hence a ‘normal’ part of aging,” says Ron Antriasian, director of sales and business development for Life Extension. “However, as awareness grows towards the effectiveness of certain products and ingredients in helping to maintain healthy cognitive function, the market has grown substantially-and will continue to grow.”
As Jarrow Formulas’ Clouatre reminds, “Cognitive health as a category may be relatively young, but the number of Americans who can benefit is large and growing. According to census data, there were 39.6 million people 65 and older in the United States on July 1, 2009, and this number accounted for 13% of the total population. These numbers will climb to 88.5 million and 20% of the population by 2050.”
“This means that the benefits of cognitive health ingredients have been under-appreciated up to this point,” he concludes.