One brain, multiple concerns: The diversity of the cognitive health category

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The cognitive health space has gone from products largely focused on age-related decline, such as memory decline, to now encompassing multiple facets of cognitive health, including mood, stress reduction, focus, and energy—all of which influence our overall daily functioning and performance. The fact is, the brain is always developing and changing, from prior to birth to old age, influenced by both internal and external factors. While some things are out of our control, such as genetics, the products we consume, the activities we pursue, and the environments we inhabit contribute significantly to our cognitive health.

Supplements can offer an elegant solution to enhancing our well-being because of their convenience and versatility. The wide range of benefits the cognitive health category now covers shows how much the market has grown and matured, targeting new consumers and niche product categories such as esports.

Nutrition and Our Brain

The connection between nutrition and the health of the brain is well-recognized, particularly when it comes to developing brains. Pregnant mothers are encouraged to eat foods rich in specific nutrients such as folate/folic acid and choline so that fetal brains develop properly. Via the 2020-2025 Dietary Guidelines for Americans, the U.S. Preventative Services Task Force recommends all women planning on becoming pregnant take a daily supplement containing between 400-800 mcg of folic acid. This is because adequate folic acid intake prior to conception and during the first trimester helps prevent neural tube defects. For other important nutrients, the guidelines stop short of recommending dietary supplements but provide guidance on ideal food sources.

Well-known minerals such as magnesium, calcium, zinc, iron, and selenium play a variety of roles in cognitive health, says John Gilligan, marketing manager for Innophos Inc. (Cranbury, NJ), which manufactures a line of chelated minerals called Chelamax. “Magnesium plays a role in neuromuscular conduction, nerve-impulse transmission, and brain cell protection. Calcium enables learning, cognition, and the retention of memories,” explains Gilligan. “Zinc is present at high levels in the brain and is essential for the formation of new neurons. Iron is a required cofactor for several enzymes that synthesize neurotransmitters, which are essential for brain function, and selenium deficiency may be linked to a reduced antioxidant capacity in the brain.”

Choline is necessary during pregnancy and lactation to both replenish maternal stores and support the growth and development of the child’s brain and spinal cord. “Choline is needed before birth to increase the number of stem cells that add to the pool of nerve cells that are available throughout life,” explains Tom Druke, marketing director of Balchem Corp. (New Hampton, NY), which manufactures the ingredient VitaCholine. “Insufficient choline in the fetal brain adversely affects the areas of the brain that regulate higher thinking and memory. Choline is especially critical to visual memory—the kind children use for mental math and which many adults employ to remember, for example, a new route after driving it only once. Choline remains important throughout all life stages as it helps maintain the integrity of communication systems for cells within the brain and the rest of the body.”

Unfortunately, choline is among the nutrients for which adequate intake goals are not met, according to the 2020 Dietary Guidelines Advisory Committee’s final scientific report. The report states that choline amounts range from 69%-89% of adequate intake for all age-sex groups. Because only a very small amount of choline is made in the liver, a majority of our choline content has to come from the diet.

“Over the last few years, awareness that most people do not get enough of this essential nutrient, coupled with research into its significant benefits, has set the stage for the quickly growing buzz about choline,” explains Druke. “This essential nutrient is being discovered by consumers, which creates an extraordinary opportunity for supplement brands. Formulators of sports nutrition products have already figured this out, with multiple new protein beverage mixes featuring choline introduced in this year alone. We expect to see this market grow significantly in coming months.”

Choline is important because it is necessary for the synthesis of the neurotransmitter acetylcholine, as well as phospholipids. “It is an integral building block of all biological membranes, including in nervous tissue,” says Patricia Williamson, PhD, principal scientist, scientific and regulatory affairs, for Cargill (Minneapolis, MN). “This allows for nutrients such as omega-3 fatty acids, which also have beneficial effects on brain health, to be transported across the blood-brain barrier from plasma to the brain.”

Choline can come in two forms, says Williamson: water-soluble choline salts or fat-soluble phosphatidylcholine. “Fat-soluble phosphatidylcholine is the main form of choline found in foods. Lecithin is a dietary source of this important nutrient and can be added to foods to help meet choline needs,” she explains. “Cargill offers fat-soluble, phosphatidylcholine (PC)-rich lecithin, which is an excellent source of this essential, but under-consumed, nutrient. Research suggests lecithin, especially PC-enriched lecithin, can be a highly bioavailable source of the essential nutrient choline.”

Interestingly enough, the majority (95%) of choline in the body is found in the phospholipid form, as phosphatidylcholine, says Andreas Berg Storsve, PhD, director of research and development, Aker BioMarine Antarctic AS (Oslo, Sweden). Krill, a good source of EPA and DHA, is also rich in phosphatidylcholine, which research has shown to be a comparable source of choline, while also supplying essential fatty acids.¹ While choline and omega-3 fatty acids play an important role in our early development, their importance does not decline as we age.

Aging

“We know from neuroscience research that 60 years of age is a ‘breaking age’ where you can see accelerated brain changes, specifically an increased rate of cortical thinning in brain areas important for episodic memory, such as the hippocampus and the temporal lobe,” explains Storsve. “However, there are great individual differences in the rate of neurostructural and cognitive changes as we age, and we need to improve our understanding of why some but not others maintain brain structure and function well into old age.”

What we have learned, however, says Storsve, is that these individual differences do correlate with DHA levels in the blood. “More specifically, higher DHA levels have been shown to be related to a reduction in the rate of cortical thinning in the temporal cortex. Furthermore, higher levels of EPA and DHA are associated with greater hippocampal volume,” Storsve explains. “Although this type of research indicates that mature individuals may benefit from krill oil supplements, it is important to realize that development and aging is a continual process throughout life and that omega-3 status has been shown to be important for cognitive functioning across the entire human lifespan.”

Our brains are constantly changing and adapting to new environmental demands, says Storsve, and omega-3 fatty acids such as EPA and DHA play an important role in this process through their involvement in synaptogenesis, neurogenesis, and neuroinflammation. The fact is the human population is aging. According to the World Health Organization (WHO), the number of people over the age of 60 will rise to two billion by 2050, making up 22% of the total global population. In the United States, the number of residents over the age of 65 years is 54 million, as of July 1, 2019, according to the U.S. Census Bureau. This means that the relevance of supplements that support age-related cognitive declines such as memory decline will continue to sustain long-term.

Of course, older individuals shouldn’t be the only ones looking after their brain health. Memory, after all, is important to everyone. “The growth of the memory-supplements market has historically been driven by an aging population, but cognitive health concerns are now shared by consumers of all ages,” says Gilligan. For example, products like Cera-Q from Innophos have been shown to improve memory scores in four clinical trials in subjects ranging in age between 7 and 65.

Derived from silkworm cocoon, Cera-Q is a silk fibroin protein that has been enzymatically processed to create hydrolysate bioactives possessing a unique amino acid profile rich in glycine and alanine peptide sequences. According to Gilligan, it is believed that the ingredient works by increasing blood flow to and within the brain, disrupting amyloid plaque and enhancing brain receptor–binding activity. Effective at a relatively low dose of 200 mg/day, the ingredient is appropriate for daily use, and because it is water-soluble, it is easy to incorporate in a number of applications beyond tablets and capsules, such as gummies, sports powders, and ready-to-drink beverages.

Brain and Beyond

Everything we do goes through the brain. Therefore, while people think of brain health in terms of memory and concentration, the way we function physically can also be an element of brain health. Choline is a great example of this in terms of how the macronutrient also plays an important role in muscle function.

“Choline also plays a critical role in both synthesis and optimization of nitric oxide (NO), a vasodilator that helps maximize the flow of oxygen and nutrients to the muscles,” says Druke. “As research has identified NO’s beneficial and desirable role in the body during strenuous activity, it has become a prominent ingredient in sports nutrition formulations over the last few years.”

NO vanishes from the body quickly, needing replenishment. Choline helps to eliminate homocysteine, which inhibits NO production. “Choline is metabolized to betaine, which then converts homocysteine (pro-oxidant) to methionine (beneficial amino acid),” explains Druke. “Since homocysteine is detrimental to NO production, that helps optimize NO levels, thus improving the flow of blood and nutrients to the muscles. Replenishing choline before and after workouts helps to maintain the body’s stores, which ensures good muscle communication.”

In the brain, the neurotransmitter acetylcholine, which Druke calls the brain’s “instant messenger,” helps transmit messages in the brain and the neuromuscular junction, sending messages to the muscles more quickly. “It also optimizes fine-motor coordination to help enhance muscle memory,” he explains. “Maintaining choline levels in the brain helps both with performance and in accurate responses and coordination.”

These NO and muscle health benefits create an excellent opportunity for the use of choline in sports nutrition products, offering dual benefits. More athletes are recognizing the importance of supporting their mind as well as their body, which can translate into benefits for things like focus and hand-eye coordination. One growing category to consider is esports, in which competitive gamers seek to maintain an edge through sharp focus, quick thinking, and fine-motor skills.

For example, a study published in Scientific Reports found that choline supplementation supported focus and accuracy in subjects performing “click and aim” tasks on a computer.² In the double-blind, placebo-controlled study, 28 subjects in their twenties were given 400 ml of orange juice with either 2 g of dissolved choline bitartrate or placebo. When performing a visuomotor aiming task, subjects taking choline demonstrated greater accuracy compared to placebo; however, the tradeoff was slower reaction times.

“Mind over matter” is a long-held cliché when it comes to physical fitness, but it looks like researchers are taking it seriously, and the future of the cognitive health space will be in performance, where brand owners can more easily target younger consumers and create innovative product formulas. “This includes from the United States military, which has ongoing projects to extend human mental performance ability for hours to days before seeing a decline (or need for a break), to, of course, e-gamers, normal sports nutrition, competitive chess, and even playing the stock market,” says Douglas Kalman, RD, PhD, representing Nutrasouce (Guelph, OH, Canada), a contract research organization. “Performance can be measured in many ways, and this is a growing and interesting category.”

These benefits also translate to the everyday consumer, particularly now as more people work remotely in long, sedentary workdays devoid of human interaction. For this, more working professionals are turning to nootropics, a class of supplements focused on optimizing and ensuring the longevity of mental processes and memory, says Lorena Carboni, product manager, SAMe, for Gnosis by Lesaffre (Lille, France).

SAMe (S-adenosyl-L-methionine), sold by Gnosis by Lesaffre as Adonat, is a compound naturally produced by the body. “SAMe is involved in more than one hundred biochemical pathways, and it has been shown to have benefits for the mood, liver, joints, and more,” says Carboni. “The body requires quantities of SAMe that the diet cannot provide alone, and decreased or low SAMe levels in some biological fluids and tissues are connected with altered body states. SAMe is a fantastic ingredient for brands building cognitive health products like nootropics.”

Stress is another important component that influences our everyday performance. That is to say, it is normal, until it becomes chronic. “Stress has always been an integral part of life as it helps stimulate motivations, muscle growth, immunity, and more,” explains Mariko Hill, product development executive for Gencor (Irvine, CA). “However, this is in context of the ‘hormesis stress theory’—that is, the adaptive response of cells and organisms to moderate stress. In other words, the degree to which we perceive and/or receive stress response will influence our physiological and psychological outcomes (i.e., acute vs. chronic).”

Unfortunately, the current global pandemic and ongoing political turmoil that has inflamed tensions throughout the world are exacerbating the stress we feel on a regular basis. For this purpose, Gencor recently launched a new ingredient called Calmaluma, which consists of an extract of the cactus-like Caralluma fimbriata.

“The beneficial outcome of its consumption is often an overwhelming feeling of calmness,” says Hill. “The mechanisms of action for enhancing mood can be attributed to the pregnane glycosides present in Calmaluma, whereby they inhibit the production of cortisol and increase serotonin levels.”

Available in a 90%-water-soluble, free-flowing powder, Calmaluma also offers heat, acidic, and alkaline stability, making it suitable for a number of delivery formats, including beverages, smoothies, capsules, tables, tea, and chocolate.

Gut-Brain

One of the most innovative areas of development in the cognitive health space is in probiotics. There is growing scientific understanding about how our gut health influences our cognitive health—known as the gut-brain axis—and growing recognition by consumers of this concept. This has resulted in the development of specific probiotic strains designed to support cognitive health—mood and stress, in particular.

There are a number of ways in which our gut influences the functioning of our brain, say Lucie Lingrand, international product manager for Lallemand Health Solutions (Rexdale, ON, Canada). The first is through neural pathways in our nervous system. “The gut is sometimes referred to as a ‘second brain’ due to its hosting the enteric nervous system (ENS), a neural network that allows the gut to work without instructions from the brain,” she explains. “The main actor in this bidirectional communication appears to be the vagus nerve. This nerve, one of the longest of the human body, connects the brain to the gut directly.”

The second mechanism through which the gut interacts with the brain is the neuroendocrine pathway, which is involved with messengers such as hormones and neurotransmitters. “The most common stress hormones are adrenaline and cortisol,” says Lingrand. “Their occurrence is a marker of stress. For neurotransmitters, including gamma-aminobutyric acid (GABA) and serotonin, they can attenuate the stress response to promote a relaxed state of mind.”

And the last mechanism, says Lingrand, is the immune pathway. “The immune system not only plays a role to defend the body against opportunistic microorganisms, but it also plays a key role in homeostasis,” she explains. “If the immune system identifies a potential threat or struggles to maintain a well-being state, the immune pathway will send a signal to the brain, especially if it perceives a signal from the gut.”

Certain probiotics maintain the immune system by providing stimuli through the intestine to keep the immune system in shape, explains Lingrand. This action sends signals throughout the body, including the brain, to confirm everything is normal. “Via this pathway, stimulation in the gut can have a positive impact on mental health through the brain-gut axis,” says Lingrand. “Hence, strengthening the natural defenses by supporting the immune system through the gut appears as an essential strategy to maintain emotional well-being.”

Lallemand’s proprietary probiotic formula containing Lactobacillus helveticus Rosell-52 and Bifidobacterium longum Rosell-175 (the ingredient Cerebiome; previously named Probio’Stick) has been shown in a number of human clinical trials to support cognitive health in multiple ways. The earliest human clinical trial conducted on the formulation in 2008 found that compared to placebo, supplementation with the formula over a three-week period may support stress-induced gastrointestinal symptoms, such as abdominal pain and nausea/vomiting.³

In 2010, a double-blind, placebo-controlled, randomized, parallel-group study with 55 healthy volunteers was the first to demonstrate the positive impact Cerebiome has on occasional stress. Supplementation with the formula over the course of a 30-day period alleviated psychological distress as measured by the Hopkins Symptom Checklist (HSCL-90) scale.⁴

A more recent randomized clinical trial published in 2019 found that supplementation with Cerebiome may support psychological outcomes in patients with major depressive disorder. In the study, 81 patients were given either the probiotic formula, prebiotic, or placebo for eight weeks. The primary outcome was the Beck Depression Inventory (BDI) score, and the secondary outcomes were the kynurenine/tryptophan ratio and tryptophan/branched-chain amino acids (BCAAs) ratios.⁵

Results showed that patients taking the probiotic formula saw significant decreases in their BDI scores compared to the placebo and prebiotic groups. No significant differences were found between groups in the secondary outcomes. Recently, a post-hoc analysis determined that the probiotic formula may work by significantly increasing brain-derived neurotrophic factor (BDNF), which is lower in depressed patients and increases after a long course of antidepressant treatment.⁶

IFF Health (formerly DuPont Nutrition and Biosciences; Wilmington, DE) also has a probiotic strain designed to support cognitive health, called Howaru Calm, which contains Lacticaseibacillus paracasei Lpc-37. A randomized, double-blind, placebo-controlled, parallel clinical trial⁷ published toward the end of 2020 found that supplementation with the strain may support psychological and physiological markers of stress and anxiety in healthy adults. In the study, 120 subjects were given either placebo or the probiotic formula for five weeks prior to the Trier Social Stress Test. Supplementation with the probiotic strain significantly reduced perceived stress following intervention and reduced exhaustion and the increase of heart rate, and normalized cortisol levels, in subjects with low chronic stress.

And don’t forget about prebiotics. Just as prebiotics have made their way into the spotlight for digestive health, so, too, are they gaining traction for cognitive health, with brands such as FrieslandCampina Ingredients (Amersfoort, The Netherlands) introducing a prebiotic ingredient for brain health in its Biotis line of products. “Galacto-oligosaccharides (GOS) have been shown to increase the relative abundance of Lactobacilli and Bifidobacteria in the gut, which correlates with a reduction of stress and anxiety symptoms,” explains Jouke Veldman, global market development manager and Biotis Brain Health lead at FrieslandCampina Ingredients. “Our solution, Biotis GOS, has been shown to stimulate Bifidobacteria as present in the gut microbiota.”

Bifidobacteria and Lactobacilli are particularly relevant for cognitive health, says Veldman. “[These bacteria] have been shown to cause an increase in the production of neurotransmitters in the brain. Specific amino acids from high-quality dairy proteins can encourage the synthesis of neurotransmitters, such as serotonin (and subsequently the synthesis of melatonin),” Veldman explains. “Serotonin is associated with calming down, and melatonin plays an important role in the sleep-wake cycle. Some amino acids can also act as building blocks and support processes that help us to recover well during the night so we feel fresh in the morning.”

The use of probiotics and prebiotics can be a versatile solution for cognitive health formulations, and versatility is highly important to consumers. “Consumers are looking for nutritious functional foods that are natural and non-addictive but also readily available in handy formats that fit seamlessly into everyday life,” says Veldman. “Our ingredients and solutions are very versatile, which makes them suitable for many formats. Consumer preference is actually for speed and convenience. So, when it came to addressing sleep, for example, our research found a clear preference for a nighttime shot drunk quickly just before bed and not adding a lot of fluid to the body ahead of sleep. It can also be formulated into an easy-to-dissolve sachet application, enabling consumers to add it to their preferred beverages.”

Cerebiome and Howaru also offer great versatility due to shelf stability, and the potential for use in multiple dosage formats, including powders, capsules, tablets, gummies, food and beverage, and sachets. While probiotic supplementation may take a few weeks to demonstrate tangible effects, its versatility allows formulators to create multi-ingredient products with complementary ingredients such as melatonin and ashwagandha.

References

1. Mödinger Y et al. “Plasma kinetics of choline and choline metabolites after a single dose of SuperbaBoost krill oil or choline bitartrate in healthy volunteers.” Nutrients, vol. 11, no. 10 (October 22, 2019): 2548
2. Naber M et al. “Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study.” Scientific Reports, vol. 5, no. 13188 (August 14, 2015)
3. Diop L et al. “Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial.” Nutrition Research, vol. 28, no. 1 (January 2008): 1-5
4. Messoudi M et al. “Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.” The British Journal of Nutrition, vol. 105, no. 5 (March 2011): 755-764
5. Kazemi A et al. “Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial.” Clinical Nutrition, vol. 38, no. 2 (April 2019): 522-528
6. Heidarzadeh-Rad N et al. “Effects of a psychobiotic supplement on serum brain-derived neurotrophic factor levels in depressive patients: A post hoc analysis of a randomized clinical trial.” Journal of Neurogastroenterology and Motility, vol. 26, no. 4 (September 30, 2020): 486-495
7. Patterson E et al. “Lacticaseibacillus paracasei Lpc-37® improves psychological and physiological markers of stress and anxiety in healthy adults: a randomized, double-blind, placebo-controlled and parallel clinical trial (the Sisu study).” Neurobiology of Stress, vol. 13 (2020)