Improvement of both human and animal memory by synergy between fructooligosaccharide and L-theanine function establishing a safe and effective food supplement

Abstract

Aging is classically associated with a decline of cognitive abilities, especially in relation to memory. While the development of potential treatments for neurodegenerative diseases has been in sharp focus, mild cognitive impairment (MCI), a form of age-related memory loss, in the absence of severe functional impairment, a condition experienced by many healthy adults, has received relatively little attention. Advances in this space would make significant contributions to the goal of healthy aging and may also help promote cognitive performance across the wider population. The individual action of either fructooligosaccharide (FOS) or L-theanine, both natural plant-derived molecules, has been tentatively linked with improvements in cognition, but our understanding remains far from complete. We therefore determined the effect of different dose combinations of FOS and L-theanine (termed MT-01/GBL-Memory¹) in mice against FOS and L-theanine monotherapy. FOS and L-theanine were found to synergistically enhance murine memory in our animal tests at a dose of 100 mg/kg (coefficient of drug interaction (CDI) < 1). In a subsequent human trial, we demonstrated that MT-01 improved the memory of healthy adults after 1 month of consumption. Our results suggest that a combination of FOS and L-theanine synergistically enhances murine memory within a specific dose range. We show that this plant natural product regimen also improves human memory in a population of healthy adults. MT-01 therefore represents a novel, safe, and effective dietary supplement to promote human memory and cognition.

Introduction

With reduced mortality of younger people in lower income countries and increased life expectancy in higher income countries, the world population is rapidly aging (Beard et al., 2016), classically associated with a decline of an individual’s physical and cognitive abilities, especially in relation to memory. In the United States, about 40% of people aged 65 or over have age-associated memory impairment; however, only about 1% of them will progress to dementia each year (Small, 2002). Mild cognitive impairment (MCI) is a form of age-related memory loss in the absence of severe functional impairment. Thus, while patients with MCI are still able to live independently, they show objective memory impairment akin to that of mild Alzheimer’s disease (AD) patients (Petersen et al., 1999). Currently, most research works in this area are focused on treating dementia or Alzheimer’s disease. Despite significant activity, little progress to date has been made regarding the development of pharmaceutical treatments. Strategies to improve MCI therefore preventing/delaying memory decline in older, largely healthy adults, by promoting cognitive function, would provide a valuable complementary strategy toward the goal of healthy aging.

Previously, multiple trials were undertaken using plant extracts, rather than giving molecules, to help improve human brain function with mixed results, with examples of the associated plants employed including coffeeberry (Jackson et al., 2023), Melissa officinalis (Noguchi-Shinohara et al., 2023), Spirulina maxima (Choi et al., 2022), and mulberry (Thukham-Mee et al., 2021). Morinda officinalis has been utilized in both food and medicine for thousands of years. In the context of traditional Chinese medicine, M. officinalis has been reported to delay aging and function as an antidepressant (Zhang & Zhang, 2022). The main components utilized in this context from M. officinalis include oligosaccharides, anthraquinones, iridoid glycosides, organic acids, trace elements, amino acids, and sterols (Zhang et al., 2022). Short-chain fructans, termed fructooligosaccharides (FOS), have been studied extensively for their therapeutic effects on gastrointestinal, immune, neurological, dermal, and cardiovascular disorders, together with calcium absorption defects (Davani-Davari et al., 2019). FOS have been shown to modulate gut microbiota to affect the central nervous system (CNS) via a “gut–brain axis” (Gaman & Kuo, 2008). Indeed, feeding rats with FOS for 5 weeks increased hippocampal brain-derived neurotropic factor expression (Savignac et al., 2013). Recently, oligosaccharides isolated from M. officinalis (OMO) have been shown to improve the memory of β-amyloid induced dementia in rats, scored by the Morris water maze (MWM) test (Chen et al., 2013). An OMO extract can also improve the function of gut microbiota related to the inhibition of AD progression in rats (Chen et al., 2017; Xin et al., 2018). Rats fed an OMO extract showed increased expression of both brain-derived neurotrophic factor and β-catenin and higher serine (Ser) 9 phosphorylation of glycogen synthase kinase-3β (GSK-3β), resulting in enhanced resilience to unpredictable stress (Xu et al., 2017). Although animal tests suggest that FOS isolated from M. officinalis may improve cognition, no human trial has been conducted to explore the potential utility of flavin-containing monooxygenase (FMO) for human health and well-being.

The non-proteinogenic amino acid, L-theanine, is the most abundant free amino acid found in Camellia sinensis (tea) plants. L-Theanine is most abundant in tea leaves, contributing 1%–2% of the dry weight and typically ~50% of the total amino acids (Dietz & Dekker, 2017). The average content of this non-proteinogenic amino acid differs between green, white, oolong, and black tea (Li et al., 2022). Importantly, L-theanine exhibits a variety of health benefits, such as antioxidant, anti-inflammatory, neuroprotective, anticancer, metabolic regulatory, cardiovascular protective, liver and kidney protective, immune regulatory, as well as urogenital and intestinal protective effects (Li et al., 2022).

It has also been shown that rodent ingestion of L-theanine improves the transfer of precursors of neurotransmitters that contribute to attention, motivation, and motor control (Canli et al., 2005; Kakuda, 2002; Kakuda et al., 2008; Yokogoshi et al., 1998). L-Theanine was found to increase serotonin and γ-aminobutyric acid (GABA) levels and to promote dopamine release, resulting in increased relaxation and improved learning ability (Bryan, 2008; Türközü & Şanlier, 2017). Mixed results have also been obtained from multiple human trials determining a possible positive role for L-theanine in human cognitive improvement. Nevertheless, effects on cognitive functions have been observed with a broad range of administered doses, from 50 to 600 mg (Dietz & Dekker, 2017). Black tea has been approved by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA), as improving attention span upon consumption (EFSA Panel on Dietetic Products et al., 2018). In this context, two substances; caffeine and L-theanine, were proposed by the applicants to exhibit bioactivity. However, the relevant review panel concluded that the effect of black tea on attention can be explained by its caffeine content, ruling out a possible effect for L-theanine. Furthermore, the EFSA Panel on NDA had previously concluded that there is no cause-and-effect relationship between consumption of L-theanine from C. sinensis (L.) Kuntze and improvement of cognitive function (EFSA Panel on Dietetic Products & Allergies, 2011).

In this report, we have identified that FOS isolated from M. officinalis and L-theanine function synergistically to enhance murine memory in classical behavioral tests. A formulation, termed MT-01, containing 0.4 g of L-theanine from Camellia sinensis and 0.2 g of fructooligosaccharides from Morinda officinalis administered per day was developed, successfully safety tested, and shown to significantly enhance murine memory in multiple behavioral tests. A placebo-controlled, randomized, double-blinded human trial was also conducted, which demonstrated that MT-01 can effectively enhance the memory of healthy human adults following 30 days of sustained consumption. Thus, MT-01 represents a novel, safe, and effective dietary supplement to promote human memory and cognition.

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2 MATERIALS AND METHODS

Li, Y., Jiang, Y., Zhang, Z., Loake, V. I. P., Bao, X., & Loake, G. J. (2024). Improvement of both human and animal memory by synergy between fructooligosaccharide and L-theanine function establishing a safe and effective food supplement. Food Science & Nutrition, 12, 4966–4980. https://doi.org/10.1002/fsn3.4145

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