Phosphatidylserine an Essential Building Block for a Healthy Brain

PS Phosphatidylserine An essential building block for a healthy brain

Scientific summary

1 Cell exterior Receptor Serine Cell interior PS Phosphate PS PS PS Glycerol PS PS 1 Introduction PS PS PS PIP3 PIP2 Cell Ras Diet PKC P interior P AKT PI3K PS PS P Protein PS MEK Raf P P PS Serine Fatty acid

Fatty acid PS Lipids are a major component of the cell membrane and serve multiple functions. They help in maintaining membrane Table 2 Normal age-related changes in brain most lipids going down after 50 years of age.(8) Total PLs structure and fluidity, function as an energy reserve, and participate in key cell signaling pathways.(3,4) Each of these membrane lipidsSynaptic (8-10, 12,13) Neuronal survivalundergo a steady yet slow decline between 20 and 80 years, functions is determined by the distribution of different lipids (structure,Choline/ amount, and proportion) across the body; even a transmission and diﬀerentiationafter which the reduction becomes more pronounced.(8) PE small alteration can generate differences in how cells perform.(4) ethanolaminePhosphatidylserine (PS) is one among a classCell of lipids exterior called and PC decrease very slowly after the age of 40 years, with a phospholipids (PLs), which play a critical role in membrane structure and signaling, in turn modulating how a cell functions.(3) loss of ≤10% thereafter.(8) PS levels, on the other hand, Decade Total lipid Total PLs PS remain constant between 10 to 33 years of age and decline PC/PE rapidly thereafter.(2, 7-13) The PS-to-cholesterol ratio of the 1 neuronal cell membrane also goes down.(8-13) In addition, 1.1 Phospholipids: the building blocks of cell aging reduces the content of long chain polyunsaturated membrane structure Figure 1 PS, an essential building block of 2 fatty acids (LC-PUFA; 20:4n-6, 22:6n-3) of PS, while The fundamental structure of the human cell membrane brain cells increasing its monounsaturated fatty acid (MUFA; 18:1n-9, is a phospholipid bilayer, peppered with proteins and 3 (~33 years) 20:1n-9) content.(14) carbohydrates bound to either proteins or lipids.(1,2) (>33 years) Approximately 50% of the mass of most cell membranes The altered brain lipid composition seen in aging is Cell interior is phospholipids (PLs), glycolipids, and cholesterol.(1-3) Serine PS associated with a number of structural and biochemical PS 4 A typical human cell membrane contains four major PLs properties of the membrane. Structural changes, mainly an Phosphate PS PS (phosphatidylserine, phosphatidylcholine, PS PS increase in viscosity, is brought about by a reduction in the Glycerol PS 5 phosphatidylethanolamine, and sphingomyelin), and one PS PS PS-to-cholesterol ratio and can impact the activity of quantitatively minor PL (phosphatidylinositol).(1-3) 6 membrane-bound enzymes and receptors that require These PLs and their arrangement are the core structure PS PS optimal fluidity.(15) Protein of the membrane and what keeps animal cells intact. PS 7

All cell membranes share the same phospholipid bilayer Fatty acid 1.3 Modern day dietary patterns reduce PS Fatty acid 8 structure but differences in the fatty acid composition of intake individual PLs can influence membrane fluidity, permeability, 9 The human body can synthesize PS de novo from substrate and signaling functions.(3) Furthermore, PL distribution in Cell exterior PLs (PC and PE), but PS is also obtained through foods such the bilayer is asymmetric, with PC and SM in the outer as fish, milk, rice and beans.(16,17) The composition of (extracellular-facing) leaflet, and PE and PS in the inner today’s diets can be important in this regard. (cytoplasm-facing) leaflet.(1) The maintenance of this 1.2 PS is essential for membrane function, but distribution is not only essential for cell function but also for declines with age The traditional Mediterranean diet, for instance, emphasizes their survival. In healthy cells, PS is preferentially found on the inner leaflet a variety of foods with a balanced nutrient profile that of the lipid bilayer, where it helps influence membrane includes a high intake of fruits, vegetables, cereals, and structure and fluidity. The presence of double bonds in the legumes, a moderate consumption of fish, and a high intake fatty acid tails of DHA-enriched PS prevents it from packing of olive oil but a low consumption of saturated fats. closely together, thereby increasing the membrane’s fluidity This balanced composition serves as a source of PS, other and flexibility.(2, 7) Additionally, PS plays essential roles in key lipids, and nutrients that support a variety of cellular Table 1 Lipid composition of cell membranes (% of total lipids) (5,6,11,22,54,55) the cell by modulating cell signaling pathways.(3) PS can also functions. On the other hand, modern diets tends to be translocate to the outer leaflet of the bilayer in an irreversible higher in saturated fats and carbohydrates, but lower in fiber, mechanism used by apoptotic (dying) cells, thereby flagging essential fatty acids, and important nutrients like PS.(18) Lipid* Typical membrane (%) Brain tissue (%) them for recognition and engulfment by the phagocytes in Modern-day diets have, indeed, reduced PS intake by charge of their disposal.(3) Hence, despite being only 10% or approximately 48% across all age groups.(19) Eating more Cholesterol 34 37 less of total membrane lipids (Table 1), PS levels and its foods that are naturally rich in PS is one way of increasing asymmetrical distribution within the inner leaflet is critical intake. However, supplementation may be needed to ensure Phosphatidylcholine (PC) 23 19 to the cell’s healthy function and survival. daily intake of PS at levels sufficient to restore balance.(19)

Sphingomyelin (SM) 17 6.0-10 Normal aging is accompanied by quantitative and qualitative changes to the overall lipid composition of the brain. (8) Phosphatidylethanolamine (PE) 11 17 Studies have been presenting evidence of these age-related changes since the 1950s. The human brain’s total lipid Phosphatidylserine (PS) 10 10 content increases during the first two decades of life, after which it begins to decrease,(9, 10) with concentrations of *Only includes lipids constituting ≥5% of the total lipids

2 3 2 PS is essential for neuronal function

2.1 PS in the human brain 2.2 PS role in neuronal survival 2.3 PS role in synaptic transmission The human brain not only has the second highest lipid content PS is localized exclusively in the cytoplasmic leaflet of Communication between neurons starts when vesicles filled with neurotransmitter fuse with the membrane of a neuron, the (after adipose tissue) among tissues in the body, it also has neuronal membranes. Being an acidic phospholipid, its presynaptic neuron. This event releases neurotransmitter into the synapse, allowing it to reach receptors in the receiving, or one of the most unique lipid compositions.(20,21) Lipids intracellular portion is negatively charged at cellular pH. postsynaptic, neuron. Calcium (Ca2+) entering the presynaptic neuron is the trigger for neurotransmitter release. PS is involved in make up to 40-55% of the brain’s dry weight, This charge makes PS interact with proteins, promoting their this Ca2+ influx and enhances the binding affinity for Ca2+ of Synaptotagmin I, a key component of the machinery involved in compared to 6-20% for other organs. PLs constitute 50% of translocation to the membrane’s proximity. Localization at neurotransmitter release.(16, 56, 57, 58) At the postsynaptic end, PS has been shown to influence the levels of receptors for the those lipids.(21,22)PS makes up 10% of total brain lipids and the membrane enables cell signaling proteins to interact with neurotransmitter glutamate, through the action of the enzyme Phosphokinase C (PKC). Regulation of glutamate receptor levels is the major acidic PL in the brain.(16) It is enriched in the intracellular portion of membrane receptors, it enables supports synaptic plasticity, the property of synapses that allows them to mediate learning and memory.(25, 59-64) unsaturated fatty acids, including oleic acid (OLA; 18:1n‐9), their activation by membrane-bound enzymes, or induces docosahexaenoic acid (DHA; 22:6n-3), arachidonic acid conformational changes that trigger further activation of (ARA; 20:4n-6), and docosatetraenoic acid (DTA; 22:4n‐6). downstream proteins. The direct participation of PS in these (11, 23) signaling cascades, especially those involving proteins Raf-1 and Akt, makes it essential for the cellular mechanisms Table 4 Major PS-dependent signaling pathways that influence neuronal function involved in neuronal survival.(16, 24) (Figure 2 and Table 4)

Pathway Role of PS Impact on neuronal function

Raf-1 (16, 66, 67) PS is required for activation of Raf-1 Inhibits apoptosis leading to which in turn activates downstream MEK/ neuroprotection and cell survival Figure 2 PS-dependent neuronal signaling pathways (16) ERK signaling and inhibits caspase-3 activity Cell Akt (16, 26, 67) PS secures the translocation and • Supports neuronal differentiation and exterior Receptor Serine Cell interior membrane binding of Akt leading to its survival PS activation • Modulates synaptic transmission by Phosphate PS regulating postsynaptic receptor levels PS PS PS Glycerol PS Synaptotagmin I (68) PS and PI binding to Synaptotagmin I Enables neurotransmitter release PS 2+ PS PIP PIP enable its ability to sense Ca PS 3 2 Ras Diet Cell P PKC AKT 2+ PS interior P PI3K Protein kinase C (PKC) (16, 56, PS interacts with PKC, in a Ca - • Modulates neurotransmitter release PS P 61, 69) dependent manner, to enable its • Modulates synaptic transmission by Protein Raf P PS MEK membrane translocation regulating postsynaptic AMPA and P PS NMDA glutamate receptor levels Serine Fatty acid

Fatty acid PS

Synaptic Neuronal survival Choline/ transmission and diﬀerentiation ethanolamine Cell exterior

PC/PE

Cell interior Serine PS PS 4 5 Phosphate PS PS PS PS Glycerol PS PS PS

PS PS Protein PS

Fatty acid Fatty acid

Cell exterior 3 PS and cognitive function

Factors like demographics, genetics, dietary patterns, and age can alter lipid homeostasis. For instance, alterations to levels and Table 5 Summary of clinical studies of PS supplementation and cognitive performance (adults) (1/2) proportions of certain lipids, like PS and cholesterol levels, alter membrane viscosity. Changes in viscosity affect neurotransmitter release, neurotransmitter receptor levels, and signaling pathways that, in turn might bring about a decline in the synaptic plasticity that underlies cognitive functions like learning and memory.(12) The brain thus needs to adapt constantly to maintain an optimal balance among its membrane lipids and ensure proper neuronal function.(8, 15) Nutrient availability is essential for Reference Population Duration Intervention; Key findings this process. Control

Studies in adults and the elderly

Maggioni N=10 15 days PS 300 mg/day; PS group showed improved long-term Figure 3 PET scan images of a 59-year-old woman with severe AD, treated with 500 mg/day of PS 1990 (29) 70–81 years placebo; Placebo memory vs. control. The effect correlated with for 3 weeks (30) Depressive 30 days attention and concentration, which can be disorders treatment compromised by depression. However, it was difficult to establish whether this was due to Low 20 PS supplementation or to the remission of the Brain patients’ depressive state. Activity 25 Before Klinkhammer N=8 3 weeks PS 500 mg/day PS increased glucose metabolism, a sign of PS 30 1991 (30) 53–73 years neuronal activity, in basal ganglia, thalamus (Figure 3) Probable and visual cortex, areas of the brain that seem 35 Alzheimer’s affected in AD patients. disease (AD) 40 Crook 1991 N=149 12 weeks PS 100 mg/day; Significant improvement in tests related to 45 (31) 50–75 years Placebo learning and memory tasks of daily life. Met age-associ- Patients who performed poorly on the 50 After ated memory performance tests at baseline were most likely PS impairment to benefit from PS treatment. The differences High 55 (AAMI) criteria in the PS group were lost upon termination of Brain treatment. Activity 60 Cenacchi N=494 6 months PS 100 mg/day; Verbal memory function significantly PET Scans at three brain levels of a 59-year-old woman with cognitive decline, 500mg/per day PS 1993 (32) >65 years Placebo (corn oil) improved in the PS group, possibly through supplementation significantly increased cerebral glucose metabolism rate (39) with moderate increasing attention and motivation. to severe cognitive decline

Given the association between development, aging and alterations in brain PLs, oral administration of PS has been studied Gindin 1993 N=72 3 months PS 300 mg/day; The PS group showed a positive influence on extensively for its potential role in managing cognitive deterioration.(25, 27) Consistent with its role in neuronal activity, PS (33) 60–80 years Placebo (lecithin) post-treatment memory testing scores, supplementation has been shown to increase brain activity in patients with Alzheimer’s Disease (AD).(30) In older individuals Some daily especially for memorizing information and with age-associated memory impairment, PS supplementation was found to improve performance on tests related to learning memory numbers, and retaining visual memory. and memory.(31, 33, 36) Studies also showed that PS, administered in combination with DHA and EPA, may improve the ability problems Though not statistically significant, a small to recall information in adults with memory complaints. improvement in the placebo group was observed, perhaps due to learning (test-retest) In children, circumstantial evidence indicates that brain lipid composition might influence levels of attention, impulsivity, and or because lecithin was chosen as placebo. emotional responses. Studies of PS supplementation showed improved visual attention, suggesting a correlation between changes in lipid balance and cognitive function.(37, 38, 41) However, additional research is needed to confirm findings in young Richter 2010 N=8 6 weeks PS 300 mg + PS-omega-3 significantly increased the ability age groups. (35) ≥60 years omega-3 (EPA, DHA) to recall words in a delayed task. Immediate Subjective 37.5 mg/day word recall remained unchanged. Overall, over 2,800 peer-reviewed publications and over 70 clinical studies have assessed the impact of PS supplementation on memory memory and other brain-relevant activities in individuals of all ages (see summaries in tables 5 and 6). complaints

6 7 Table 5 Summary of clinical studies of PS supplementation and cognitive performance (adults) (2/2) Table 6 Summary of clinical studies of PS supplementation and cognitive performance (children)

Reference Population Duration Intervention; Key findings Reference Population Duration Intervention; Key findings Control Control

Studies in adults and the elderly Studies in children

Kato- N=78 6 months PS 100 mg/day; In the subjects with low baseline scores, both Hirayama N=15 2 months PS 200 mg/day PS supplementation significantly Kataoka 50–69 years PS 300 mg/day; doses of PS significantly improved memory 2006 (40) 6–12 years improved ADHD symptoms (inattention and 2010 (36) Mild cognitive Placebo function, likely due to better delayed verbal Suspected hyperactivity and impulsiveness), and visual impairment recall, a memory ability attenuated in the ADHD perception, but not visual and auditory earliest stage of dementia. short-term memory.

Vakhapova N=157 (core) 15 weeks Core Core Vaisman N=83 3 months PS 300 mg + omega Continuous performance test results (visual 2010 (core N=122 (OLE) core + PS 300 mg + PS-Omega3 significantly improved memory 2008 (41) 8–13 years 3 (EPA, DHA) 250 sustained attention performance) were study); 50–90 years 15 weeks Omega3 (DHA, EPA) (verbal immediate recall). A subset of Impaired visual mg/day; significantly increased in the PS-Omega3 2014 Non-demented OLE 79 mg (DHA:EPA participants with good cognitive performance sustained Fish oil (FO); group and, to a lesser extent, in the FO group. (open-label with memory 3:1)/day; at baseline showed significant treatment- attention Placebo A significant correlation between the extension or complaints Placebo (cellulose) associated improvements in immediate and performance alterations in plasma fatty acids and increased OLE) (37, 38) delayed verbal recall, learning abilities, and visual sustained attention performance OLE time to copy a complex figure. Scores was observed in the PS-Omega3 PS 100 mg + group. Omega3 (DHA, EPA) OLE 26 mg/day PS-omega3 preserved the effect observed Manor 2012 N=200 (core), 15 weeks PS-Omega3 Core: during the core study and sustained the (28) 150 (OLE) Core Placebo Parents noted a reduction in the children’s cognitive status of participants. PS-omega3 Mean 9.2 years study ; restless-impulsive subscale and improved also resulted in significant improvement in Confirmed 15 weeks parent impact-emotional subscale in the sustained attention and memory in new ADHD OLE PS-Omega3 group. Teachers, however, failed participants. to detect significant effects. In a subgroup of children with more pronounced hyperactive Richter 2013 N=30 12 weeks PS 300 mg/day Between baseline and 12 weeks, PS and impulsive behavior, a significantly greater (39) 50–90 years significantly improved memory recognition attenuation in ADHD symptoms was Memory and recall, and had a significant positive effect observed. complaints on executive functions and mental flexibility. A non-significant improvement was also OLE: detected in focused and sustained attention, Sustained efficacy was observed in all the visuospatial learning, and spatial short-term subscales in children who continued to memory. receive PS-Omega3. Additional improvements in child health questionnaires were observed Kennedy N=28 Each Ginkgo biloba GBE+PS significantly improved accuracy and suggesting a positive effect on quality of life. 2007 (34) 20.4±1.2 years treatment extract (GBE) 20 mg; speed of memory task performance. No effect Healthy on GBE 120 mg + PS; observed with GBE alone, while GBE+PC Hirayama N=36 2 months PS 200 mg/day; PS supplementation resulted in significant separate GBE 120 mg + PC; resulted in a modest improvement. 2013 (42) 4–14 years Placebo improvements in ADHD symptoms, short- days, 7 Placebo ADHD term auditory memory, inattention, and days apart impulsivity.

8 9 4 PS in stress, mood, and sleep

Stress is a reaction of the body to either mental or physical Figure 4 HPA axis Table 7 Summary of clinical studies of PS supplementation and psychological stress, mood, and sleep factors and is regulated by the hypothalamic-pituitary- adrenal (HPA) axis.(43) In response to acute stress, the Stress hypothalamus triggers the release of cortisol, via a hormonal cascade.(43, 44) While normal cortisol production is essential (+) Reference Population Duration Intervention; Key findings for the adaptation to stress, abnormal and chronic Hypothalamus (−) Control production can have deleterious effects on psychological and CRH physical wellbeing. (43, 44) (+) Maggioni N=10 women 15 days PS 100 mg/day; PS significantly reduced depressive and 1990 (29) 70–81 years placebo; PS 300 mg/day; anxiety symptoms, and improved drive, Pituitary (−) Prolonged mental stress has the potential to induce high- Depressive 30 days Placebo interests, and socialization. cortisol, hyperactive states linked to insomnia, depression ACTH disorders treatment and anxiety. In studies where individuals have increased cortisol levels, intake of PS supplements has been shown to Cenacchi N=494 6 months PS 100 mg/day; PS significantly ameliorated reduction or loss reduce the feeling of stress, induce a relaxed state and 1993 (32) >65 years Placebo (corn oil) of motivation, and improved initiative, interest positively influence mood, likely via a reduction in cortisol Moderate to in the environment, and socialization. (+) (+) (see a summary in Table 7).(29, 32, 33, 43, 47) severe cognitive Adrenal cortex Cortisol decline

Jager 2007 N=20 42 days PS 200 mg/day; PS supplementation significantly improved (46) Healthy young Placebo golf performance (the number of good ball Cortisol golfers flights during tee-off) and resulted in a trend of improved perceived stress levels during Adaptation to stress tee-off.

Hellhammer N=75 42 days PS-phosphatidic Induction of acute stress resulted in hyper- 2014 (43) 25.92±1.32 acid complex (PAS) responsivity of cortisol response measured by years (200 mg) 200 mg/day; cortisol levels in saliva and serum. PAS 400 26.48±1.37 PAS 400 mg/day; normalized cortisol response in chronically years (400 mg) Placebo high-stressed but not in low-stressed subjects. 26.64±1.48 PAS 200 did not result in significant years (placebo) differences. Healthy

Gindin 1993 N=72 3 months PS 300 mg/day; The placebo group experienced a significant (33) 60–80 years Placebo (lecithin) increase in depressive symptoms between late Functioning, summer and winter while the PS group with some daily showed a positive influence on mood by memory preventing seasonal affective disorder. problems

Komori 2015 N=18 12 weeks PS 300 mg + DHA Depressive symptoms were significantly (48) ≥65 years 357 mg + EPA 210 improved in all subjects taking PS-Omega3. Major depressi- mg/day Furthermore, 8 “responder subjects” showed on decreased salivary cortisol level to normal levels, and resumed a regular circadian rhythm.

10 11 5 Versatile applications of dietary PS supplementation

Physical stress also provokes the body to increase production of cortisol, but with considerable interindividual variability due to The physicochemical properties of PS make it well suited for In Europe, multiple product applications are approved and differences in training level, age, nutritional status, and multiple variables of the physical activity that induces the stress various food applications. PS can therefore be used in an listed in the annex II of the Phosphatidylserine from soya response.(45) Due to this high variability in stress responses, the data supporting the effect of PS supplementation is not as array of food products, including dairy-based products, phospholipids as a novel food ingredient under Regulation strong. However, some research has shown that PS may help to moderate the increase in exercise-induced cortisol levels and powdered drinks, shakes, toddler and children formula, (EC) No 258/97 (40-350 mg/100g of finished product might help attenuate subjective measures of overtraining, like the perception of fatigue, well-being and muscle soreness see nutrition bars, feeding solutions, and supplements in tablet, depending on application), and the novel food authorization summary in Table 8 below). (45, 49-53) soft gel, capsule, syrups, sachets, or gummy formats. of the Finnish Food Safety Authority (30-100 mg/serving or 800 mg/day for supplements). The European Food Safety In the United States, soy- and sunflower-derived PS can be Authority (EFSA) concludes that the current evidence is still found in a variety of marketed food, sports nutrition, and preliminary and does not support a health claim. Table 8 Summary of clinical studies of PS supplementation and exercise-induced stress dietary supplement products. In the later category, they are available, at least, since 1995 under the Dietary Supplement In China, soy-derived PS usage is approved in foods (up to 600 Health and Education Act of 1994. Multiple food uses and mg/day) excluding formula for infants and toddlers (0-3 years medical food use GRAS status has been affirmed in GRNs of age). Reference Population Duration Intervention; Key findings 186, 197, 223, 545, 636, and 637 (20-100 mg/serving for Control foods and 300 mg/serving for medical foods). The Food and In Australia and New Zealand, PS is considered as lecithin and Drug Administration (FDA) concludes that the following can be used as emulsifier in all foods since it complies to the Monteleone N=8 10 PS 50 mg; Both does of PS significantly blunted cortisol qualified health claim for conventional foods and dietary specifications for lecithin. PS can also be used as nutritive 1990 (49) 24–42 years minutes PS 75 mg; responses to physical. supplements is allowed: “Consumption of phosphatidylserine substance in therapeutic goods lawfully supplied in Australia Healthy Placebo may reduce the risk of dementia orcognitive dysfunction in following listing on the Australia Register of Therapeutic the elderly. Very limited and preliminary scientific research goods. Although a claim on the “Maintenance and/or improve- Monteleone N=9 10 days PS 800 mg/day PS significantly blunted the cortisol responses suggests that phosphatidylserine may reduce the risk of ment of cognitive function and brain health” 1992 (50) Healthy to physical exercise. cognitive dysfunction in the elderly. FDA concludes that there is feasible based on the available evidence, supplement is little scientific evidence supporting this claim.” manufacturers need to notify FSANZ. Fahey 1998 N=11 2 weeks PS 800 mg/day; PS decreased post-exercise cortisol levels, and (51) Trained Placebo the PS group showed improved perception of well-being and muscle soreness in response to intense weight training.

Kingsley N=16 10 days PS 750 mg; PS might have improved running performance Table 9 Typical PS dosage per application 2005 (52) 21.7±0.3 years treatment Placebo (glucose by increasing exercise running time to (PS) in polymer) exhaustion, but the trend was not significant. 22.6±0.7 years between There was not significant effect on cortisol Application Typical dosage (Placebo) two response, perceived soreness, and markers of Healthy soccer exercise muscle damage following exhaustive running. Powder beverages 3.5 g/100 g (equivalent to 40 mg/100 ml ready to drink) players trials Beverages based on yogurt 50 mg/100 ml Kingsley N=15 10 days PS 750 mg; PS significantly improved exercise capacity 2006 (45) 23.4±1.9 years treatment Placebo (glucose during a staged intermittent cycling protocol Foods based on yogurt 80 mg/100 g (PS) in polymer) (measured as time to exhaustion). PS did not 22.2±1.1 years between significantly affect serum cortisol. Cereal bars 350 mg/100 g (placebo) two Active and exercise Chocolates 200 mg/100 g healthy trials Food supplements ≤600 mg/day Starks 2008 N=10 10 days S-PS 600 mg/day; PS supplementation resulted in significantly (53) 26.2 ± 1.5 years Placebo lower plasma cortisol levels before and during Medical foods (enteral and ONS) 300 mg/per serving Healthy exercise-induced stress

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