Exploring the role of Lutein in maternal and infant health

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1 Exploring the role of Lutein in maternal and infant health Seminar Nutrition for Maternal and Infant Health November 21 st 2018 Filipa Quintela Technical Services Associate Pharm.D. IMG-KI-00508

2 Overview Diet recommendations and Lutein/Zeaxanthin intake Role of Lutein during pregnancy, infancy and childhood The science on Lutein for prenatal and infants FloraGLO Lutein s unique position Shutterstock:

Lutein & Zeaxanthin and the Macular Pigment Lutein (L) and zeaxanthin (Z) are carotenoids that the body naturally and selectively deposits in the macula of the eye to create a protective layer known

3 Lutein & Zeaxanthin and the Macular Pigment Lutein (L) and zeaxanthin (Z) are carotenoids that the body naturally and selectively deposits in the macula of the eye to create a protective layer known as MACULAR PIGMENT. Macular Pigment (MP) Comprised of L, Z and meso-zeaxanthin (MZ) 1-5 While L and Z are exclusively of dietary origin, MZ originates from the conversion of L exclusively in the macula The macula lutea has the highest concentration of carotenoids in the human body: 0,1-1mM Active uptake mediated by specific xanthophylls-binding proteins o o GSTP1 Zeaxanthin and Meso-zeaxanthin StARD3 Lutein Photomicrograph under license from Dr. Max Snodderly 1. Krinsky et al. Annu Rev. Nutr 2003,23: ; 2, Johnson et al. Inves Ophthalmol Vis Sci 2005;46(2): , Bernstein et al Vision Res.2010;50: Oct 23; 4, Neuringer M., et al IOVS 2004; 45(9): ; 5, Shyam e al. Proc. Natl Acad Sci USA.2017Oct 10;114/41):

4 How well do we eat? Shutterstock:

Global Diet Recommendations: UK, WHO, Singapore UK: Five fruit and vegetables per day 1 World Health Organization: Eat at least 400 g, or 5 portions, of fruits and vegetables per day 2 Singapore

National Health Service, UK. 2. Healthy diet, World Health Organization Fact sheet N 394, updated September 2015 3. Singapore Heart Foundation, http://www.myheart.org.

5 Global Diet Recommendations: UK, WHO, Singapore UK: Five fruit and vegetables per day 1 World Health Organization: Eat at least 400 g, or 5 portions, of fruits and vegetables per day 2 Singapore Heart Foundation servings per day 3 Food Group Children Adolescents Fruits & Vegetables* 2+2 (of each type) 2+2 *Vegetable = leafy vegetables as well as non-leafy, cruciferous, or root vegetables 1. National Health Service, UK. 2. Healthy diet, World Health Organization Fact sheet N 394, updated September Singapore Heart Foundation, Image adapted from:

Children Eat Few Dark Green Vegetables Average Intake of Food Group (g/day) Dark Green Vegetables in US 1 Age (y) Boys 2 to 5 14 6 to 11 11 12 to 19 16 Age (y) Girls 2 to 5 9 6 to 11 14 12

Grams calculated considering 1 cup of cooked vegetables equivalent to 225 grams Mean children intake (g/day) 36 months up to 9 years of age 2 EU country Vegetables Fruits intake France 84

2 Source: (1) What We Eat in America, NHANES 2013-2014, individuals 2 years and over (excluding breast-fed children), day 1 dietary intake data, weighted.

6 Children Eat Few Dark Green Vegetables Average Intake of Food Group (g/day) Dark Green Vegetables in US 1 Age (y) Boys 2 to to to Age (y) Girls 2 to to to Indicates an estimate with a relative standard error greater than 30. Grams calculated considering 1 cup of cooked vegetables equivalent to 225 grams Mean children intake (g/day) 36 months up to 9 years of age 2 EU country Vegetables Fruits intake France Spain UK Germany Italy EU citizens fail to consume the recommended 400 grams a day of Fruits and Vegetables. 2 Source: (1) What We Eat in America, NHANES , individuals 2 years and over (excluding breast-fed children), day 1 dietary intake data, weighted. Food Patterns Equivalents Database (FPED) (2) Source EU data: National Nutrient Database for Standard Reference Release 28 slightly revised May, 2016 SHUTTERSTOCK: ,

7 mg/day mg/day U.S. Lutein Intake (mg/d) Lutein Lutein Children eat less than 1 mg lutein from diet. Greater lutein intake with age. Younger woman have lower Lutein intake than older one. Johnson et al. J Am Diet Assoc 2010;110(9):

Diet Recommendations and Status Worldwide recommendation for vegetables consistently 2 servings per day. Dietary intake is below recommendations in EU countries for children.

8 Diet Recommendations and Status Worldwide recommendation for vegetables consistently 2 servings per day. Dietary intake is below recommendations in EU countries for children. American children eat less than 1 mg lutein and 0.1 mg or less zeaxanthin from diet per day. Dietary supplementation is a viable option to fill the gap in addition to nutritional recommendation. Sources: Johnson et al. J Am Diet Assoc 2010;110(9): , Mean Amounts of Food Patterns Cup Equivalents Consumed per Individual, by Gender and Age, in the United States, Shutterstock:

9 Role of Lutein in Pregnancy, Infancy and Childhood Shutterstock: ;

Lutein and Zeaxanthin Deposit in Critical Locations Mother plasma L/Z during 2 nd & 3 rd trimester 1 L/Z are present in cord blood 1-3 L in maternal plasma persists in postpartum 1-2,4 Breast milk

10 Lutein and Zeaxanthin Deposit in Critical Locations Mother plasma L/Z during 2 nd & 3 rd trimester 1 L/Z are present in cord blood 1-3 L in maternal plasma persists in postpartum 1-2,4 Breast milk lutein is dependent on maternal intake 5,6 L in plasma & breast milk decreases during lactation 5,6 Child L/Z are deposited in specific areas of the baby s body. 6-8 Eye Brain High in polyunsaturated fatty acids 9 High metabolic activity 9 1.Oostenbrug GS, et al. Br J Nutr 80:67-73, 1998.; 2.Kiely M, et al. Eur J Clin Nutr 53: , 1999; 3.Yeum KJ, et al. J Am Coll Nutr 17: , 1998; 4. Yamini S, et al. Eur J Clin Nutr 55: , 2001; 5. Sherry C, et al. J Nutr. 144: , 2014; 6. Zielinska Nutrients Aug 4;9(8) 7. Vishwanathan R. et al. J Pediatr Gastroenterol Nutr. 2014; 8.Bone RA, et al Invest Ophthalmol Vis Sci 29: , 1988; 9. Johnson E. Nutr Rev Sep;72(9): Shutterstock ; ;

Nature Provides Lutein and Zeaxanthin Lutein is a major carotenoid in colostrum and breast milk. 1,2 The colostrum is heavily fortified with critical antibodies, proteins, L & Z.

3,5 Lutein is 2 to 3 times more concentrated than β-carotene in breast milk. 2 Lutein concentrations in breast milk are proportional to maternal intake.

11 Nature Provides Lutein and Zeaxanthin Lutein is a major carotenoid in colostrum and breast milk. 1,2 The colostrum is heavily fortified with critical antibodies, proteins, L & Z. The yellow of colostrum is due to the high concentration of carotenoids. 1 Lutein levels in mom s blood and breastmilk decreases during breast feeding. 3,5 Lutein is 2 to 3 times more concentrated than β-carotene in breast milk. 2 Lutein concentrations in breast milk are proportional to maternal intake. 4 Nature puts L & Z in the colostrum to help deliver an initial boost of protection that the baby needs for healthy development. (1) Patton S, et al. Lipids 25: , (2)Khachik F, et al. Anal Chem 69: , (3)Schweigert FJ, et al. Eur J Nutr, 43(1): p , (4)Cena, H., et al. Public Health Nutr, 12(10): p ; (5)Sherry et al., Journal Nutr First published ahead of print June 4, 2014 as doi: /jn Shutterstock:

12 Eye Development

Early Need for Lutein and Zeaxanthin First 16 weeks of life Cone cells gradually become predominant in the fovea resulting in improved visual acuity.

13 Early Need for Lutein and Zeaxanthin First 16 weeks of life Cone cells gradually become predominant in the fovea resulting in improved visual acuity. 2 The outer plexiform layer becomes discernible within the retina (layer that contains the highest concentration of L & Z) to 22 weeks of gestation Lutein is present in the fetal retina. 1,2 By 4 years of age The photoreceptors have reached near-adult lengths and the outer plexiform layer is fully formed and visual acuity is approaching adult levels. 2 (1) Bone RA, et al. Invest Ophthalmol Vis Sci 29: , (2) Handelman GJ, et al. Invest Ophthalmol Vis Sci 29: , (3) Hendrickson (2016) Am J Ophthalmol Jan;161:29-35.e1. Shutterstock:

14 Infant Versus Adult Eye The changes in L/Z ratio in the macula appear to be closely related to steps in anatomical development. 1,2 In adults ratio of L to Z in the central macula are approximately equivalent. 1 In infants L & Z concentration in the fovea increase during childhood 1,2 Lutein is the dominant carotenoid in infant retina Premature infants have undetectable MP (1) Bone RA, et al. Invest Ophthalmol Vis Sci 29: , (2) Berstein PS et al. IOVS;54: , 2013 Shutterstock:

susceptible to UVA and blue light damage 1 Fovea Poorly developed and nonfunctional at birth 1,3-5 Immature cone receptors, maturity of the fovea but the third to forth postnatal year 5,8 Cone

15 Why are children particularly susceptible? Orbital Size The size and length of the eye is smaller in infant 1 Increases significantly during the first 4 to 6y 1 Increased retinal light dose 2 Lens Infant lens is transparent to light 1 More susceptible to UVA and blue light damage 1 Fovea Poorly developed and nonfunctional at birth 1,3-5 Immature cone receptors, maturity of the fovea but the third to forth postnatal year 5,8 Cone density increases 80% from birth to 4-5y 1 Rapid changing area, maturation in the first 4y 6 Increased metabolic activity Oxidative stress 7 Accumulation of lipofuscin in the first years 4 Adult 60-70y Child <9y 1.Hammomd BR. Nutr Rev. 66(12): , 2008; 2. Quigley et al, Invest Ophthalmol Vis Sci Aug 1;59 3.Abramov I, et al. Science, 217:265-7, (SA ) 4. Wing GL et al. IOVS.17: , Bone RA, et al. Invest Ophthalmol Vis Sci 29: , Hendrickson et al, Ophthalmology Jun;91(6):603-12; 7. Zielinska Nutrients Aug 4;9(8); (8) Hendrickon et al, Ophthalmology Jun;91(6): Images Adapted from SCENIHR Health Effects of Artificial Light, European Commission, 2012 Blue Blue Visible >500nm Visible >500nm Absorption Transmitted Absorption Transmitted

16 Brain Development

17 Preferential Uptake of Lutein into the Infant Brain Department of Health and Human Services. CDC. Vital and Health Statistics, Series 11, Number 245. July 2002 Vishwanathan R, et al., J Pediatr Gastroenterol Nutr 2014, 59(5): Reviewed in Maci S. at al. Nutrafoods :

18 Lutein and Cognitive Performance Key Findings Children Study Participants Key Findings 56 preadolescent (8-9y) 40 preadolescent (7-10y) 51 healthy children (49% female) from 7 13y Retinal L and Z, measured as MPOD, is positively related to academic achievement, mathematics and written language in children MPOD positively and significantly predicted hippocampal-dependent memory performance MPOD positively and significantly associated with a spatial reconstruction task designed to assess hippocampal-dependent relational memory performance Link between higher carotenoid status and improved cognitive functioning MPOD was significantly correlated to: Global Intelligence (p<0.05) Executive Processes (p<0.05) Spatial Relations subtest (p=0.035) Approached significance in Cognitive Efficiency (p=0.074) MPOD Macular pigment optical density L, Z Lutein and Zeaxanthin Shutterstock:

Lutein & Zeaxanthin Key Findings - Children Lutein is the predominant carotenoid in infant brain 1 Preterm infants have decreased concentrations of brain carotenoids 1 Higher carotenoid status linked

to conception along with folate may help reduce risk of neural tube defect-affected pregnancies 4 L is concentrated in regions important for learning and memory (FC, HIP, OC), and is correlated with

19 Lutein & Zeaxanthin Key Findings - Children Lutein is the predominant carotenoid in infant brain 1 Preterm infants have decreased concentrations of brain carotenoids 1 Higher carotenoid status linked to improved cognitive functioning in preadolescent children 2 L and Choline work together in support of infant brain development and subsequent cognitive development 3 Intake of L by the mother prior to conception along with folate may help reduce risk of neural tube defect-affected pregnancies 4 L is concentrated in regions important for learning and memory (FC, HIP, OC), and is correlated with fatty acids, phospholipids and amino acid neurotransmitters in the brain 5 FC Frontal Cortex HIP - Hippocampus OC Occipital Cortex L Lutein MPOD Macular Pigment Optical Density Associations between MPOD, and cognitive performance 6, memory 7 and academic achievement 8 Vishwanathan R. et al. J Pediatr Gastroenterol Nutr Saint et al. Nutrients Feb 10;10(2). pii: E193. doi: /nu Cheatham et al. Nutrients 2015, , haw GM, et al. Epidemiol. 10: , Lieblein-Boff et al. PloS ONE 2015, 10 e Walk A et al., childhood International Journal of Psychophysiology 118 (2017) Hassevoort K et al J Pediatr Apr;183: Barnett S et al., 2017 Nutritional Neuroscience.

Mechanisms of Action Lutein and Zeaxanthin Lutein integrates into cellular membranes into specific directions, likely

1 Antioxidant and antiinflammatory properties 6 May increase the speed with which messages are transmitted across neurons

rapidly moving objects Increases visual processing speed and vision under dim light 3-5 1.

04. 2. Stahl W, Biofactors, 15:95-98, 2001. 3. Hammond BR, et al., Ophthalmic Physiol Opt. 25:315-9, 2005. 4.

20 Mechanisms of Action Lutein and Zeaxanthin Lutein integrates into cellular membranes into specific directions, likely influencing the functional properties of synaptic membranes. 1 Antioxidant and antiinflammatory properties 6 May increase the speed with which messages are transmitted across neurons 1,2 Enhances gap junction communication 2 Light processing in the retina Helps improve reaction time and processing of rapidly moving objects Increases visual processing speed and vision under dim light Gruszecki WI, Carotenoids in Health and Disease. New York: Marcel Dekker, Inc , Stahl W, Biofactors, 15:95-98, Hammond BR, et al., Ophthalmic Physiol Opt. 25:315-9, Renzi LM, et al. Ophthalmic Physiol Opt. 30:351-7, Renzi LM, et al. Exp Eye Res, 91: , Mares J. Lutein and Zeaxanthin Isomers in Eye Health and Disease Annu Rev Nutr Jul 17; 36: ; Photos: IMG-KH (eye) and shutterstock_ (brain).

21 Shutterstock: ;

22 Baseline values Clinical Studies - Sherry C, et al. Effects of FloraGLO Lutein supplementation in lactating women 1 82 breastfeeding women, 4-6 weeks postpartum 6 week supplementation of placebo, 6 mg or 12 mg FloraGLO Lutein Assessed maternal plasma, maternal breast milk, infant plasma Total lycopene was the most abundant in maternal plasma. Total L + Z was most abundant carotenoid in breast milk. Infant plasma carotenoids most closely matched that of breast milk. Sherry C, et al. J Nutr. 144: , 2014.

23 Total L + Z in Maternal Plasma (mg/dl) Total L + Z in Breast Milk (mg/dl) Clinical Studies - Sherry C, et al ** # ** ** # ** ** ** * # ** Placebo 6 mg Lutein Per Day 12 mg Lutein Per Day Baseline 6 Weeks Change Baseline 6 Weeks Change * p < 0.05 compared to baseline., ** p < compared to baseline, p < 0.05 between treatments. Results : Total L + Z significantly increased with both lutein dosages compared to baseline in maternal plasma and in breast milk. At 6 weeks the change in total L + Z concentration was significant between groups for the 12 mg/day dosage for both maternal plasma and breast milk. FloraGLO Lutein Supplementation increases the amounts of L & Z in bloodstream and breast milk of healthy pregnant women. Sherry C, et al. J Nutr. 144: , 2014.

24 Total L+Z in infant plasma (µg/dl) Sherry C, et al. results - Effect of Supplementation in Infants Increase in total L+Z concentration in infant plasma o 180% and 330% greater concentrations for the low and high dose, respectively, at the end of the study vs the placebo group (p < 0.05) weeks after maternal lutein supplementation * No differences in other non lutein carotenoids in infant plasma Breast milk total L+Z was significantly correlated with both maternal and infant plasma at the end of the study o r = 0.74 and r = 0.81, respectively p< for both Maternal and infant plasma total L+Z were also significantly correlated (r =0.82, p < ) Placebo * Low Dose (6mg L/Day) * p<0,05 versus placebo High Dose (12mg L/Day) Sherry et al., Journal Nutr First published ahead of print June 4, 2014 as doi: /jn

25 Safety, Bioavailability and Suitability of FloraGLO Lutein for Infant- and Follow-on Formulae EFSA Opinion (2008) on the Safety, bioavailability and suitability of lutein for the particular nutritional use by infants and young children The Panel considers that the information provided in the dossier does not raise concerns about the safety of lutein in infant formulae at the levels achieved through the natural content of ingredients nor at the level of use (concentration of added lutein 250µg/l) proposed by the applicant for infant formulae with a low natural lutein content (about 20 µg/l or lower). Based on the studies provided, the Panel concludes that lutein from FloraGLO is bioavailable in infant formulae.

Infant Nutrition FloraGLO Supplementation doses clinically tested: 1.

Pigment Optical Density (MPOD) Serum Lutein Concentrations Visual Function And Performance *Review

26 The Most Clinically Researched Lutein Brand Worldwide* Over 80 human clinical trials published in peer-reviewed journals Brain Health and Cognitive Function AMD Progression (AREDS2) Maternal and Infant Nutrition FloraGLO Supplementation doses clinically tested: 1.7 to 40mg/day for periods of up to 5 years Skin Health Absorption and Bioavailability Macular Pigment Optical Density (MPOD) Serum Lutein Concentrations Visual Function And Performance *Review of the scientific literature available through PubMed as of November 1, 2017 KHTL Human Clinical trials with FloraGLO Lutein

27 Why FloraGLO Lutein? The L brand clinically proven safe for use in infant nutrition 1 The only L brand GRAS for infant formula 1 The most researched L brand worldwide 2 The lutein brand chosen by the US National Eye Institute for use in AREDS2, the largest L supplemental trial to date 3 The #1 doctor recommended lutein brand (USA) 4 Kemin owns a patent showing how lutein protects individuals with three common ocular disorders from blue light or lightinduced damage associated with computers, smartphones and sunlight 5 GRAS Generally recognized as safe 1.U.S. Food & Drug Administration, GRAS Notice Inventory, GRN No. 140, 221 and PubMed, Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 309, (2013). 4. Based on the results of the US Quintiles IMS National Disease and Therapeutic (NDTI) syndicated report among US physicians who recommend a dietary supplement with lutein for eye health between April 1, 2016 to March 31, US Patent 9,226,940 B2, Method of Treating Ocular Disorders, Issued Jan. 5, 2016 to Kemin Industries These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. This business-tobusiness communication is not intended to be directed to the final consumer.

28 Thank you

KEMIN nd Pentvision White Paper.indd 1

KEMIN nd Pentvision White Paper.indd 1 KEMIN011838-03-2nd Pentvision White Paper.indd 1 2 Exploring the Lutein Link in Ocular and Neural Health Lutein, a dietary carotenoid common to fruits and vegetables, has strong support for its role in