Nutraceutical in AgingSpecial emphasise on cognitive aging Prof

Nutraceutical in Aging…Special emphasise on cognitive aging Prof Dr Suzana Shahar Community Rehabilitation and Aging Research Centre, Faculty of Health Sciences, UKM

Malaysia Aged Population 2050 Birth Mortality Malaysian population pyramid according to age groups and gender 2000 and 2010

Aging Rapidly q Malaysia aged population 2043 (2020: 7% 65 years ++) → 14 % year 2043 (23 years) q 7% → 14%: France (115 y), UK (45 y), US (69 y) (Ismail et al. 2015) Increase in lifespan (Gender & Ethnic)

Aging at a Higher Disability Rate Model in developed countries, population productive up to the age of 65 y, however, in Malaysia the level of disability for similar age cohorts is much higher than in a developed country (Australia). So realistically our local population can be expected to be productive until the age of 60 years or les * Local surveys: Determinants of Wellness among Older Malaysians: A Health Promotion Perspective (Wellness 2008), Mental Health and Quality of Life among Older Persons in Malaysia (MHQo. L 2006), Patterns of Social Relationships and Psychological Well Being Among Older Persons in Peninsular Malaysia (PWB 2007). Total 7328 subjects.

Aging at a Higher Disability Rate * Local surveys: Determinants of Wellness among Older Malaysians: A Health Promotion Perspective (Wellness 2008), Mental Health and Quality of Life among Older Persons in Malaysia (MHQo. L 2006), Patterns of Social Relationships and Psychological Well Being Among Older Persons in Peninsular Malaysia (PWB 2007). Total 7328 subjects .

Causes Aging at a Higher Disability Rate Middle age risk factors (Enter aging at little body reserves): q Obesity: Raised body mass index has been identified by WHO (2016) as an important cause of chronic disease in Malaysia, stating that at least 80% of premature heart disease, stroke and type 2 diabetes could be prevented through healthy diet, in addition to regular physical activity and avoidance of tobacco products. q Cardiovascular, hypertension, diabetis mellitus, cancer, osteoporosis and demensia q Poor diet, sedentary lifestyles, physical inactivity q Lack of infrastructure and support for rehabilitation.

LRGS TUA- Neuroprotective Model for Healthy Aging for Malaysian Older Adults (2012 -2016)

q First in Malaysia (aging): Prospective cohort study; 0, 18, 36 month q 60 years and above, n=2000+++ q Multidisciplinary q Multi institutional

Successful Aging (SA), Usual (UA) & Mild Cognitive Impairment (MCI) (n=2122) (Shahar et al. 2015 a) 16% 11% SA UA MCI 73% Successful aging/ Healthy aging (Rowe & Kahn 1997, Hamid et al. 2012): 1. Free from diseases (DM, HPT, canser, CVD, Respiratory, stroke) 2. No functional limitation 3. Good cognition/ mental health 4. No depression 5. Good quality of life 6. Good self perception on health

25. 0 21. 1 22. 1 20. 0 Percentage (%) Higher Prevalence of MCI among B 40 Group, Cheras Cohort Prospective Study (CCP): Low-Moderate income Older Persons (n=318) Men (n = 130) Women (n = 188) 16. 9 14. 6 15. 0 10. 0 6. 5 5. 2 5. 0 0. 0 All Type MCI Am-MCI Nam-MCI Lee LK et al. (2011). Prevalence of gender disparities and predictors affecting the occurrence of mild cognitive impairment (MCI). J Gerontol.

Prevalence of Healthy Ageing 2002 - 2015 Malaysia 13% 2002 - 2006 *Different criteria USA Thailand Eropah Singapura Malaysia 10. 9% 27. 5%* 8. 5% 17. 8%* 11% 2010 2011 2012 2013 2015

15

Mild Cognitive Impairment (MCI) MCI Pre-demented stage of Alzheimer disease (AD) Transitional stage of normal aging and a very mild dementia Reversible if getting detect early 10 -15% per year Conversion rate To AD 16

Risk Factors of Cognitive Decline Diet (+): -Tropical fruits/ juices, oats, bread -Calorie Restriction (Sunnah fasting & Healthy vegetarian diet) Socio-demography & co-morbidity: -↓Education level -↑Age -Hyperlipidemia - ↑Blood sugar Frailty/ Falls MCI(At baseline) Anthropometry: BMI ≥ 26 kg/m² -Waist circumrence: Men≥ 90 cm; Women ≥ 82 cm Calf circumference: Men≤ 29 cm; Women≤ 26 cm Physical fitness: Handgrip strength Timed up and Go Lifestyle (mental, physical & social) Mediators Functional disablity Screening for Mild cognitive impairment (MCI) ‘TUA Wellness’ (Vanoh et al. 2016 a, b)

Predictors Cognitive (At 18 Months) Diet: Fruits & Juices Not practicing CR (Sunnah fasting & Healthy vegetarian diet) Sosio-demography & co-morbiditiy Education Hyperlipidemia Hyperglycaemia Functional disabilty MCI (18 months) Lifestyle: - Not engage in technical activity -Less usage of modern technology -Less involvement in mental activity*

Factors influencing cognitive impairment Environmental stimulation Existing disease status Genetic Lifestyle Smoking MCI Alcohol drinking Supplements intake APOE allele Family history Social Dietary Physical activity Social engagement Omega-3 FA Immobile Social background Folate Active Education level Antioxidants Epidemiological studies reported that biophysical health, lifestyle, dietary pattern and social interaction are associated with cognitive decline leading 19 to dementia (Deweerdt S. 2011; NATURE OUTLOOK).

LRGS TUA: NUTRIENT INTAKE AND COGNITION . In men, inadequate energy and thiamine were the highest in MCI, followed by UA and SA A higher percentage of women with MCI had an inadequate intake of vitamin A, vitamin C and iron (p< 0. 05) as compared to UA and SA.

NUTRIENT INADEQUACY 1996 Vitamin A, B, tiamin, riboflavin, niasin & calcium 2000 Energy, tiamin, riboflavin, niacin, vitamin E, Iron, calcium 2007 2016 Energy, thiamin, riboflavin & calcium Tiamin, niacin, folic acid, vitamin E, calcium, zink, vitamin A, C, riboflavin & iron (Suriah et al. 1996, 2000, Suzana et al. 2000, 2016).

Physiological changes with aging: Implication on food intake and nutritional status Reduced sight & hearing Cognitive decline leading to cognitive impairment Anorexia: alteration taste & smell Maldigestion & malabsorption: Constipation Diarrhea Hormonal changes: Chronic diseases Body composition changes: % Body Fat Lean Body Mass Total Body Water Bone density

Okinawan Centenarians : 50 per 100, 000 vs 5 -10 per 100, 000 USA

Mediterranean Diet Reducing risk of obesity, diabetes, heart disease, depression and Alzheimer

Okinawa Mediteranean Cereals Rice, Sweet Potatoes Rice, Pasta, Wholegrain bread, Potatoes Protein Fish, taufoo & soy bean Fish, seafood, skinless chicken, nuts Limit red meat Vegetables & Fruits 10 servings/ d 9 servings/d Types of veges Bittergourd Seaweed Tomato, Olive, Tomato paste Oils Vegetable & olive Cooking Method Slow cooking, turmeric, Spices & herbs, grill/ soup bake Snack Fruits, nuts & legumes, cheese, yogurt Beverages Green tea Wine Eating habit Eat little Eat slowly Lifestyle Physical activity, social Physical activity, family (moai), spiritual & tie, social positive (Ikigai)

Caloric restriction improves memory in older adults (Witte et al. 2009) • Animal studies: diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age (Keys et al. 1957). • n=50 healthy, normal- to overweight elderly subjects (29 females, mean age 60. 5 years: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. • Before and after 3 months of intervention, memory performance was assessed under standardized conditions.

Caloric restriction improves memory in older adults (Witte et al. 2009) • A significant increase in verbal memory scores after CR (mean increase 20%; P < 0. 001), correlated with decreases in fasting insulin levels and high sensitive CRP among subjects with best adherence to CR( p< 0. 05). • Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity.

Fasting Calorie Restriction • 25 healthy aging Malay men, BMI 23 -29 kg. m 2, mean age years: 55 y • FCR: reduction of 300 -500 kcal/d from habitual intake + 2 days sunnah Muslim fasting • FCR: Reduced BW, BMI, body fat, depression & increased Qo. L • % reduction of BW FCR (-3. 4%) > CR (-2. 7%)(Witte et al. 2009) • FCR: reduced tension, anger, confusion and Total Mood Disturbance • • Nur Islami Mohd Fahmi Teng; Suzana Shahar et al. (2011). Physio & Behavior; 104(5): 10591064. N. M. Hussin; S. Shahar et al (2013). J. Nutr Health Aging; 17(8): 674 -680.

Sustainability FCR (LRGS TUA) q Baseline: Sunnah fasting/ healthy vege diet reduce risk of MCI q At 3 years: Regular or occasional faster reduce DNA damage & lipd peroxidation & increase activity of antioxidant enzyme 20 10 0 * * * 3 2. 6 2. 2 Momen ekor (%) Ekor DNA (%) Perbezaan Status Amalan Puasa Sunnah dengan Kerosakan Ekor DNA (%) dalam Kalangan Warga Emas 30 MCI Perbezaan Status Amalan Puasa Sunnah dengan Kerosakan Momen Ekor (%) dalam Kalangan Warga Emas MCI * 1. 8 1. 4 1 0. 6 * 0. 2 Kerap Jarang Tidak -0. 2 Kerap Status Amalan Puasa 36 Bulan Perbezaan Status Amalan Puasa Sunnah dengan Aras MDA dalam Kalangan Warga Emas MCI * 100 50 Jarang Status Amalan Puasa Dasar 100 80 Aras SOD MDA (nmol/mg protein) Dasar 150 * * Tidak 36 Bulan Perbezaan Status Amalan Puasa Sunnah dengan Aras SOD dalam Kalangan Warga Emas MCI * 60 40 20 0 0 Kerap Jarang Status Amalan Puasa Dasar 36 Bulan Tidak

Cognitive Status after 36 Months Sunnah fasting Cognitive status Regular Occasionally None Successful aging (SA) 6 (42. 9) 2 (14. 3) Mild cognitive impairment (MCI) 1 (4. 5) 5 (22. 7) 16 (72. 7) Usual aging (UA) 37 (58. 7) 14 (22. 2) 12 (19. 0)* *p<0. 05 Chisquare test

ENERGY AND NURIENT REQUIRMENT (RNI) FOR OLDER INDIVIDUALS AGED 60 AND ABOVE (NCCFN 2017) Nutrient Energy (kcal/d) Men Women Food sources 1780 -2540 1550 -2220 - 58 50 Lean meat, chicken, fish, egg, nuts, legumes 1000 1200 Milk and milk’s products, legumes, tempeh, tafoo Ferum (mg/d) 14 (10% bio) 9 (10% bio) 11 (10% bio) 8 (15% bio) Lean meat, chicken, green leafy vegetables Zinc (mg/d) 6. 3 (60 -65 y) 6. 2 (>65 y) 4. 4 (60 -65 y) 4. 3 (>65 y) Lean meat, fish, seafood, egg, milk and milk’s products Selenium (µg/d) 31 (60 -65 y) 30 (>65 y) 23 Fish, organ meat, egg, milk, shellfish Thiamin (mg/h) 1. 2 1. 1 Rice, cereals, nuts, legumes Riboflavin (mg/h) 1. 3 1. 1 Milk and milk’s products, cereals, green leafy vegetables Protein (g/h) Calcium (mg/d)

Niacin (mg NE/s) 16 14 Lean meat, chicken, fish, nuts, legumes, cereals Folate (µg/d) 400 Green leafy vegetables, nuts, cereals Vitamin C (mg/d) 70 70 Citrus fruits, vegetables Vitamin A (µg/d) 600 Liver, milk, vegetables, orange Vitamin D (µg/d) 15 (60 -65 y) 20 (>65 y) 15 (6065 y) 20 (>65 y) Fortified milk, sardine, liver, egg Vitamin E (mg/d) 10 7. 5 Vegetables, cereals, nuts, cereals

Do elderly individuals need vitamin, mineral and dietary supplement? No need if able to take a well balance diet to meet nutritional requirement. Anorexic, avoidance of specific food. Bernstein & Munoz (2012). Position of the Academy of Nutrition and Dietetics and Nutrition for Older Adults: Promoting Health and Wellness; Journal of th Academy of Nutrition and Dietetics; 112 (8): 1255 -1277

Why US Adults Use Dietary Supplements (Bailey et al. 2013; JAMA Intern 2013; 173(5): 355 -361) • National Health and Nutrition Examination Survey, 2007 -2010, ≥ 20 years; n = 11956. • More than half used dietary supplements • • Reasons usage: “improve” (45%) or “maintain” (33%) overall health. Women: calcium products for “bone health” (36%), men: “heart health or to lower cholesterol” (18%). Older adults (≥ 60 years) were more likely than younger individuals to report motivations related to site-specific reasons like heart, bone and joint, and eye health. Only 23% of products were used based on recommendations of a health care provider. Multivitamin-mineral products were the most frequently reported type of supplement taken, followed by calcium and ω-3 or fish oil supplements. • • Supplement users are more likely to report very good or excellent health, have health insurance, use alcohol moderately, eschew cigarette smoking, and exercise more frequently than nonusers.

Dietary supplement use among adults in Malaysia: finding from Malaysian Adults Nutrition Survey (MANS 2014) Mohd Zaki et al. 2015; MJM, Vol 70 (Suppl 1) • Vitamin/mineral supplements (VMS): 28. 1%; Female, urban, educated, higher monthly income. • Vitamin C, multivitamin and calcium. • Food supplements (FS): 34. 0% • Fish oil, royal jelly and spirulina • Reasons: health reasons, increase energy level and prescribed by doctors.

LRGS TUA (n=2274) • Supplement user 29. 1%; women (32. 1%), Men (25. 8%) • Higher education (college/ university) (50%) • Multivitamin, calcium, vitamin E, fish oil, vitamin C

Why Nutraceuticals? • Traditional dietary approaches have proven successful as part of the treatment for obesity & cardiometabolic derangements within clinical trial scenarios, less sustainable, long term, poor compliance. • Difficulties to get adequate nutrition from the routine food. • Highly toxic environment, filled with pollution and pesticides: increased requirements for nutrients? • Natural ingredients (long half life, easily absorbed) to strengthen body system vs antibiotic & side effects from drugs • Feeling stronger and healthier, more energy and prevent illness. • Alternative for standard treatments for specific illnesses or adjunct therapy of modern medicine

PARADIGM SHIFT: SINGLE NUTRIENT SUPPLEMENT (HIGH DOSAGE → MULTIVITAMIN (LOW DOSAGE) → NUTRACEUTICALS -Carotene & Retinol Increase Lung Cancer Incidence Active Treatment 4 3 Placebo Cumulative Incidence of 2 Lung Cancer (%) 1 0 0 12 24 36 48 60 Months After Randomization ABC and Caret Trial: Omenn et al. (1996) 72

Nutraceuticals: nontoxic food component, non-specific biological therapies used to promote wellness, prevent malignant processes and control symptoms. Dietary supplements Functional Foods Nutraceuticals Definition More defined health roles: vitamins, minerals, herbs/ botanicals, AA/ other dietary substances supplementing the diet by increasing the total dietary intake of these ingredients Food products taken as part of the usual diet to have beneficial effects beyond what are known as traditional nutritional effects Products extracted, purified or produced from plant/ animal/ marine (e. g. demonstrated to have a physiological benefit/ protection chronic disease) Purpose Supplement the diet, not intended to treat or cure disease Prevention or treatment Protection chronic of diseases disease Examples Vitamin and mineral supplements, oral nourishing fluids Milk, cheese and eggs enriched with omega-3 fatty acids; probiotics; Drinks increased antioxidant levels; cereals enhanced dietary Antioxidants (blueberries, elk velvet, fish oils), dried, powdered/ pressed plant material

Food & Nutraceutical for the Brain • Polyphenols (Berries) (Willis et al. 2009; Roe et al. 2008) • Plant foods [fruits, vege, nuts (almonds, walnuts)] (Nurk et al. 2010) • Curry (curcumin) (Ng et al. 2006) • Tea (Ng et al. 2008), Green Tea (Kuriyama et al. 2006) • Fish (Barberger-Gateau et al. 2002, Kalmijn et al. 1997, Morris et al. 2003) • Most are epidemiological studies

Fish Consumption • Chicago Health and Aging Project (CHAP) Study: Cognitive decline rate 10% slower if consumed 1 fish meal per week & 13% slower if consumed 2 or more fish meal per week (Morris et al, 2003) • Non MCI subjects consuming more fish rich in omega-3 fatty acid (ie. Black pomfret) as compared to MCI(p<0. 05)(Shahar et al. 2012). • Omega 3 FA neuroprotective by reducing CVD risk and nonhaemorrhagic stroke risk (antiarrhythmic, antithrombotic, anti- inflammatory and antiatherogenic effects), thus reducing the synthesis of pro-inflammatory components, maintain membrane integrity and neuronal function. • Omega 3 FA: expression of ß-amyloid (AD)

Super food: Fish • Omega 3 fatty acids, ‘brain food’ and ‘heart food’ • 1 – 2@ more servings/ week: Reduce cognitive decline 10% - 13% • Tropical fish less omega 3 FA (Osman et al. 2001). • 5 sevings/ week (Johari et al. 2014) → omega-3 FA, 500 mg/ d (NCCFN 2005; Ng 2006).

Omega 3 Fatty Acids Food Sources Type of food Serving size Weight (g) Omega 3 (mg) Salmon Kembung 1 pc 1 medium 55 55 930 814 Cencaru Tamban ½ whole 1 medium 55 55 814 517 Bawal putih Sembilang ½ whole 1 medium 55 55 506 500 Bawal hitam Senangin Jelawat Tenggiri papan Omega 3 egg ½ whole 1 pc 1 whole 55 55 50 468 363 350 341 300 Crab Tuna Sardine ½ whole 1 medium 55 55 55 170 165 Prawn 9 medium pieces 55 135 Siakap Milk fortified omega 3 1 pc 4 dsp/ 1 cup 55 31/ 250 ml 130 90 Haruan Anchovies 1 pc ¼ ccup 55 10 20 5 Ng (2006) dan Osman, Suriah and Law (2001)

CCP study: Efficacy of fish oil supplementation in delaying cognitive decline in MCI individuals (Lee et al. 2013) Single-Blind, Randomised Controlled Trial -----12 months: Feb 2010 -Feb 2011 ü Matching variables: Age, gender and ethnic FIRST ARM (GRP A) SECOND ARM (GRP B) • Fish oils capsule (DHA 1290 mg, EPA 450 mg) • N = 20 • Isocaloric placebo oil • (corn oil) N = 20 ü Inclusion criteria: MCI, not taking fish oils supplements, not taking medicine that may affect lipid profile 4 -Dec-08 45

Neuropsychological Test Cognitive Domain Assessed Test Cognitive Function Global cognition MMSE Global function Dementia CDR Memory (Learning/Recall) WMS-R Visual Reproduction I & II WMS-R Digit span RAVLT Cortical function Executive function WAIS-III Block design WAIS-III Matrix reasoning CDT Subcortical function Attention/Processing speed WAIS-III Digit symbol Depression Geriatric Depression Scale (GDS)

Efficacy of fish oil supplementation on Neurocognitive Tests’ Score Cognitive domain Neurocognitive Test Intervention effect (ηp 2) Time effect (ηp 2) Group effect (ηp 2) Global function MMSE 0. 023 0. 228* 0. 016 Memory RAVLT 0. 119* 0. 231* 0. 026 Total Digit Span 0. 157* 0. 001 0. 100 Visual memory reproduction I 0. 086 0. 251* 0. 012 Visual memory reproduction II 0. 084 0. 204* 0. 018 Attention Digit Symbol 0. 024 0. 019 0. 005 Executive functioning Matrix reasoning 0. 033 0. 042 0. 037 Block design 0. 036 0. 019 0. 037 CDT 0. 032 0. 107* 0. 004 GDS 0. 033 0. 024 0. 028 Depression *p<0. 05 using repeated measure (ANCOVA), with total years of education as covariate Lai Kuan Lee; Suzana Shahar; Ai-Vyrn Chin; Noor Aini Mohd Yusoff (2013). Psychopharmacology; 225(3): 605 -612.

Increase consumption of vegetables and fruits Aging, Inbalance of Free Radicals and Antioxidant Fruits & veges: antioxidant & Poliphenol, free radical scanvenger Fiber & natural detox

Recommendations of Fruits & Vege 400 g/ d 2 Fruits & 3 Veges • Malaysian Adults Nutrition Survey (MANS): • Fruits not listed as top 10 food consumed daily/ weekly. • 4 in 10 adults consume green leafy veges routinely (Norimah et al. 2008).

Older adults not consuming enough veges & fruits • Risk of MCI (LRGS TUA) (Ishak et al. 2015, Vanoh et al. 2016 a). • Barriers: dental, food belief and cost (Ishak et al. 2015). • 50% chewing difficulties and food belief (Shahar et al. 2000). • v v v Implication to policy and promotion strategy: ‘Edible garden’ Dental Modification texture, preparation Sensitivity, food belief, culture Role of neutraceuticals

Recent advances in berry supplementation and age-related cognitive decline (Willis et al. 2009, Rao et al. 2008) • Berry fruit supplementation demonstrates efficacy in reversing age-related cognitive decline in animal studies. • Mechanisms (animal models): berries can influence cell-signaling cascades both in vivo and in cell culture systems, not just oxygen radical neutralizers in the aging central nervous system: neuroprotective (Rao et al 2008).

Concord Grape Juice Supplementation (Krikorian et al. 2010; 2012) • Concord grape juice contains polyphenol compounds, which have antioxidant and antiinflammatory properties and influence neuronal signalling. • 1 st trial: n=12 older adults with memory decline but not dementia, RCT, double blind, 12 weeks. • A significant improvement in verbal learning and non-significant enhancement of verbal and spatial recall. A small increase in fasting insulin was observed for those consuming grape juice. • 2 nd trial: Older adults with MCI, RCT, 16 w, memory function and brain activation f. MRI pre- and postintervention. • • • Participants consumed grape juice: Reduced semantic interference on memory tasks. Greater activation in anterior and posterior regions of the right hemisphere (f. MRI) • Concord grape juice enhance neurocognitive function in older adults with mild memory decline, however, more comprehensive investigations to evaluate potential benefit and assess mechanisms of action.

Mental health and polyphenol q 3 to 4 in 10 middle aged adults had reduced mental health q Min polyphenol intake lower in individuals with lower mental health (sx anxiety and insomnia) (Rosli, Shahar et al. 2017) Phenolic aci Anxiety and insomnia No Yes 346. 0 ± Flavonoid >0. 05 Antocyanin 277. 9 ± 1. 30 0. 02* 378. 2 207. 5 593. 2 ± 210. 0 ± 497. 3 176. 9 2. 7 ± -1. 74 0. 12 5. 9 9. 8 ± 11. 2 * p<0. 05, independent sample t test 53

‘Super food’: Tropical fruits (Shahar et al. 2016) Nutrients q Formulation of mixture of tropical fruits ‘TP 3 -in-1’ rich in polyphenol q Middle-aged women (aged 45 -59 years) with signs of impaired cognitive (n=11 intervention, n=10 control). q 500 ml juices (BF, Lunch and Dinner) 3 x weeks (10 weeks) (9135 mg GAE phenolic) q Positive effect on short term memory and oxidative stress (p<0. 05 for both parameters). q Tropical fruits similar to Mediterrnean fruits, eg. Berries (brain fruits), improve cognitive function. Juice (per 100 ml) Placebo (per 100 ml) Moisture (%) 90. 00 90. 34 Ash (%) 0. 15 0. 00 42 43 Protein (%) 0. 16 0. 00 Fat (%) 0. 00 CHO (%) 10. 31 10. 69 4 - Total sugar (g/100 ml) 10. 9 11. 2 Total phenolic content (mg GAE/100 ml) 609. 00 3. 10 Total anthocyanins monomer (mg/100 ml cyanidin-3 -glucoside) 12. 94 0. 08 Energy (kcal) Vitamin C (mg/100 ml)

fat intake Hypercholesterolemia lignan intake flavonoids intake iron intake FA RIS CT K OR S MENTAL HEALTH AND COGNITIVE STATUS • Verbal memory, learning, memory retention • Processing speed, sequencing, mental flexibility & visual-motor skills TEMPORAL LOBE IVE T EC RS T O PR ACTO F POLYPHENOLSRICH TP 3 -in-1™ juice *Increase in blood sugar Lipid peroxidation Thyroxine (stability to human transthyretin) Metabolites profiles 3 -methyladenine (activation of autophagy) 55

Novel concepts on functional foods and nutrigenomics in healthy aging and chronic diseases: a review of fermented papaya preparation research progress (Marotta et al. 2012); Functional Foods in Health and Disease; 2 (5) • Papaya and its fermentation product are specific products derived from the technologically advanced and controlled environmental-friendly bio-fermentation process. • for a long time that the natural anti-oxidant properties of papaya, mainly depending on vitamins A and C in addition to certain amino acids, were consistent both in the fruit and derived from the papain enzyme • The benefits of fermented papaya preparation are discussed in nutrigenomic basis and it is reported to have an. important antioxidant and transcriptomic potential which deserves further investigation • Fermented papaya preparation represents a Functional Food highly compliant with the novel features of the new nutrigenomic-driven action plan strategy aimed to reduce the incidences of diseases and successful integration within specific pharmacological treatments.

Super Food: Ulam/ Herbs • The Effect of Polygonum Minus (Line. Minus. TM) Extract on Cognitive and Psychosocial (Shahar et al. 2015; Clin Int Aging). • PM extract: flavonoids, antioxidants, anticholinesterase activity (George et al. 2014) • A randomized, double-blind, placebo-controlled trial 35 healthy middle-aged women, 250 mg PM/ placebo 100 mg maltodextrin twice daily, six weeks. • PM supplementation: o ↑ memory & social function, respondent with mood disturbance o ↑ IQ, respondent with no mood disturbance

(Al-Isra’: 82)

Super Food: Talbinah • 1 in 4 -5 older adults, depressive symptoms • Talbinah (barley cooked with milk & honey (25 g talbinah in 100 ml warm water), 1 serving/d, 3 weeks • Reduce risk of depression, stress and bad mood & increase positive mood.

Talbinah profiles in 1 serving (25 g) Item Content RNI% Men Women Energy 94 kcal 4. 9% 5. 2% Carbohydrate (86. 4%) 21. 6 g – – Protein (AA Triptofan: BCAA=1: 2; 1. 2 g 2% 2. 3% Fat 0. 2 g – – Natrium 3. 1 mg – – Magnesium 14. 5 mg – – Calsium 12. 7 mg 1. 2% Zink 5. 2 mg 83. 8% 120% Iron 0. 34 mg 2. 4% 3. 1% AA Tryp: AA neutral = 1: 21)* *Synergistic effect: High compared to milk (1: 4), barley (1: 11). High ratio enable uptake of tryp to brain & stimulate serotonin excretion [Wurtman et al 2003].

The effects of long-term honey, sucrose or sugar-free diets on memory and anxiety in rats (Chepulis et al. 2009), Physiology & Behavior; 97 (3– 4): 359 -368 • • • Sucrose detrimental to health, giving rise to deterioration of the body associated with ageing. Aim: Replacing sucrose in the diet long-term with honey (has a high antioxidant content) decrease deterioration in brain function during ageing? . Methods: 45, 2 -month old Sprague Dawley rats fed ad libitum for 52 weeks on powdered diet, sugar-free (7. 9% sucrose) or 10% honey. Outcome: Anxiety (Elevated Plus Maze), memory (Y maze & Object Recognition task), locomotor activity (Open Field task). Results: Anxiety decreased overall from 3 to 12 months, but the honey-fed rats showed significantly less anxiety at all stages of ageing compared with those fed sucrose. Honey-fed animals displayed better spatial memory throughout the 12 -month period: at 9 and 12 months a significantly greater proportion of honey-fed rats recognised the novel arm as the unvisited arm of the maze compared to rats on a sugar-free or sucrose-based diet. No significant differences among groups were observed in the Object Recognition task, and there appeared to be no differences in locomotor activity among groups at either 6 or 12 months. In conclusion, it appears that consumption of honey may reduce anxiety and improve spatial memory in middle age rat.

Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation (Beilharz et al. 2016, Behavioral Brain Research; 306 (1): 1 -7 • Chronic high-energy diets induce obesity and impair memory; inflammation in brain areas crucial for memory. • Aim: whether inflammation could also be related to diet-induced memory deficits, prior to obesity. • Method: Rats exposed to chow supplemented with a 10% sucrose solution (Sugar) or a diet high in fat and sugar (Caf + Sugar) • Outcome: hippocampal-dependent and perirhinal-dependent memory at 1 week. • Results: Both high-energy diet groups displayed similar, selective hippocampal-dependent memory deficits despite the Caf + Sugar rats consuming 4– 5 times more energy, and weighing significantly more than the other groups. • Conclusion: • Liquid sugar rapidly elevate markers of central and peripheral inflammation, associated with hyperglycemia, and this may be related to the memory deficits in the Sugar rats.

The effect of Nigella sativa Linn. seed on memory, attention and cognition in healthy human volunteers (Sayeed et al. 2013; J Ethnopharmacology; 148(3): 780 -786 Nigella sativa (seed) neuroprotective, nephroprotective, lung protective, cardioprotective, hepatoprotective activities (animal studies) Aim: To investigate the effects of NS on memory, attention and cognition in healthy elderly volunteers. Safety profile of NS assessed. • Methods: 40 elderly randomly divided (Group A 500 mg NS bd & group B placebo), 9 weeks. Outcome: Neuropsychological state and safety profile & cardiac, liver, kidney biomarkers • Results: Significant difference (p<0. 05) in the score of logical memory test-I and II, total score of digit span, 30 min delayed-recall, percent score in Rey-Osterrieth complex figure test, time taken to complete letter cancellation test, time taken in trail making test-A and test-B, score in part C of stroop test. No significant changes (p>0. 05) in biomarkers. • Conclusions: NS in enhanced memory, attention and cognition, however, need study with large population size for longer period of time for novel drug discovery from NS for treating cognitive disorders.

Cautious of mixture prophetic foods • Hadith- Prophet Muhammad SAW prevent mixture of raisins and dates, and specific dates (busr) with others (rutab) especially in drinks, nabiz (Khadher et al. 2015). • Scientifically, both raisins and dates contain high carbohydrate, resulted in alcohol fermentation in 3 to 4 weeks. Both also has rather similar nutrients, mixture will increase sugar, antioxidant and CHO, leading to diabetes, cancer, obesity (Sumaiyah 2014). • Khadher Ahmad, Mohd Yakub @ Zulkifli Mohd Yusoff, Monika@Munirah Abd Razak, Siti Sarah Izham, Mohd Farhan Md Ariffin (2015). Salah Faham Terhadap Istilah Makanan Sunnah Dalam Kalangan Masyarakat Islam Di Malaysia: Satu Analysis. • Mohd Tarmizi, Ishak Suliaman, Halijah Ibrahim (2014). The Prophetic Tradition and Nutrition: Issues of Mixing Raisins and Dates, Online Journal of Research on Islamic Studies, 1(2) 78 -88

Source: Haslina et al. 2017 se Qa k G To Juice Product r ah ie m P re ld ay u ur . . . as m ah nn Su E m a H id rm Go h Ku an an io iu m re a B lim De ak M ti Pa Juice Products DPPH Scavenging Activity (%) 3500 3000 2500 2000 1500 1000 500 0 a P Folin Ciocalteu's Assay im el P. . . ld Go h . . a. Su se ie r h ay a em id Pr d Go l h u . . . ur k G rm a H To A s S ah nn m as E io m iu m re a B lim Ku an an Qa ak i M Pa t De el im a P FRAP Value (m. M) 30 25 20 15 10 5 0 Bi od se Qa u ur ay a H id rm Ku . . . an an k G To ak . . . E. . . io a B lim i M Pa t De a P re el im od Bi Total Phenolic Content (µg GAE/ml) Bi od Antioxidant analysis of nutraceuticals Mixture of Prophetic Foods FRAP Assay Out of 6 products analysed only 2 Products contain high antioxidants Juice Products DPPH Assay 100 90 80 70 60 50 40 30 20 10 0

Goat milk Cow’s milk Difference (%) for goat milk C 4: 0 Butyric 0. 13 0. 11 SCFA -antibacterial C 6: 0 Caproic 0. 09 0. 06 C 8: 0 Caprylic 0. 10 0. 04 MCT - absorption C 10: 0 Capric 0. 26 0. 08 C 12: 0 Lauric 0. 12 0. 09 C 14: 0 Myristic 0. 32 0. 34 C 16: 0 Palmitic 0. 91 0. 88 C 18: 0 Stearic 0. 44 0. 40 C 18: 1 Oleic 0. 98 0. 84 C 18: 2 Linoleic 0. 11 0. 08 CLA – immunity (Ig. E) C 6 -14 total MCT 0. 89 0. 61 +46 C 4 -18 total SFA 2. 67 2. 08 +28 C 16: 1 – 22: 1 Total MUFA 1. 11 0. 96 +16 C 18: 2 -18: 3 total PUFA 0. 15 0. 12 +25 PUFA

Analysis of Fatty Acids of Commercial Goat Milk (Harith et al. 2017) • Out of 20 samples being analysed, only one brand (PURENAT) consists of fatty acids, MCT comparable with control (C: 6, C: 8, C: 10). • Most likely nondairy creamer added to the products

Greek physician Hippocrates’s (2, 500 years ago), “Let food be thy medicine & medicine be thy food”. strong Evidence-based clinical practice guidelines Meta-analysis & systematic reviews Randomized controlled Double Blind studies Cohort studies Case-control studies Case series Case reports Level of scientific evidence Primary Sources Secondary sources Ideas, editorials, opinions Animal Research In vitro (‘test tube’) research 10/29/2020 69 Weak

1001 Secrets of Foods & Nutraceuticals Need to be Explored Scientist Discovery Early 900 AC, Abu Bakr Muhammad Zakaria Al Razi (Al Razi) Al Asrar (Book of Secrets) Categorise food items as animal, vegetables and mineral Early 19 centuries, Mc. Collum & Davis (1913) Identify nutrients in foods (vitamin A & B) Late 1980 an Discover polifenol flavonoids, cafeic acid, tannin, antocyanin and resvatrol (Scalbert and Williamson 2000).

1001 Secrets of Foods & Nutraceuticals Need to be Explored: Cutting-Edges Technology- OMICS q Mixture of tropical juice ‘TP 3 -in-1’: metabolites metiladenine in urin q Activate autophagy process: reduce risk of demensia q Other nutraceuticals

1001 Secrets of Foods & Nutraceuticals Need to be Explored: Cutting-Edges Technology- ‘Neuroinformatics’ Special Interest Group for Neuroinformatics in Aging: International Neuroinformatics Coordinating Facility (INCH), 22 Ogos 2017, Double Tree-Hilton, KL Ongoing trial: P. Minus MCI older adults, 6 months, f. MRI

Conclusion & Recommendations • Nature is the best medicine • Searching for nutraceuticals and neuroprotective food is on going, but also need to explore the neurotoxicity • Stronger evidence for efficacy of nutraceuticals among older adults with functional deficits, not the healthy individuals. • In 2014, a Regional Framework for Action on Ageing and Health in the Western Pacific, 2014 - 2019: 1) promote healthy aging over the life-course and prevent functional decline and disease among older people; 2) to strengthen the evidence based on aging and health (larger RCT, longer duration)

THANK YOU