Effects of Green-MED Diet Via the Gut-fat-brain Axis

Study Overview
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Brief Summary
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Mediterranean (MED) diet, richer in plants/seeds (and dietary polyphenols) and low in processed meat (green-MED diet) may have a pronounced beneficial effect on age-related declines that begin in middle age, reflected by changes in adiposity, cognitive function, and cardiometabolic risk. The investigators hypothesize that long-term intake of this diet will significantly potentiate the effects of a healthy lifestyle (physical activity and Mediterranean diet), constituting a powerful strategy to halt or even reverse the progression of several age-related processes related to adiposity, cardiometabolic health and cognition. The investigators further hypothesize that lifestyle intervention might modify the gut microbiota profile and that autologous fecal microbiota supplement derived from the time of maximal weight loss might halt the expected subsequent regain phase.

Detailed Description
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The investigators aim to compare the effect of green-MED diet+ physical activity (PA) vs. MED diet+ PA vs. PA on the gut-fat-brain axis and to explore the additional contribution of autologous fecal microbiota derived at the rapid weight loss phase on regain phase. Mediterranean (MED) diet, richer in plants/seeds (and dietary polyphenols) and low in processed meat may have a pronounced beneficial effect on age-related declines that begin in middle age, reflected by changes in adiposity, cognitive function, and cardiometabolic risk. The investigators hypothesize that long-term intake of this diet will significantly potentiate the effects of a healthy lifestyle (physical activity and Mediterranean diet), constituting a powerful strategy to halt or even reverse the progression of several age-related processes related to adiposity, cardiometabolic health and cognition. The investigators further hypothesize that lifestyle intervention might modify the gut microbiota profile and that autologous fecal microbiota supplement derived from the time of maximal weight loss might halt the expected subsequent regain phase. The investigators will follow the participants with magnetic resonance imaging (MRI) that will include abdominal and hepatic fat, cardiac and anatomic/functional brain assessments. The investigators will perform cognitive tests and will measure changes in gut microbiota and sub-metabolomic profiling. The trial will be performed in an isolated workplace (the Nuclear Research Center) which holds an exclusive cafeteria that provides free, dietary -monitored, lunch, and an internal medical department. The exclusive nutritional profile of walnuts, with its relative high polyphenols content and unique composition, may benefit several health outcomes. Epidemiologic studies and RCTs suggest that walnuts consumption is associated with better weight status, adiposity measures and cardiometabolic state. However, some individuals avoid walnuts because they are calorie-dense, and fear that they will promote weight gain. Walnuts contain numerous well-characterized beneficial nutritional components, such as unsaturated fats, especially omega-3 fatty acids, dietary fibers, and high levels of vitamins and minerals. Among other well-recognized components, nuts are highly rich in polyphenols, mainly flavonoids. Polyphenols may potentially interact with physical activity and promote neurogenesis; a process that may significantly contribute to the brain's ageing process. Similarly, the polyphenol epigallocatechin-3-gallate (EGCG, a type of catechin found in green tea), was proposed to exert neuroprotective effects. New specific developed strain of duckweed [Wolffia globose, Mankai] , an aquatic plant, which might serve as a protein source and contains all the 9 essential and the 6 conditional amino acids. Mankai [(Generally recognized as safe (GRAS)] is a cultivated strain of Wolffia globosa, which is an aquatic plant, part of the family of plants known commonly as duckweeds. Duckweeds are very simple flowering aquatic plants, which float on or just beneath the surface of still or slow-moving bodies of water. There is a long history of the use of Wolffia species, in particular Wolffia Globosa, as food, especially in Southeast Asia: Burma, Laos and northern Thailand, where it has been used as a vegetable for many generations. The nutritional composition of Mankai has been determined and found to be high in protein, containing all the essential and conditionally essential amino acids, dietary fibers and several vitamins and minerals.

Official Title
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Effects of Green-MED Diet Via the Gut-fat-brain Axis; DIRECT-PLUS

Conditions
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Abdominal Obesity Metabolic Syndrome

Intervention / Treatment
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* Other: Physical activity
* Other: Physical activity+ MED diet
* Other: Physical activity+green MED diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age >30 years with abdominal adiposity (waist circumference: men > 102 cm, women > 88 cm) or dyslipidemia (TG>150mg/dl and HDL-c <40mg/dL for men and <50mg/dL for women) Exclusion Criteria: Individuals who may not be able to partake in PA in the gym; TGs>400 mg/dL; serum creatinine>2 mg/dL; disturbed liver function; major illness that might require hospitalization; pregnant or lactating women; presence of active cancer, is receiving or received chemotherapy in the last three years; participation in another trial; participants who are treated with Coumadin (warfarin) - given its interaction with vitamin K and high level of this vitamin in Mankai green shake; pacemaker or platinum implant, because of the impossibility of MRI screening.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Physical activity<br>Physical activity (PA) group will receive free gym memberships and the instruction necessary to engage in moderate-intensity physical activity,  80% of which will have an aerobic component. The participants will get basic health promoting guideline for healthy diet . | Other: Physical activity<br> <br> |
| Experimental: Physical activity+ MED diet<br>On top of the PA intervention described in Arm 1, the participants will be guided for moderate weight loss with a traditional Mediterranean (MED) diet, low in simple carbohydrates. The diet will include 1oz/day of walnuts that will be provided free of charge. | Other: Physical activity+ MED diet<br> <br> |
| Experimental: Physical activity+ green-MED diet<br>On top of the PA intervention described in Arm 1, the participants will guided for moderate weight loss with a MED diet, low in simple carbohydrates that will be rich in plants and polyphenols and low in processed meat. The diet will include 1oz/day of walnuts, 3-4 cups/day of green tea and  500cc green shake/dinner based on specific strain of duckweed [Wolffia globose, Mankai], an aquatic plant, which might serve as a plant protein source. All the above will be provided free of charge. | Other: Physical activity+green MED diet<br>* ****Sub-study from all 3 main arms: Autologous fecal microbiota supplement intervention derived from the time of maximal weight loss: At the 6-month time period, the time of anticipated greatest weight reduction, participants's feces samples will be processed to capsulized inocula. Samples will be frozen within 2 hours and will be kept at -80c pending analysis. Participants will be randomized to receive either research capsules or identical placebo capsules between 8 and 14 months time period. Placebo capsules will consist of a combination of powdered cocoa and vegetable gelatin in normal saline/glycerol and will be identical in appearance to research capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abdominal fat | Changes in visceral fat (MRI) | 18 months | 
| Hepatic fat | Changes in hepatic fat (MRI) | 18 months | 
| Obesity | Changes in body weight and waist circumference | 6, 14, 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain anatomy | Changes in hippocampus volume, diffusion Tensor Imaging (MRI) | 18 months | 
| Cognitive function-MRI | Changes in resting state connectivity (MRI, sub-study) | 18 months | 
| Cognitive function | cognitive tests | 18 months | 
| Cardiac state | Changes in cardiac anatomy (MRI, substudy) | 18 months | 
| Cardiac state | Changes in cardiac function (MRI, substudy) | 18 months | 
| Endothelial dysfunction | Changes endothelial function (ECG) | 18 months | 
| Lipid profile | Changes in lipid biomarkers (blood draw) | 6 , 14 and 18 months | 
| Glycemic control | Changes in glycemic biomarkers (blood draw) | 6 , 14 and 18 months | 
| Inflammatory state | Changes in inflammatory biomarkers (blood draw) | 6 , 14 and 18 months | 
| Metabolomic | Changes in sub-lipids (blood draw) | 18 months | 
| Metabolomic | Changes in sub-proteins ( blood draw) | 18 months | 
| Liver function (blood biomarkers) | Changes in liver function biomarkers (blood draw) | 6 and 18 months | 
| Genetic signature | SNPs associated with fat distribution and visceral fat | baseline | 
| Epigenetics | changes in mRNAs | 18 months | 
| Epigenetics | changes in genes' methylation | 18 months | 
| Well being | assessed by questionnaire | 18 months | 
| Fecal microbiota profile | Diversity Index as a key measure | 6, 14, 18 months | 
| 24h- continuous glucose levels | 24h dynamics of glucose using continuous glucose monitor. substudy | 2 weeks |