Maintaining Immune and Mitochondrial Functions in Old Adults With SAfe Nutrition.

Study Overview
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Brief Summary
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Aging is associated with an increased inflammation named inflammageing and with an altered immune response. Different mechanisms have been proposed to explain the phenomenon of inflammageing and increased oxidative stress: deficiencies in essential amino acids, and some micronutrients have an important impact and may induce immune cell dysregulation. Mitochondrial dysfunction may explain the complex relationship between malnutrition sarcopenia, immune dysfunction and aging. Therefore, a personalized nutritional strategy aiming to improve mitochondrial function, decrease oxidative stress, down-regulate inflammation and restore immunity appears to be a logical approach in order to treat malnutrition and its biological and clinical consequences. MIMOSA will investigate the role of nutritional supplements in rescuing altered mitochondrial function and redox state imbalance.

Detailed Description
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The study participants will all receive optimal standard care ensuring the optimal protein and energy intakes, with at least 1 g protein per kg body weight and day, and 30 kcal per kg body weight and day (or the measured energy expenditure (EE) value). This will be realized by the daily administration of oral nutritional supplements (ONS) providing whole proteins together with dietary advice [according with the ESPEN nutrition guidelines. All the patients will receive the standard commercially available product used at CHUV (Resource protein ®, nestle) and nutritional counselling (SC). SC-Placebo: These patients will receive ONS and maltodextrin 4 g BCAAs: In addition to the ONS these patients will receive 4 gram per day of BCAAs mixture. Ratio between the BCAAs will be Leucine/Isoleucine/Valine=2:1:1, as delivered in our previous study. Micronutrient complements (Micro). In addition to the ONS the patients will receive a combination of micronutrients. After enrollment patients will be subjected to evaluation of muscle mass by bioimpedance (BIA), muscle strength will be by handgrip strength and muscle performance by the Short Performance Physical Battery (SPPB). Nutritional status will be evaluated by the Mini Nutritional Assessment short form (MNA-SF), Nutrition Risk screening (NRS) score and Body mass index (BMI). Energy expenditure (EE) will be measured by indirect calorimetry using a canopy. Moreover appropriate experiments will be carried out in order to evaluate mitochondrial bioenergetics, replication, and fusion, as well as of redox state. Analyses of inflammageing and immune-senescence will be will be done by appropriate lab experiments. Micronutrient status will be measured by ELISA or HPLC and ICPMS respectively. Patients will be evaluated at inclusion, at rehabilitation discharge, and one and two months after rehabilitation discharge. The volume of blood required for the above investigations will be 3 x 30 ml over the 2-month period.

Official Title
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Maintaining Immune and Mitochondrial Functions in Old Adults With SAfe Nutrition: the MIMOSA Study.

Conditions
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Malnutrition, Sarcopenia

Intervention / Treatment
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* Dietary Supplement: BCAA
* Dietary Supplement: Micronutriments
* Dietary Supplement: standard treatment + placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥75 years Patients entering a rehabilitation program Diagnosis of malnutrition defined by a MNA-SF (mini-nutritional assessment short form) score below 11 points. Commitment to accept the nutritional supplement proposed, willing and able to give written informed consent Ability to understand and comply with the requirements of the study Exclusion Criteria: Presence of malignancy, Life expectancy of less than two months calculated by Multidimensional Prognostic Index (MPI ), Congestive heart failure (NYHA IV), Chronic renal disease (creatinine clearance <40 ml/min calculated by cockroft), Liver cirrhosis (Child B-C), Tube/percutaneous endoscopic gastrostomy feeding or parenteral nutrition, Severe dysphagia, Mini-Mental State Examination (MMSE)≤18 and MNA>11 points. MMSE ≥ 18 identifies patients with mild form of cognitive impairment; those patients generally do not have problems in swallowing and are able to take drugs. Severe anaemia (Hb<10 g/l) or leukopenia (<2G/l).

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: three arms study double blind placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Standard treatment (SC)<br>nutritional counselling (SC) + Placebo: These patients will receive Oral Nutrient Supplementation (ONS) and maltodextrin 4 g | Dietary Supplement: standard treatment + placebo<br>* daily administration of oral nutritional supplements (ONS) 1) providing whole proteins together with dietary advice according with the ESPEN nutrition guidelines. All the patients will receive the standard commercially available product used at CHUV (Resource protein ®, nestle ) and nutritional counselling (SC) and maltodextrin 4 g as placebo<br>|
| Experimental: Branch-chained aminoacids<br>In addition to the ONS these patients will receive 4 gram per day of BCAAs mixture. Ratio between the BCAAs will be Leucine/Isoleucine/Valine=2:1:1. | Dietary Supplement: BCAA<br>* daily administration of oral nutritional supplements (ONS) 1) providing whole proteins together with dietary advice according with the ESPEN nutrition guidelines. All the patients will receive the standard commercially available product used at CHUV (Resource protein ®, nestle) and nutritional counselling (SC) and 4 gram per day of BCAAs mixture. Ratio between the BCAAs will be Leucine/Isoleucine/Valine=2:1:1<br>|
| Experimental: Micronutrients<br>In addition to the ONS the patients will receive a combination of micronutrients | Dietary Supplement: Micronutriments<br>* daily administration of oral nutritional supplements (ONS) 1) providing whole proteins together with dietary advice according with the ESPEN nutrition guidelines. All the patients will receive the standard commercially available product used at CHUV (Resource protein ®, nestle ) and nutritional counselling (SC) and Vitamin A 1200 mg RE, Vitamin D3 2000 IU, Thiamine B1 100 mg, Cobalamin B12 10 mcg, Ascorbic acid C 200 mg, Iron 30 mg, Selenium 100 mcg, Zinc 20 mg, Omega-3 PUFA 1 g<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitochondrial ATP production (nmol/ml) | Production of ATP will be measured using the ATP Bioluminescent Assay Kit | change vesus baseline at 30, 60 days after discharge | 
| Change in redox state (plasmatic concentration of metabolites) | analyses of thiometabolome contains: methionine, methionine sulfone, methionine sulfoxide, cysteine, homocysteine, homocystine, cystathionine, formylmethionine, cystine, glutathione, glutathione disulfide, taurine, S-adenosylmethionine, S-adenosylhomocysteine, N-acetylcysteine, cysteic acid, serine, glycine, glutamic acid, lypoic acid, selenocysteine, thioctic acid, pyruvic acid. | change vesus baseline at 30, 60 days after discharge | 
| Change in mitochondrial electron flux (nmol cit/min/mg prot) | The activity of Complex I and III will be measured on non-sonicated mitochondrial samples | change vesus baseline at 30, 60 days after discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change micronutrients status (concentration of micronutrients) | Blood levels of Vitamins A, B12, D and E, as well as of trace elements Cu, Fe, Se, and Zn will be determined by ELISA or HPLC and ICPMS | change versus baseline at 60 days after discharge | 
| change in inflammation | Production of pro-inflammatory cytokines involved in inflammageing and in muscle waste will be measured by ELISA technique; we will measure IL-6 and TNF-alpha (pg/ml). | change versus baseline at 30, 60 days after discharge | 
| change phase angle (score) | Bioelectrical impedance analysis (BIA) will be carried out | change versus baseline at rehab discarge (21 days), 30, 60 days after discharge | 
| muscle function (score) | Short performance physical battery will be used to measure muscle performance | change versus baseline at rehab discarge (21 days), 30, 60 days after discharge | 
| muscle mass (Kg/body weight) | Bioelectrical impedance analysis (BIA) will be used to measure muscle mass | change versus baseline at rehab discarge (21 days), 30, 60 days after discharge | 
| muscle strength (Kg) | Hand grip will be used to measure muscle strenght | change versus baseline at rehab discarge (21 days), 30, 60 days after discharge | 
| change in perceived health status (score) | questionnaire | change versus baseline at rehab discarge (21 days), 30, 60 days after discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malnutrition, sarcopenia, immune system, Mitochondria, oxydative stress, inflammaegeing, branch-chained aminoacids, micronutrients, nutrition