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

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.

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.

malnutrition, sarcopenia, immune system, Mitochondria, oxydative stress, inflammaegeing, branch-chained aminoacids, micronutrients, nutrition

The intervention nutrients will be delivered as powder in sachets identified as B (BCAA, 4 gr) or C (mixture of micronutrients, 4 gr), placebo sachets identified as A will contain maltodextrin, (4 gr); the sachets will be mixed by the patients in a juice. Blinding will be maintained until interim evaluation and after for the full trial. In order to assure the blinding the sachets will be opaque identified by a single letter ready to be mixture with a juice with similar taste and texture between the different formulations

nutritional counselling (SC) + Placebo: These patients will receive Oral Nutrient Supplementation (ONS) and maltodextrin 4 g

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.

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

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

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

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.

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

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).

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).

The data will be shared according to the F.A.I.R. principles as follows. Findable- Accessible. All data collected will be uploaded to the Redcap research data repository after anonymization. Interoperable. The majority of the raw data produced will be in standard formats for which there is suitable open source software available. Reusable. Data publicly available will use the Creative Commons Attribution version 3.0 (http://creativecommons.org/licenses/by/3.0/) license that permits free sharing and adaptation of the licensed data with the restrictions depicted above and any related scientific publications as well as documenting any changes. Each dataset will contain appropriate citation details in the accompanying README file. We will make data open immediately if not sensitive for IP protection. Data with sensitive IP will be made available after 5 years from the end of the project,

We will make data open immediately if not sensitive for IP protection. Data with sensitive IP will be made available after 5 years from the end of the project