Polyphenols From Nonalcoholic Red Wine and Healthy Aging: an Opportunity to Understand Diet Modulation of the Aging Process From a Multidimensional Perspective

Polyphenols, precisely resveratrol, with red wine as the most substantial source, was associated with improvements in cognitive function. Also, the loss of muscle mass and strength in elderly, that significantly increases dependency of these people, it could be attributed to alterations in gut microbiota through the "gut-muscle axis" and this underline the urgent need to efficiently find out any intervention or preventive approach via modulation of gut microbiota to improve muscle function in elderly. In this context, red wine polyphenols exert their effects through interaction with gut microbiota following the well-known two-way interaction between polyphenols and gut microbiota by promoting the proliferation of beneficial bacteria and increasing their abundance. Similarly, aging cognitive decline can be modulate by microbiota, notably through "gut-brain axis". Additionally, dietary polyphenols can delay inflammation or/and oxidation on the onset of age-related cognitive decline or muscular oxidation or cardiovascular factors risk factors, all of them relevant factors for the onset of physical frailty and dependence in elderly.

Moreover, wine is a singular alcoholic beverage with a high content of phenolic compounds of a very diverse nature on which numerous protective effects on health have been described. In fact, wine, in addition to alcohol, contains a complex mixture of polyphenols, including anthocyanins and non-coloured phenols as proanthocyanidins, flavonols, hydroxycinnamic and hydroxybenzoic acids, stilbenes and lignans. Thus, the bioprotective effects of wine polyphenols could be the consequence of the synergistic effect of this complex mixture of polyphenols from the grape and the winemaking process. That is why it is essential to clarify whether consumption of polyphenols from red wine provided by a nonalcohol red wine within a healthy diet can produce beneficial effects on health, differentiating this pattern from a general consumption of alcohol generally associated with negative effects. Based on the ethical limitations to carry out diet intervention studies with wine in humans, this project proposes the use of a nonalcoholic wine as vehicle of the complex mixture of red wine polyphenols.

The hypothesis of our research is that regular consumption of red wine polyphenols, 150 mg/day, delivered through a nonalcoholic red wine, in the context of a Mediterranean diet (MD pattern), could promote protective mechanisms for a healthy aging, especially through its beneficial effects on cognitive and locomotor abilities and mediated by the modulation of the intestinal microbiota (composition, function and associated metabolome). The main objective of the WinAging project is to add knowledge concerning the diet modulation of molecular mechanisms of the aging process through multi-omic approaches based on the potential health effects of a dietary strategy by a sustained MD supplementation with nonalcoholic red wine rich in polyphenols to tackle cognitive and locomotor abilities in early elderly home-dwelling subjects.

The specific objectives:

• Objective 1. To develop a nonalcoholic red wine with high phenolic content and sensorial acceptability.

• Objective 2. To evaluate the chronic effects of the intake of wine polyphenols (average dose 150 mg/day) delivered through a nonalcoholic red wine in the context of a MD in early elderly home-dwelling subjects, and applying participatory research to increase adherence of subjects in the clinical intervention study.

• Objective 2.1. To identify selective biological phenolic metabolites in human urine samples to be used as biomarkers of nonalcoholic red wine intake.

• Objective 2.2. To assess the effects of the diet supplementation with red wine polyphenols on the improvement of cognitive ability.

• Objective 2.3. To assess the effects of the diet supplementation with red wine polyphenols on the improvement of locomotor ability

• Objective 2.4. To evaluate the effect of the diet supplementation with red wine polyphenols on the improvement of cardiovascular disease (CVD) risk factors.

• Objective 3. To unravel the underlying mechanisms involved in the potential beneficial effects of red wine polyphenols on aging.

• Objective 3.1. To evaluate the influence on microbiota composition, function and microbial catabolites.

• Objective 3.2. To evaluate the impact on inflammation and gut health.

• Objective 3.3. To evaluate the impact on metabolic pathways related with aging

• Objective 3.4. To analyze the impact on age-related epigenetic modifications

• Objective 3.5. To deeply characterize the underlying muscle signalling pathways affected using an animal model of aging.

• Objective 4. To apply integrative computational analyses for the identification of variables (clinical or gut-related) more determinant for a successful prevention of locomotor and cognitive abilities associated with wine polyphenols.