The dramatic ageing of population worldwide will result in highly increased numbers of individuals with cognitive impairment, with tremendous medical care and social problems. Protein malnutrition is frequent during ageing and high protein diets exert beneficial effects. However, each amino acid subserves distinct functions in the brain, the effect of specific amino acid supplementation is poorly studied. The conditional non-essential amino acid L-Serine is of particular interest: cognitive decline during ageing is critically influenced by sharp reduction of D-Serine, produced in the brain from L-Serine.

 Previous data support a beneficial role of L-Serine in longevity, neuroprotection, stress, sleep and metabolism. No systematic clinical trial on the benefit of L-Serine on brain ageing was done up to date. Here we plan to investigate in a multicentric clinical trial conducted at 3 sites (Fribourg, Vienna and Brescia) the effect of oral L-Serine on cognitive decline during ageing, alone or in association with physical exercise in participants with sarcopenia, or in subjects suffering from late-life depression, often accompanied by cognitive deficits.

The analysis will comprise a large multidisciplinary approach, using psychometric, morpho-functional, neurotrophic- and stress-related, metabolomic, proteomic, transcriptomic and gut microbiome parameters. It will be accompanied by corresponding in-depth analysis of effects of L-Serine in mice, including in specific dietary patterns. Main interests are on translational analysis and complex modelling of brain oscillatory activity, as correlate of higher cognitive processes, and on gut-brain interactions, due to the role of L-Serine malnutrition in gut dysbiosis and inflammation, the latter associated with higher risk and earlier onset of dementia. Our project aims to determine the therapeutic potential of L-Serine as accessible and effective preventive intervention towards alleviating cognitive decline during ageing.