Targeting the mitochondria-tyr kinase axis to prevent age-associated neuronal decline
Mitochondria represent central regulators of nutritional homeostasis and of the aging process. Epidemiological studies, including data from our cohort, indicate nutritional risk and preventive factors associated with dietary intake for the development of age-related parameters. Notably, studies from this network revealed the importance of a finely tuned mitochondria-autophagy axis as a preventive mechanism against aging. However, whether and how specific dietary interventions can modulate mitochondrial function in turn impacting on age-associated neuronal and cognitive decline is largely unknown. Tyr-kinases are emerging as important regulators of mitochondrial function and have been implicated in the development of age-associated disorders. In our consortia we specifically addressed whether selected nutrients, mainly polyphenols founds in fruits and vegetables, regulate a mitochondria-tyr kinase crosstalk, to delay/prevent the neuronal and cognitive decline observed during physiological and accelerated aging.
Through four distinct but complementary working packages we aimed: (i) to assess whether selected nutritional factors are associated with and can delay age-associated neuronal changes (WP1-2); (ii) to unravel underlying molecular mechanisms of selected nutritional factors through targeted (i.e. the mitochondrial-tyr kinases axis) and unbiased approaches (i.e. GWAS and – omics studies (WP1-3); (iii) to assess the implications of relevant pathways and interventions to alleviate cognitive disorders in mice (WP1&4).
Through an interdisciplinary, multisystemic approach, this consortium attempted to deliver biological outputs that may suggest novel molecular mechanisms and preventive strategies for future clinical studies. We specifically identified the potential beneficial effects of selected nutrients, mainly polyphenols founds in fruits and vegetables (together with susceptibility genes), in protecting against age-associated neuronal degeneration. Additional work will be required to actually define the underlying molecular mechanisms of selected compounds and to validate their effects in mammalian systems. Our project is therefore expected on the long term to provide guidelines for clinicians to interpret potential effects of nutritional factors thus contributing to the knowledge for the preventive potential of diet on cognitive disorders.
|IUF – Leibniz Research Institute for Environmental Medicine
|University of Rome
|Centro de Biologia Molecular
Our combined data from the epidemiological analysis (SNPs analysis in the SALIA cohort) together with in vivo (C. elegans), ex vivo (primary neurons from mice) and in vitro (HEK293 cells) data indicate a positive impact of dietary components associated with a Mediterranean diet on signs and symptoms of age-associated neuronal decline.
- We identified an interaction between weighted genetic risk scores (GRS) for specific SNPs and the Mediterranean diet on cognitive impairment in the SALIA cohort.
- Complementary to these observations in humans, we observed an extension of health- and life-span in C. elegans models of Alzheimer’s disease when fed with different nutraceuticals or upon suppression of expression or activity of the Tyr kinase Abl (which also improve learning ability). We are currently trying to understand whether selected compounds work through or in parallel to Abl.
- We found that treatment with the nutrient quercetin, an abundant flavonoid in Mediterranean diets, affects the proteolytic processing of APP in primary cortical neurons from wild type mice and in HEK293 cells stably overexpressing the brain specific splice variant of the human Alzheimer-related protein APP695.
- Our obtained results in mammalian cells also indicate, for the first time, a protective role of lutein on oxidative stress induced Aβ generation in primary neurons as well as in HEK293 cells. In further experiments the underlying molecular mechanism will be explored.