Effect of polyphenolic extract from extra-virgin olive oil on a yeast model of aging and proteotoxicity.

In 1959, Mortimer and Johnson suggested that the budding yeast Saccharomyces cerevisiae might serve as a model for aging. Although the causes of aging are multifactorial, all eukaryotes present conserved longevity pathways and molecular mechanisms involved in this process [1]. Yeast cells are able to divide in a nutrient rich medium until an hypometabolic state, where can remain for weeks, characterized by nutrients exhaustion. Yeast chronological aging is also characterized by a shift in energy utilization, which is derived mainly from mitochondrial respiration; this leads to an increase in mitochondrial-derived ROS which contribute to the aging of post-mitotic cells like observed in neurons. Saccharomyces cerevisiae can serve as a model to study the molecular mechanism underlying human neurodegenerative disease, including Huntington’s disease [2]. For this reason we have created a yeast strain that can express a glutamine repeat domain (103Q) of Huntingtin (HD) which represents the causing agent of protein misfolding leading to Huntington disease. In our study we have monitored the chronological aging of yeast strains containing the mutated glutamine repeat domain of Huntingtin, in comparison with the wild type strain, by assessing the cell viability, the NAD related metabolic profile and the proteomic pattern. NAD biosynthesis and utilization pathways play a major role in cell protection against proteotoxicity and in increasing yeast lifespan. In both yeast strains we have also tested the effect of an extra virgin olive oil polyphenolic extract added to the culture medium. Tyrosol, hydroxytyrosol, and their complex derivatives (e.g oleuropein and other secoiridoids), the most abundant olive polyphenols, are known to exert a protective effect against oxidative damage, one of the main factors associated with age-related pathologies. In our study we have observed that the yeast strain expressing the 103Q mutant HD protein decreases cell viability more rapidly than the wild type, due to the neurotoxicity of the mutant protein. Regarding nucleotide analysis, we have observed an increase in NaMN levels in the 103Q HD containing strain could be in agreement with the increase of NAD+, which exerts a protective effect against neurodegeneration; the increase of NaM levels in the strain expressing the mutant protein and treated with the polyphenolic extract could suggest the role of these compounds on sirtuins activation.