Causal epigenetic changes during aging and caloric restriction

Aging is accompanied by cellular and/or organismal deterioration, causing multiple diseases and ultimately resulting in death. Some of these diseases can be ameliorated pharmacologically or using a dietary approach. In our aging society, the need for anti-aging therapies is becoming more and more obvious and a focus point of many studies in a range of organisms, from yeast to human. However, the regulatory mechanisms underlying the complex process of aging are not yet extensively clarified. Especially the knowledge on the extent and exact pathways of the causal epigenetic impact on aging (influence based on the gene activity) is quite fragmentary, even though the existence of such impact is well documented. Tracking the etiology of age-related disorders directly in humans is not feasible due to their complexity and the experimental burden of maintaining similar conditions within the groups. Therefore, suitable model organisms are needed to reveal the regulation mechanisms during the progression of aging. Yeast has proven a perfect choice for elucidation of basic mechanisms of many aging and cell death-related processes from programmed cell death to autophagy (a regulated cellular recycling process of unnecessary or dysfunctional cellular components) and epigenetic regulation thereof. Yeast has also been successfully used as a screening tool for new anti-aging and neurodegeneration drugs. Combined with the fruit fly Drosophila melanogaster, a well-established model organism to study human development, aging and diseases due to its widely investigated anatomy and the broad spectrum of applicable genetic and molecular techniques, it makes a perfect start-up toolbox for deciphering complex and dynamically regulated processes like aging. Importantly, both organisms are easy to handle, inexpensive and robust. Here, we propose a project for systematic and near-exhaustive analysis of epigenetic regulation of aging processes and its influence on mechanisms of established anti-aging strategies like caloric restriction and caloric restriction mimetics (spermidine intake). The main part of the project will be carried out in the yeast model: we will use established mass spectrometry methods for elucidation of the differences in epigenetic marks appearing with progression of aging, among them the causal marks will be identified using histone mutant strains, and then the direct influence of the significantly different marks on the lifespan using mutant strains will be accessed. The results will then be confirmed in a fly model. As a result, even in the case of a partial success, we expect the project to yield new insights into the epigenetic regulation of aging and of pro-longevity mechanisms in eukaryotes and potentially new molecular targets for pro-longevity pharmaceutical interventions in humans.