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Epigenetic Regulation of Ageing

Final Report Summary - EPIAGE (Epigenetic Regulation of Ageing)

The central question in aging research is whether epigenetic components govern the aging of animals. Insight into the genome-wide deposition of epigenetic marks in the course of aging should facilitate revealing novel aging-related genes. The discovery of an epigenetic landscape of aging will moreover provide markers, quite like the length of telomeres is an aging marker, which might be helpful to determine the age of an animal. Our research therefore focusses on typical chromatin components including transcription factors and epigenetic enzymes and the respective modifications they catalyze at chromatin. To this end, we have established a liquid culture based RNAi screening method for the model organism C. elegans that allows us to screen hundreds of epigenetic components over the full lifespan of the animal. Importantly, nearly all RNAi screenings conducted so far in the nematode have been carried out with young animals of the L1 and L4 larvae stages. We have devised a post-reproductive screening method, which allowed us to look into late-life gene function for the very first time. In this screen C. elegans is fed on RNAi producing bacteria only after the full development is completed (day 9 of life). This is of utmost importance to not measure developmental effects that later impinge on the life of the nematode but rather to identify regular aging mechanisms. We have utilized a synchronized population of worms, which we cleaned up by sorting with a Biosorter to make sure that no offspring (with an intact germ line) contaminates the aging assays. Following this we have screened a chromatin factor RNAi library for genes that upon knockdown lead to an extension of the lifespan. We have found about 40 genes that upon late-life knockdown cause a dramatic change in the lifespan. Amongst these 40 candidates we have found one gene that had been strongly linked to aging previously. Therefore, we have focused on describing the late-life function of this gene in detail. We have found that a late-life knockdown of this gene not only significantly increases the lifespan but also the health span of the animals as demonstrated by a better conservation of muscles and the pharynx. Further and in accordance with these findings, the knockdown of the gene of interest caused better movement of the animals even at old ages. We have further looked into factors operating downstream of the protein encoded by the gene of interest. Our data show that a prominent metabolic pathway is coordinated by the protein product of the gene of interest and that the lifespan and health span extension are transmitted through the aforementioned metabolic pathway. Furthermore, our findings show that the candidate protein is not affected by any of the canonical aging signalling pathways arguing that a yet unidentified signalling pathway must exist that contributes to organismal aging after reproduction. Moreover, we have found that the knockdown of the aforementioned gene and its impact on longevity occurs mainly in one tissue of the animal. In sum, we have delineated new functions for chromatin-associated factors in determining life and health span of the nematode C. elegans.

Taken together our findings have a great socio-economic importance as they demonstrate that gene regulation has a profound impact on aging and that interference with gene function late in life can result in healthier aging. Given that the candidate gene and its function are evolutionary conserved it is comprehensive to assume that similar processes might occur in humans. Compounds that inhibit the function of the candidate gene would therefore prolong life and health span the worm but potentially also in higher species such as mice or human. Future work will therefore need to address whether the genes identified by the post-reproductive RNAi screen are drugable and whether age-related diseases could be alleviated by such drugs.