ISOLATION OF NATURAL COMPOUNDS THAT MODULATE THE PROTEOSTASIS AND MITOSTASIS NETWORKS

Objectives: Organismal ageing is a complex molecular process driven by diverse molecular pathways and biochemical events. We recently reported that proteasome dysfunction in Drosophila flies disrupts mitostasis and triggers the activation of an Nrf2-dependent tissue- and age-specific regulatory circuit aiming to adjust proteasome activity according to physiological demands; prolonged deregulation of this proteostasis network circuit accelerates ageing1,2. Thus, mild activators of the proteostasis, and likely, mitostasis networks could confer anti-ageing effects. Methodology: Natural compounds extracted by advanced phytochemical methods from Greek and Chinese plants were screened in normal human diploid fibroblasts (HDFs) for their effects on proteostasis and mitostasis networks modules. Results: We report herein that natural compounds from olive oil, Sideritis raeseri, Sideritis scardica, Sideritis syriaca and Ginkgo biloba exerted no cytotoxicity on HDFs and activated key modules of the proteostasis network, namely proteasomal and lysosomal peptidases. Bioactive compounds conferred protection against oxidative stress; suppressed senescence-mediated accumulation of carbonylated proteins and protected HDFs from stress-induced premature senescence. Furthermore, selected bioactive compounds affected mitochondrial dynamics and were found to modulate proteasome genes, as well as genes involved in mitochondrial functionality. Conclusion: The isolated natural products hold promise for anti-ageing effects by modulating the cellular proteostasis and mitostasis networks.