| Popis: |
Aging is considered a multifactorial biological process, wherein gradual loss of cellular function and physiological integrity lead to increased vulnerability to death. It is the main risk factor for many prominent and debilitating diseases in modern society including cancer, type II diabetes and neurodegenerative diseases. Since the discovery in the 1980's that aging can be altered by modulating certain conserved genetic pathways and biochemical processes, scientists have been looking for promising pharmaceutical compounds that act on these pathways to confer increased longevity. It is believed that by modulating the human aging process itself, the impact of multiple age-related conditions may be limited. As such, substantial health, economic and social benefits could be realized. We here report on the mode of action of the pro-longevity compound royalactin. This glycoprotein is involved in queen differentiation in honey bee larvae by stimulating the epidermal growth factor (EGF) signaling pathway, and ultimately leads to epigenetic changes and a long-lived queen phenotype. Ingestion of royalactin induces proliferative effects and health benefits that appear to be largely conserved across several different species. For instance, in 2011 it was shown that royalactin extends lifespan of Drosophila melanogaster by 20 to 30%. Yet, the fundamental mechanism by which royalactin exerts these effects remained unknown. We set out to characterize the effects of royalactin on longevity of the popular model organism for aging research, Caenorhabditis elegans, and to clarify the possible involvement of EGF signaling in this process. We demonstrated that royalactin extends lifespan of this nematode - hereby providing the first proof that royalactin can prolong lifespan outside of the order of insects - and that both EGF (LIN-3) and its receptor (LET-23) are essential for this lifespan extension. Also in human A431 cells, we detected activation of EGF signaling upon royalactin treatment, supporting our observations in C. elegans. Additionally, royalactin enhances locomotion of C. elegans during mid-adulthood as well as resilience to various biotic and abiotic stressors (e.g. oxidative, reductive and heat stress), further suggesting a positive influence on organismal health. Combining proteomics and functional genetics approaches, we show that royalactin treatment results in increased protein translation in C. elegans and that this increase is required for lifespan extension. We also observed increased activity of the ubiquitin-proteasome system and found no obvious trade-offs between royalactin-induced longevity and several life history traits. Our data point towards a rather unexpected strategy to support healthy aging, which is focused on the rebuilding of cellular components (i.e. a proactive strategy), in contrast to the more commonly seen strategy in literature, which consists of stabilizing the existing proteome and preventing the onset of molecular damage (i.e. a defensive strategy). We propose that royalactin feeding might not be the only life-extending intervention following this 'proactive' strategy (that seems to be mediated by EGF signaling) and expect more dietary and genetic interventions to follow suit in future discoveries. Taken together, our results indicate that the honey bee glycoprotein royalactin is indeed a lifespan-extending factor and acts by promoting EGF signaling and subsequent alterations to protein homeostasis. Further work will be needed to assess the universality of royalactin's beneficial effects on longevity and healthspan, as they may differ depending on environmental conditions or the targeted cell types and tissues. status: published |
