Author:

Keywords:

Aging, Royalactin, Protein translation, MRJP1, mRNA, Proteasome

Abstract:

Via an integrative approach using proteomic, biochemical and phenotypic techniques, we have gained molecular understanding of the physiological changes elicited by the longevity-promoting compound royalactin. While global metabolic heat output remains largely unaltered upon royalactin treatment, translation-associated molecular effectors including eukaryotic elongation factor 2 (EEF-2) and p70 S6 kinase (RSKS-1) are highly upregulated and crucial for the lifespan-extending effect of royalactin in Caenorhabditis elegans. Global protein synthesis measurements and lifespan experiments using cycloheximide-treated nematodes, indeed point towards augmented in vivo protein translation in royalactin-fed animals. This is a rather paradoxical outcome, since longevity is more commonly associated with reduced protein translation and turnover. Yet, here we identify and characterize a novel lifespan-extending intervention, where enhanced translation seems to be beneficial for the aging organism. Additionally, we discovered that royalactin enhances activity of the ubiquitin proteasome system (UPS) in multiple tissues, indicative of an increase in protein degradation as well. This points towards an alternative strategy to maintain protein homeostasis and support healthy ageing, focused more on actively removing damaged proteins and rebuilding cellular components (rather than preventing cellular damage and protein aggregation). The PLZF transcription factor EOR-1 seems to drive this process. Royalactin is a royal jelly glycoprotein essential for queen differentiation in honeybees. Royalactin plays a central role in this process by switching on the epidermal growth factor (EGF) receptor signaling pathway, which ultimately leads to epigenetic changes and a long-lived queen phenotype. We previously provided the first evidence for its longevity-promoting actions in a non-insect species by studying royalactin-fed C. elegans (Exp. Geront. 2014). We demonstrated that royalactin requires both EGF (LIN-3) and its receptor (LET-23) for extension of nematode lifespan by ~25%. Royalactin also increases body size, maintains fecundity and enhances multiple forms of stress tolerance (Worm 2016) and locomotion in adult nematodes, suggesting a positive effect on healthspan as well. Yet, the mechanism by which royalactin exerts these pro-longevity effects remained fundamentally unknown. In short, we present new insights into the molecular mechanisms of a rather unique lifespan-extending compound, which paradoxically increases global protein translation and turnover, and displays no trade-off regarding reproductive capacity, body size and longevity. Further work is now being carried out to unravel which mRNAs are exactly targeted by royalactin and the role of chaperones in this process, and assess whether its effects are also present in other organisms.