Popi Syntichaki, Christos Zervas and colleagues recently published a paper in eLife

Ageing is an inevitable process that affects all living organisms, and is often accompanied by an increased risk of several diseases. An important goal of ageing research is to understand the ageing process, delay its rate and prolong healthspan in humans. A new study, conducted in two model organisms by researchers at Biomedical Research Foundation of Academy of Athens (BRFAA), demonstrates that mRNA decapping function in neuronal cells can modulate lifespan in both worms and flies, through insulin-like peptide signaling.

The nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster are two popular invertebrate models that have contributed greatly towards understanding the molecular genetics of ageing and identifying key evolutionarily conserved pathways that influence metabolism and longevity. One of the most intriguing studies regards the insulin/insulin-like growth factor signaling (IIS) pathway, the downregulation of which extends lifespan across species, from invertebrates to mammals. IIS mediates the communication of multiple tissues to regulate the rate of ageing, through insulin-like peptides and the function of FOXO transcription factors.

In the current study, the researchers showed that DCAP-1 activity in the nervous system of worms regulates a neurosecreted insulin-like peptide, which ultimately affects the function of DAF-16/FOXO transcription factor in distal tissues, having an influence on lifespan. DCAP-1 is the regulatory subunit of the core mRNA decapping enzyme that removes the 5’ cap structure of mRNAs, promoting their degradation or their storage in cytoplasmic RNA granules. In previous studies, the team had reported that depletion of dcap-1 gene has a negative impact on worm’s physiology, provoking developmental defects and a short lifespan. Now, it was shown that overexpression of dcap-1 only in neurons, is sufficient to extend nematode lifespan and delay the onset of age-dependent phenotypes. Neuronal DCAP-1 activity mainly controls the stability of ins-7 mRNA, encoding an insulin-like peptide that is normally upregulated during ageing and activates IIS. This regulation of ins-7 mRNA abundance in neurons by the decapping complex modulates longevity in a cell non-autonomous way, through neurosecretion and intertissue signaling that controls DAF-16/FOXO in other tissues.

In many organisms, the nervous system seems to serve as a hub that integrates environmental and intracellular signals, and communicates them across tissues, to coordinate the rate of ageing in the whole body. IIS plays a prominent role in the neuroendocrine control of lifespan in both C. elegans and Drosophila, with insulin-like peptides to mediate such intertissue cross-talks. Thus, the researchers tested whether the conserved mRNA decapping complex could affect the lifespan of flies, in a similar manner. They showed that neuron-specific knockdown of the fly dcap-1 ortholog DCP1 greatly reduces lifespan, whereas its neuronal overexpression, when occurring post-developmentally, confers longevity. Moreover, neuronal DCP1 deficiency affects wing morphogenesis, again cell non-autonomously, possibly due to altered insulin-like peptide signaling during development of the fly.

These data demonstrate a tissue-specific role of the decapping complex in post-transcriptional control of neuronal targets, involved in the systemic regulation of lifespan. They also support an evolutionarily conserved role of the decapping complex in neuronal functions that govern both developmental and ageing processes.

mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing
Fivos Borbolis, John Rallis,George Kanatouris, Nikolitsa Kokla, Antonis Karamalegkos, Christina Vasileiou,
Katerina M Vakaloglou, George Diallinas, Dimitrios J Stravopodis, Christos G Zervas*, Popi Syntichaki*
eLife 2020;9:e53757. DOI: https://doi.org/10.7554/eLife.53757