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Functions of non-coding RNAs in protein synthesis and homeostasis during aging

Periodic Reporting for period 1 - RncRNAA (Functions of non-coding RNAs in protein synthesis and homeostasis during aging)

Reporting period: 2015-04-01 to 2017-03-31

1a) What is the problem/issue being addressed?
Reduction of the Insulin / Insulin Growth Factor Signaling pathway (IIS) is known to increase lifespan in multiple species. Under normal physiological conditions IIS regulates a multitude of processes, including development, growth, metabolism, stress resistance and reproduction. Which of these mechanisms are involved in the regulation of lifespan in IIS mutants remains to be elucidated. An important factor in growth and metabolism is translation, the production of proteins in the cell by ribosomes.
In the C. elegans IIS mutant daf-2, translation is reduced and lifespan increased through a highly upregulated ribosome bound non-coding RNA, tts-1. We set out to determine whether this mechanism is conserved to Drosophila and mouse IIS mutants.
1b) Why is it important for society?
The average age in modern societies has been steadily rising for at least last half a century. The burden on society of age-related diseases has increased accordingly. It is therefore key to determine what underlying mechanisms regulate healthy ageing and how they can be manipulated to maintain better health in old age.
1c) What are the overall objectives?
We aimed to discover whether translation is decreased in Drosophila and mouse IIS mutants and whether this is regulated by ncRNAs with a function similar to tts-1.
Similar to the daf-2 worms, the long lived Drosophila IIS mutant dilp2-3,5 had previously been shown in our lab to have decreased polysome formation. Polysomes are messenger RNAs bound by multiple ribosomes and the level of polysomes is seen as a proxy for reduced translation. The reduced polysomes in the dilp2-3,5 were observed in the gut and fatbody, the functional equivalent of the liver and adipose tissue in insects. Sequencing of polysome bound RNAs in these tissues revealed no highly upregulated ncRNAs in the dilp2-3,5 mutant. In another long lived Drosophila IIS mutant, InsP3-GAL4/UAS-rpr, we observed similar regulation of protein synthesis.
In the long lived mouse IIS mutant Irs1-/-, protein synthesis was reduced in skeletal muscle, as determined by ex vivo incorporation of radiolabeled amino acids. This is not directly mediated by reduced IIS, as muscle-specific loss of Irs1 failed to replicate this phenotype. Reduced protein synthesis occurred in these mice without a simultaneous reduction of polysomes, suggesting differences in regulation of translation between mice and C. elegans. This argues against a tts-1-like mechanism in Irs1-/- mice.
In conclusion, regulation of translation occurs in both Drosophila and mouse IIS mutants, but the tissues in which this occurs differ between Drosophila and mice, gut and fatbody vs skeletal muscle respectively. Unlike C. elegans and Drosophila, reduced translation occurs without a reduction in polysomes in mice, suggesting that the mechanisms of regulation differ. Investigating how translation is regulated in mice is the next priority.
Dr Paul Essers