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
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.
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.