Biogenesis of translation machinery and longevity

Abstract

The extension of health and life spans can be achieved by changes in gene expression. Partial inhibition of PoI III has recently been shown to produce an evolutionarily conserved lifespan extension in yeast, worms, and flies. In this research, using Drosophila melanogaster the effect on lifespan of partial inhibition of transcription factors (TFs) required for Pol III transcription was investigated to determine which of the hundreds of Pol III targets are the most relevant to its effects on lifespan. The significant role of tRNA genes in lifespan extension downstream of Pol III is demonstrated by the discovery that the TFIIIC mutant (dGTF3C5KG04199/+) is considerably long-lived. Additionally, TFIIIC mutant (dGTF3C5KG04199/+) flies exhibit improved health in terms of intestinal permeability and muscle activity, which even outweighs the benefits achieved by Pol III loss of function. Further experiments indicate that TFIIIC and Pol III likely drive ageing through the same mechanism, as expected. In humans, we use Mendelian Randomization(MR) to examine whether human ageing is influenced by adult, tissue-specific biogenesis of translation machinery. We use MR to evaluate naturally occurring variation in the expression of genes encoding specific subunits for Pol I and III, as well as ribosomal protein (RP) genes. We find each causally associated with human longevity (ß=-0.15±0.047, p=9.6x10-4; ß=-0.13±0.040, p=1.4x10-3; ß=-0.048±0.016, p=3.5x10-3, respectively). These correlations don't seem to be caused by a different sensitivity to a particular disease. Intriguingly, we discover that reduced expression of Pol III, RPs, or Pol I promotes longevity from various organs, including visceral adipose, liver, and skeletal muscle. This finding supports the tissue-specificity of ribosomopathies and provides evidence that Pol I and RPs may act from organs where their expression is restricted. Our findings expand on the evolutionary conservation of protein synthesis as a process of animal ageing that also applies to humans