The role of specialized ribosomes in stress resistance and healthy aging

• Applicant: Martin Kos, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; Biochemistry
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280594475

Aging is a complex process characterized by a decline in cellular homeostasis and accumulation of damage that can lead to age-related pathologies. One of the few conserved mechanisms involved in the regulation of aging of a wide range of organisms is the reduction of overall protein translation converging on the ribosome. Over the last few years it has become clear that the ribosome is not a static, but a dynamic machine that responds to various stimuli by adapting its structure, molecular composition, post-translational and post-transcriptional modification status and in consequence its function. Such structurally distinct 'specialized ribosomes' are considered to be engaged in translating specific subsets of cellular messages. We recently reported such a link between specialized ribosomes and organismal aging: Lack of a single, conserved C5 methylation of ribosomal RNA by deletion of the methyltransferase NSUN5 extends the lifespan and stress resistance of yeast, worms and flies. We could show that lack of methylation at rRNA residue C2278 alters ribosomal structure and thus translational fidelity, resulting in a 'reprogramming' of the ribosome towards translation of mRNAs involved in cellular stress-response. This discovery prompted us to hypothesize more generally that alterations in the protein composition, the rRNA modification patterns or in the non-coding RNA interactome of the ribosome are involved in regulation of the life span and stress resistance in several model organisms, from yeast to human cells. Thus, we here aim to systematically identify and characterize these changes and their functional consequences in the context of aging and stress resistance. The gained insights into the underlying mechanisms will help to design preventative strategies to postpone or decrease the onset of age-associated diseases.

• DFG Programme: Research Grants
• International Connection: Austria, Switzerland
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF); Schweizerischer Nationalfonds (SNF)
• Cooperation Partners: Professor Dr. Johannes Grillari; Professor Norbert Polacek, Ph.D.