The role of specialized ribosomes in stress resistance and healthy aging

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.

The role of specialized ribosomes in stress resistance and healthy aging Ribosomes are molecular machines carrying out cellular protein synthesis. In the last few years it became clear that this is not a pure mechanical process, but that it is actively regulated by differentially composed ribosomes. By building these "specialized" ribosomes, cells are better able to react to different environmental conditions, such as heat, starvation and other types of stress. Modifications of ribosomal RNAs, as well as changes in the composition and phosphorylation of ribosomal proteins can lead to this specialization. A look at demographic analysis is sufficient to understand that age-associated diseases will be among the most pressing challenges our health care systems will face during the next decades. Since the complex and still not well understood processes of ageing are the substrate on which age-associated diseases grow, it is clearly necessary to better understand the cellular and molecular basics of ageing. So far it is already known that reduction of overall protein synthesis by ribosomes leads to an extension of life- and healthspan. However, the role of specialized ribosomes during biological ageing was not yet explored. We hypothesized that a complex process such as ageing influences the composition, structure and function of ribosomes. In addition, different species of specialized ribosomes might either promote, or slow down biological ageing. We therefore investigated the role of ribosomal RNA and -protein modifications during biological ageing and stress within this project using cells from human skin, yeast and nematodes as model systems. Indeed, we identified alterations of ribosomes during ageing and showed that targeting them does influence the life- and healthspan of model organisms. Furthermore, we identified changes in structure and function of ribosomes during the aging process. Thus, having successfully accomplished this project, we contributed to a better understanding of specialized ribosomes during biological ageing and might have identified hints towards new strategies to improve health and quality of life at old age in the future.