Only 100 years ago, people lived to just about 50 on average. Today, more and more people are celebrating their hundredth birthday. Increasing life expectancy can be seen as a great success story for humankind, but this also involves challenges. Over the years, the body’s own processes and environmental factors increasingly cause cell-level changes, which in turn become a hotbed for age-associated diseases such as cardiovascular diseases, osteoporosis and cancer.
What causes cells to age
Cell ageing is accelerated in particular by physiological and oxidative stress – which is stress caused, for example, by UV radiation or free radicals. This is precisely the research area of Johannes Grillari and Markus Schosserer from the Institute of Molecular Biotechnology at the University of Natural Resources and Life Sciences, Vienna. For three years, the two scientists have been exploring the role of specialised ribosomes in cell ageing as part of a project funded by the Austrian Science Fund FWF. Research teams from Germany and Switzerland were also involved in the project. “We suspected that a complex process such as ageing has an influence on the structure and composition of ribosomes. And, conversely, that differently structured ribosomes exert positive as well as negative effects on cells during ageing,” says Johannes Grillari about the origins of their research. The results obtained have confirmed his hypothesis. The researchers have actually succeeded in extending the life and health span of model organisms (yeast, nematode and fruit fly) by manipulating ribosomes in a specific way.
The cells of an organism contain molecular machines that decode genetic information and can then produce proteins based on these blueprints. The process can be pictured as being similar to what a 3D printer does. “In recent years, it has become clear that this is not an unchangeable process, but that ribosomes produce specific proteins depending on the conditions of the environment. This is something we didn’t know anything about for a long time,” explains Markus Schosserer, who is particularly keen to explore this area that has not been researched intensely. Hence, if only one building block changes in a ribosome, which consists of thousands of building blocks, the ribosome has then become specialised. These specialised ribosomes support the cell in reacting quickly to outside influences.
In just one single ribosomal building block, more than 200 different modifications can occur. Grillari and Schosserer studied three of them. “While we already have the technical capabilities to study all modifications, we had to limit ourselves to three because of cost.” It turned out that tiny switches on the molecular complexes can positively influence the ageing of yeast, nematode worms and fruit flies because they boost the synthesis of special proteins that organisms need in stressful situations. “If you remove or decrease a protein called NSUN-5 in flies, worms and yeast, their average lifespan increases by up to 20 percent,” notes Schosserer. The researchers noted not only an increase in lifespan but also an improvement in fitness. In worms and flies this was translated, for instance, into greater mobility, and in yeast into higher resistance to oxidative stress. A similar protein called NSUN1 also impacts ageing processes in nematodes. “It has to be noted that we could only detect this positive effect in older organisms,” says Schosserer. “After modifying NSUN1 in a young organism we observed reduced fertility as a consequence.”
Significance for humans
How meaningful are results in yeast, flies and nematodes for the human organism? Schosserer says: “In an ongoing follow-up project funded by the FWF, a mouse model seems to confirm these experiments. I would say the results are conclusive.” In practice, this could translate into new interventions for patients at some future point. “Or it could furnish new markers to tell us who ages faster or slower, and who is susceptible to certain diseases,” so Grillari’s hope for future results.
Grillari, for whom ageing research has become “a great passion”, notes that basic research in the field of ageing processes is essential. “Ageing research is one of the major topics of the future. We should not only concern ourselves with climatic changes, but also with demographic changes.” According to Grillari, the ultimate objective is for people to be able to live as long as possible in good health, whereby ethical considerations should always be taken into account. Extending a lifespan does not automatically mean extending good health. At any rate, this research project contributes to a better understanding of specialised ribosomes and biological ageing processes and may point to new strategies for boosting health and quality of life in old age in the future.
Johannes Grillari is Director of the Ludwig Boltzmann Institute for Experimental and Clinical Traumatology and Head of the Christian Doppler Laboratory for Biotechnology of Skin Ageing at the University of Natural Resources and Applied Life Sciences Vienna (BOKU).
Markus Schosserer works as a Senior Scientist at the Institute of Molecular Biotechnology at BOKU. He heads his own research group there.
Grillari and Schosserer share the same research focus: improving our understanding of the molecular and physiological changes that occur during cell ageing, their effects on the ageing and regeneration of organisms – particularly in skin and bone. In the course of the FWF project “The role of specialised ribosomes in cell ageing and stress defence”, which was funded with EUR 280,000, the researchers investigated changes in ribosomal RNAs as well as ribosomal proteins during biological ageing processes and stress defence.
Heissenberger C., Grillari J., Schosserer M. et al.: The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans, in: eLife, 9:e56205, 2020
Heissenberger C., Grillari J., Schosserer M. et al.: Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth, in: Nucleic Acids Research, 2019
Schosserer M., Grillari J. et al.: Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan, in: Nature Communications, 2015