Universität zu Köln

Mayr, Felix ORCID: 0000-0003-4884-4491 (2025). Investigating the metabolic and genetic regulation of ageing using forward genetics screens. PhD thesis, Universität zu Köln.

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Abstract

Metabolic state, protein biogenesis, and the tuning of stress response pathways become dysregulated with ageing and their modification can prolong survival. Their coordinated interaction, however, remains poorly understood. In a forward genetic screen in Caenorhabditis elegans for resistance to the ribosomal inhibitor geneticin (G418), I discovered a mutation in the gene encoding for pyrroline-5-carboxylate reductase-1 (pycr-1), responsible for the last step in de novo proline biogenesis. pycr-1 mutant worms were long-lived, but had only slightly reduced proline levels. Intriguingly, I identified that low SAM induced by impaired de novo proline biosynthesis is required for pycr-1 mutant G418 resistance and lifespan extension since dietary supplementation of methionine fully suppressed these phenotypes. Strikingly, treatment of wildtype (WT) worms with polyamine precursors mimicked pycr-1 mutant resistance to G418 toxicity. Thus, tuning of the proline-polyamine- SAM axis is the metabolic mechanism of pycr-1 mutant longevity. SAM is required for ribosomal RNA (rRNA) maturation and thus essential for ribosome biogenesis (ribogenesis). I detected altered rRNA levels, and a selective reduction in translation of messenger RNAs involved in ribogenesis, including ribosomal proteins. Ribosomal stress activates heat shock transcription factor HSF-1, and a transcriptome analysis of pycr-1 mutants revealed significant HSF-1 target gene expression. Consistently, pycr-1 longevity and G418 resistance was hsf-1 dependent, directly linking the metabolic state of pycr-1 mutants to their stress resilience. Strikingly, transcriptional changes of pycr-1(wrm22) mutants strongly associate with the presence of histone modifications in WT worms. This observation provides a plausible alternative mode-of-action by which low SAM modulates gene transcription and regulates HSF-1 target gene expression. Of note, long-lived fruit flies under methionine restriction (MR) and mice under dietary restriction (DR) also showed decreased SAM levels and upregulation of HSF-1 target genes, suggesting that this mechanism is conserved from worms and flies to mammals. Overall, my data demonstrate that low SAM induced by impaired de novo proline biosynthesis is a shared characteristic with polyamine supplementation regimes, as well as DR and MR. Intriguingly, all three have been shown to extend lifespan in various model organisms. Therefore, my data imply inhibition of PYCR-1 as potential therapeutic approach to prolong health- and lifespan in humans.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Mayr, Felix felix.mayr@gmail.com orcid.org/0000-0003-4884-4491 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-780716
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Mathematics and Science Education > Institute of Biology Education
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language longevity English metabolism English nematodes English
Date of oral exam:	13 April 2022
Referee:	Name Academic Title Denzel, Martin Dr. Schumacher, Bjoern Prof. Dr. Baumann, Ulrich Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78071