Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Samim Sharifi, Prerana Chaudhari, Asya Martirosyan, Alexander Otto Eberhardt, Finja Witt, André Gollowitzer, Lisa Lange, Yvonne Woitzat, Eberechukwu Maryann Okoli, Huahui Li, Norman Rahnis, Joanna Kirkpatrick, Oliver Werz, Alessandro Ori, Andreas Koeberle, Holger Bierhoff () and Maria Ermolaeva ()
Additional contact information
Samim Sharifi: Friedrich Schiller University Jena
Prerana Chaudhari: Leibniz Institute on Aging – Fritz Lipmann Institute
Asya Martirosyan: Leibniz Institute on Aging – Fritz Lipmann Institute
Alexander Otto Eberhardt: Friedrich Schiller University Jena
Finja Witt: University of Innsbruck
André Gollowitzer: University of Innsbruck
Lisa Lange: Friedrich Schiller University Jena
Yvonne Woitzat: Leibniz Institute on Aging – Fritz Lipmann Institute
Eberechukwu Maryann Okoli: Leibniz Institute on Aging – Fritz Lipmann Institute
Huahui Li: Leibniz Institute on Aging – Fritz Lipmann Institute
Norman Rahnis: Leibniz Institute on Aging – Fritz Lipmann Institute
Joanna Kirkpatrick: Leibniz Institute on Aging – Fritz Lipmann Institute
Oliver Werz: Friedrich Schiller University Jena
Alessandro Ori: Leibniz Institute on Aging – Fritz Lipmann Institute
Andreas Koeberle: University of Innsbruck
Holger Bierhoff: Friedrich Schiller University Jena
Maria Ermolaeva: Leibniz Institute on Aging – Fritz Lipmann Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Ribosome biogenesis is initiated by RNA polymerase I (Pol I)-mediated synthesis of pre-ribosomal RNA (pre-rRNA). Pol I activity was previously linked to longevity, but the underlying mechanisms were not studied beyond effects on nucleolar structure and protein translation. Here we use multi-omics and functional tests to show that curtailment of Pol I activity remodels the lipidome and preserves mitochondrial function to promote longevity in Caenorhabditis elegans. Reduced pre-rRNA synthesis improves energy homeostasis and metabolic plasticity also in human primary cells. Conversely, the enhancement of pre-rRNA synthesis boosts growth and neuromuscular performance of young nematodes at the cost of accelerated metabolic decline, mitochondrial stress and premature aging. Moreover, restriction of Pol I activity extends lifespan more potently than direct repression of protein synthesis, and confers geroprotection even when initiated late in life, showcasing this intervention as an effective longevity and metabolic health treatment not limited by aging.

Date: 2024
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DOI: 10.1038/s41467-024-46037-w

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