Restriction of RNA Polymerase I Activity Extends Life in Nematode Worms
RNA Polymerase I (Pol I) is prominent in the regulatory systems managing the nutrient-driven tradeoff between growth and longevity. It is responsible for producing a sizable fraction of RNA, reading from gene sequences and assembling corresponding RNA molecules. As such, it is responsible for initiating some of the most energetically expensive processes in the cell, including translation of messenger RNA into proteins. Suppression of the production of proteins is a consequence of low calorie intake, an intervention known to slow aging, and researchers have shown that interfering in RNA synthesis can also extend life in short-lived species. Here, researchers dig further into the connection between Pol I activity and aging, showing that reduced Pol I activity extends life in nematode worms.
The insulin/insulin-like growth factor signaling (IIS) and the mechanistic target of rapamycin (mTOR) promote anabolic reactions upon nutrient availability, whereas in a fasted state the adenosine monophosphate-activated protein kinase (AMPK) and the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases trigger catabolic processes. Shifting the balance from IIS and mTOR signaling towards AMPK and sirtuin activity by diverse interventions promotes longevity in short-lived species.
The IIS, mTOR, AMPK, and sirtuin pathways impinge on Pol I-mediated transcription of ribosomal RNA (rRNA) genes (rDNA) into pre-rRNA, a precursor transcript comprising the three largest rRNAs. Notably, Pol I activity accounts for the major part of cells' transcription and, together with pre-rRNA processing and synthesis of ribosomal proteins, consumes a large portion of the cellular biosynthetic and energetic capacity. Moreover, ribosome biogenesis is required for mRNA translation, placing pre-rRNA synthesis at the origin of the most energy-demanding cellular activities.
Two recent studies reported that perturbation of rRNA synthesis entails pro-longevity effects in C. elegans and D. melanogaster, either by inducing structural changes in the nucleolus, the organelle implicated in ribosome biogenesis, or by limiting protein synthesis, respectively. However, the interplay between metabolic costs of Pol I activity and aging has not been explored in these studies.
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 C. 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.