Moderation of rRNA gene activity triggers metabolic adaptation promoting geroprotection in Caenorhabditis elegans

Despite aging being inevitable, the rate of aging is malleable. An energy-saving, catabolic state promotes longevity, whereas major anabolic activities like ribosome biogenesis and protein synthesis are linked to accelerated aging. Both processes are hinged on the transcription of rRNA genes (rDNA) into a pre-ribosomal RNA (pre-rRNA) by RNA polymerase I (Pol I). Pol I accounts for most of the cell’s transcriptional output and presides over major pathways of macromolecule biosynthesis; however, its role in aging is not well understood. To investigate how the Pol I transcription machinery impacts lifespan and healthspan, its activity was manipulated in the roundworm Caenorhabditis elegans (C. elegans). First, NCL-1, a repressor of ribosome biogenesis, was knocked down, leading to elevated pre-rRNA levels but reduced lifespan. The negative correlation between pre-rRNA synthesis and lifespan was corroborated by overexpression of the essential transcription factor TIF-IA. In contrast, TIF-IA depletion impaired rDNA activity and prolonged the survival of worms. To understand how TIF-IA KD promotes longevity, metabolic adaptation to moderate pre-rRNA synthesis was investigated. TIF-IA KD repressed the age-dependent accumulation of yolk proteins, revealing another way of alleviating the metabolic burden. Accordingly, old and young TIF-IA depleted worms exhibited a marked increase in ATP levels compared to age-matched control worms. Given the close relationship between energy and lipid metabolism, lipidomics demonstrated that the profile of membrane and storage lipids was altered towards a longevity signature upon TIF-IA KD. Taken together, this study has uncovered how moderation of pre-rRNA synthesis concerts metabolic responses that promote healthy aging in C. elegans. Based on the structural and functional conservation of the Pol I machinery, these insights are likely translatable to mammalian aging, rendering Pol I a prime candidate for novel aging interventions.


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