Abstract
Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Here we show that NCL-1/TRIM2/Brat tumour suppressor extends lifespan and limits nucleolar size in the major C. elegans longevity pathways, as part of a convergent mechanism focused on the nucleolus. Long-lived animals representing distinct longevity pathways exhibit small nucleoli, and decreased expression of rRNA, ribosomal proteins, and the nucleolar protein fibrillarin, dependent on NCL-1. Knockdown of fibrillarin also reduces nucleolar size and extends lifespan. Among wildtype C. elegans, individual nucleolar size varies, but is highly predictive for longevity. Long-lived dietary restricted fruit flies and insulin-like-peptide mutants exhibit small nucleoli and fibrillarin expression, as do long-lived dietary restricted and IRS1 knockout mice. Furthermore, human muscle biopsies from individuals who underwent modest dietary restriction coupled with exercise also display small nucleoli. We suggest that small nucleoli are a cellular hallmark of longevity and metabolic health conserved across taxa.
Highlights
Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive
Our studies reveal that several C. elegans longevity pathways impinge on regulators of nucleolar function, including NCL-1, a homologue of BRAT/TRIM2, which inhibits production of FIB-1/fibrillarin, a nucleolar protein involved in the regulation and maturation of rRNA
NCL-1 is an ortholog of the TRIM2/BRAT tumour suppressor, which inhibits rRNA transcription and protein synthesis[12]
Summary
Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Over the last several decades, studies in model genetic organisms have revealed that animal lifespan is plastic and regulated by evolutionarily conserved signalling pathways These pathways include reduced insulin/IGF and mTOR signalling, reduced mitochondrial function, dietary restriction mediated longevity, and signals from the reproductive system, which act through specific constellations of transcription factors to extend life[1]. Whether they converge on common regulators or shared downstream processes, has remained largely an open question. Our work suggests that small nucleoli are a visible cellular hallmark of longevity and metabolic health, and that molecules associated with nucleolar function might serve as predictive, causal biomarkers of life expectancy
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