NUAGE SIGNED

Project "NUAGE" data sheet

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 Project objective

Research over the last few decades has revealed that animal life span is malleable and regulated by conserved metabolic signaling pathways, including reduced insulin/IGF signaling, mTOR, mitochondrial function, dietary restriction, and signals from the reproductive system. Whether these various pathways converge on common processes, however, has remained elusive.

We recently discovered the nucleolus to be a crucial focal point of regulation in all these pathways. The nucleolus is a subnuclear organelle dedicated to rRNA production and ribogenesis, but also controls assembly of other ribonucleoprotein complexes including spliceosomes, signal recognition particle, small RNA processing, stress granules, and responds to growth and stress signaling. Remarkably we found that small nucleoli are a cellular hallmark of longevity in diverse species, and a correlate of metabolic health in humans. At the molecular level, long-lived animals show reduced levels of the nucleolar ribosomal RNA methylase, fibrillarin (FIB-1), and knockdown of C. elegans FIB-1 reduces nucleolar size, extends life span, and enhances innate immunity. Conversely, knockout of NCL-1/TRIM2 expands nucleolar size, suppresses life extension of major longevity pathways, and renders animals pathogen sensitive, revealing key regulators of nucleolargenesis, immunity and longevity.

Here I propose to (Aim 1) clarify the mechanism of action of NCL-1, FIB-1 and interacting molecules (2) perform novel genetic screens for nucleolargenesis in C. elegans (3) uncover global transcriptomic and proteomic changes induced by NCL-1 and FIB-1 and survey several candidate nucleolar processes in regulating longevity and immunity (4) probe NCL-1/TRIM2 regulation of longevity in the short-lived killifish, Notobranchius furzeri, and develop nucleolar biomarkers of metabolic health in humans. These groundbreaking studies should illuminate how conserved signaling pathways work through the nucleolus to regulate health and life span.