Project description
'Little nuclei' confirm that bigger is not always better
The nucleolus, or little nucleus inside the cell's nucleus, was first formally described in the 1830s. It took more than a century for scientists to discover that it is the site of ribosome production, and almost another half-century to realise it has other equally far-reaching roles. It is the site of signal recognition particle synthesis, a regulatory zone for cell-cycle progression mediators and other functions yet to be discovered. The EU-funded NUAGE project has found a relationship between nucleolar size and longevity, with small nucleoli corresponding to longer life in diverse species. Smaller is better for human metabolism as well. High-tech methods in several animal models could elucidate conserved molecular mechanisms with implications for metabolic health and lifespan.
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.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
80539 Munchen
Germany