Innovating Works

NUAGE

Financiado
Nucleolar regulation of longevity
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... 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. ver más
31/12/2025
MPG
3M€
Perfil tecnológico estimado
Duración del proyecto: 78 meses Fecha Inicio: 2019-06-04
Fecha Fin: 2025-12-31

Línea de financiación: concedida

El organismo H2020 notifico la concesión del proyecto el día 2019-06-04
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2018-ADG: ERC Advanced Grant
Cerrada hace 6 años
Presupuesto El presupuesto total del proyecto asciende a 3M€
Líder del proyecto
MAXPLANCKGESELLSCHAFT ZUR FORDERUNG DER WISSE... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5