Universität zu Köln

Tiku, Varnesh (2017). Small Nucleoli and Reduced Ribosomal Biogenesis are Hallmarks of Longevity. PhD thesis, Universität zu Köln.

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Abstract

In the last decades a great deal of work in model organisms has revealed that lifespan of an organism is regulated by conserved signaling pathways including the insulin/IGF-1 and the target of rapamycin (TOR) signaling pathways that mediate longevity across species. A number of conserved transcription factors have been identified that work downstream of these pathways to modulate lifespan extension. However, it still remains elusive if there are common downstream targets and shared mechanisms that are affected by all these pathways to bring about a change in organismal lifespan. It is therefore of great interest to understand these convergent mechanisms because fine-tuning of the factors involved in these mechanisms may be sufficient to induce longevity and lead to resistance against age-associated diseases. Therapeutic interventions could be designed to modulate the function of these convergent mechanisms, which may prove to be sufficient to avail of the benefits of improved health and longevity. In this study we found ncl-1 as a convergent regulator of C. elegans lifespan working downstream of different longevity pathways. We identified ncl-1 in RNAi based genetic screens as a suppressor of dietary restriction (DR) mediated longevity, using the eat-2 mutant, which is the genetic model of DR in C. elegans. ncl-1 encodes a cytoplasmic B-box zinc finger protein that inhibits rRNA and 5S RNA transcription and protein synthesis. Consistent with a role in ribosome biogenesis, NCL-1 regulates nucleolar size and ncl-1 mutants have larger nucleoli especially in neuronal, muscle and hypodermal cells. Lifespan analyses revealed that ncl-1 is required for longevity conferred by DR, reduced insulin/IGF-1 and reduced TOR signaling pathways. ncl-1 was also required for mitochondrial and gonadal longevity models in C. elegans indicating that NCL-1 works as a common downstream regulator of longevity in C. elegans. Consistent with these findings, ncl-1 over-expression was sufficient to promote longevity. Since loss of ncl-1 enlarges nucleoli of worms in different tissues, we investigated nucleolar size in different long-lived worms representing different longevity pathways in C. elegans. Strikingly we observed that all the long-lived animals tested, exhibited smaller nucleoli in different tissues compared to wildtype. Among wildtype animals there is a high variation in nucleolar size, however we found that it is highly predictive for lifespan in an isogenic population. Consistent with smaller nucleoli, all these different long-lived animals possessed reduced ribosome biogenesis and reduced levels of the nucleolar marker FIB-1/Fibrillarin and these effects were reversed with the loss of ncl-1. In accord with reduced levels of FIB-1/Fibrillarin in long-lived animals, a modest reduction of FIB-1/Fibrillarin in wildtype animals increased their lifespan. Consistent with our findings in C. elegans, we observed smaller nucleoli, reduced ribosome biogenesis and reduced FIB-1 levels in long-lived Drosophila. We also detected smaller nucleoli in different tissues of long-lived DR and IRS-1 knockout mice and also in humans who undergo modest dietary restriction coupled with exercise. Thus it is highly suggestive that smaller nucleoli and reduced ribosome biogenesis are hallmarks of longevity across species.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Tiku, Varnesh varneshtiku@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-76478
Date:	20 June 2017
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Aging, Ribosome Biogenesis, Nucleolar function English
Date of oral exam:	4 November 2016
Referee:	Name Academic Title Antebi, Adam Prof. Dr. Hammerschmidt, Matthias Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/7647