Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan

Borland, G., Wilkie, S. E., Thomson, J., Wang, Z., Tullett, J. M.A., Alic, N. and Selman, C. (2024) Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan. Aging Cell, (doi: 10.1111/acel.14141) (PMID:38465473) (Early Online Publication)

Abstract

The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/−). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/− mutation on health. Female Polr3b+/− mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/− mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/− mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health.

• Item Type: Articles
• Additional Information: This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/S014357/1 to CS, JMAT and NA. SEW was funded through a Medical Research Council Doctoral Training Program to CS (Reference MR/N013166/1).
• Status: Early Online Publication
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Thomson, Mrs Jackie and Selman, Professor Colin and Wilkie, Mr Stephen and Borland, Dr Gillian
• Authors: Borland, G., Wilkie, S. E., Thomson, J., Wang, Z., Tullett, J. M.A., Alic, N., and Selman, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Aging Cell
• Publisher: Wiley
• ISSN: 1474-9718
• ISSN (Online): 1474-9726
• Published Online: 11 March 2024
• Copyright Holders: Copyright © 2024 The Authors.
• First Published: First published in Aging Cell 2024
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
304005		MRC Precision Medicine Training Grant	Morven Barlass	Medical Research Council (MRC)	MR/N013166/1-LGH/MS/MED25	SCMH - Cardiovascular & Metabolic Health