The role of RNA Polymerase III in the ageing process

Wang, Zhe (2026) The role of RNA Polymerase III in the ageing process. PhD thesis, University of Glasgow.

Abstract

Ageing arises from the gradual accumulation of molecular and cellular damage that affects tissues in different ways and increases disease susceptibility. Nutrient-sensing pathways that regulate protein synthesis influence the rate of ageing, and studies in invertebrates have shown that reducing RHA Polymerase 111 (Pol Ill) activity can improve lifespan and stress tolerance. Reducing Pol Ill altered translational capacity in both invertebrate and vertebrate models. However, far less is known about how a reduction in Pol Ill activity influences mammalian physiology. This thesis addresses this gap using mice heterozygous for Polr3b (Polr3b⁺/⁻) to achieve a partial loss-of-function in Pol Ill and examine how reduced Pol Ill activity affects molecular readouts of its function, reproductivity performance, immune balance, and tissue integrity in age-associated contexts.
The first part of the thesis investigates molecular features associated with Pol Ill function across liver, brain, skeletal muscle, and primary dermal fibroblasts. Polr 3b heterozygosity alters protein synthesis and the expression of Pol Ill components and regulators in a manner that is tissue- and sex-dependent, with effects observed in liver, brain, and dermal fibroblasts but not in skeletal muscle.
Phenotypic analyses reveal that reduced Pol 111 activity has systemic consequences. Polr3b⁺/⁻· mice showed increased litter size, at birth but impaired postnatal survival, including increased pre-weaning mortality and reduced male pup weight. Change in endocrine gene expression suggests altered ovarian function, supported by reduced Cype19a1 expression in Polr3b⁺/⁻ ovaries. In parallel, a retrospective cohort analysis identifies increased susceptibility to idiopathic dermatitis in Polr3b⁺/⁻ females, accompanied by elevated circulating IL-6, splenomegaly, altered inflammatory gene expression, and changes in dermal composition, despite largely preserved skin structure.
The final experimental chapter examines liver physiology. Despite reduced Polr3b expression, no overt structural or pathological changes are observed. Instead, mild alterations in inflammatory gene expression suggest a role for Pol Ill in maintaining hepatic immune balance.
Together, these finding indicate that reduced Pol III activity in mammals produces subtle, tissue- and context-dependent effects rather than widespread dysfunction. While core tissue structure is largely preserved, Pol III activity influences reproductive outcomes, as well as protein synthesis and immune regulation in some tissues, highlighting its role as a regulator of metabolic and immune homeostasis in vivo. These findings provide evidence that modulation of Pol III-dependent translational capacity contributes to mammalian ageing and diseases susceptibility.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Supervisor's Name: Selman, Professor Colin and Salt, Dr. Ian
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-86060
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 Jun 2026 08:33
• Last Modified: 25 Jun 2026 08:53
• Thesis DOI: 10.5525/gla.thesis.86060
• URI: https://theses.gla.ac.uk/id/eprint/86060

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