Investigation of the impact of ageing on the haematopoietic stress response

Hellmich, Charlotte (2022) Investigation of the impact of ageing on the haematopoietic stress response. Doctoral thesis, University of East Anglia.

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Abstract

The ageing population is gradually growing and with it the incidence of age-related diseases, including malignancies and infections. Understanding how physiological processes change during ageing is key to determining how they contribute to the development of pathologies. The regulation of the maintenance and differentiation of haematopoietic stem cells (HSCs) in the bone marrow (BM) is essential for normal blood homeostasis, as well as the haematopoietic response to stress. In order to support an increased demand for blood cell production, HSCs quickly upregulate their energy production by shifting from glycolysis to oxidative phosphorylation. During infections, this allows the rapid production and mobilisation of mature immune cells which can help to clear and overcome the infection. However, in the ageing population, symptomatic infections occur more frequently and are often associated with increased morbidity and mortality. This suggests that the immune response is diminished and, in this thesis, I examine the metabolic changes within the haematopoietic cell populations that contribute to this age-related change.

This study demonstrates that HSCs and haematopoietic progenitor cells (HPCs) acquire metabolic changes with age. These are analysed by measuring mitochondrial membrane potential, mitochondrial content and mitochondrial reactive oxygen species (ROS). Furthermore, this research shows that these age-related metabolic changes impact on the HSC and HPC stress response. The results described here show that this metabolic change is driven by senescent changes in the BM microenvironment, in particular the BM stromal cells (BMSCs). Removing HSCs from the aged BM using transplant models or targeting the BMSCs with senolytic agents can reverse some of the metabolic changes observed in aged HSCs and improve the haematopoietic stress response (1). Together, these findings demonstrate that ageing in the BM microenvironment drives intrinsic metabolic changes in the haematopoietic cell populations and this impairs their ability to effectively respond to stress.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	22 Feb 2023 14:32
Last Modified:	22 Feb 2023 14:32
URI:	https://ueaeprints.uea.ac.uk/id/eprint/91249
DOI:

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