Mylonas, Katharine

Emmerson, Elaine

Jenkins, Stephen

Ferenbach, David

Campbell, Ross Alexander

2024-10-04T12:43:25Z

2024-10-04T12:43:25Z

2024-10-04

With increased ageing there is a general decline in health, increased chance of mortality, and higher chance of disease onset. These are called age-associated diseases, and can reduce the healthy years of life, causing a period of increased medical interventions to try to treat symptoms and improve quality of life. The geroscience hypothesis proposes that ageing should be treated as a disease itself, and that by researching and targeting key drivers of ageing, the co-morbidities (age-associated diseases) can be better treated or prevented entirely, thereby improving quality of life in advanced age. Senescence of a cell is characterised as irreversible growth arrest by exit from the cell cycle. These cells remain metabolically active, generating a wide array of chemokines, cytokines and matrix metalloproteases, called the Senescence-Associated Secretory Phenotype (SASP). The incidence of kidney disease increases with age, with senescent cells being more abundant in older renal tissue. Senescence has been shown to be a cause and consequence of ageing, seen not just in humans but numerous other species as well, including mice. Due to the extensive characterisation of mice and the existing genetic toolkits available, this makes them a good model for research, to translate to humans. Macrophages are the professional phagocytes of the immune system, involved in wound healing, organogenesis and homeostasis, with each of these functions involving phagocytosis and clearance of senescent cells. However, their capacity to clear cells decreases with age, with the causes of this not fully known. Macrophages are highly plastic and show great sensitivity to their environment. Due to these facts, this thesis aimed to unravel the relationship between senescent cells and macrophages in animal and human models. The data in this thesis shows that the SASP of senescent cells drives upregulation of numerous inflammatory genes, leading to an inflammatory phenotype and significantly decreased macrophage/monocyte phagocytic functions. In vivo models showed that the induction of senescent cells in renal tissue stimulates a strong macrophage response and leads to significantly higher fibrosis in the absence of injury. In addition to this, results determined that reducing the immune-evasion employed by senescent cells leads to a better functional outcome of kidneys in injury. These results show the importance of the ongoing relationships of senescent cells and macrophages, and their importance as a focus for translational therapies.

https://hdl.handle.net/1842/42255

https://orcid.org/0000-0003-2298-9887

http://dx.doi.org/10.7488/era/4975

en

The University of Edinburgh

Campbell, Ross A.; Docherty, Marie Helena; Ferenbach, David A. and Mylonas, Katie J. (2021) ‘The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis’, Frontiers in Immunology, 12(2), pp. 1–2. doi: 10.3389/fimmu.2021.700790.

CC BY-ND 4.0 Attribution-NoDerivatives 4.0 International Deed

https://creativecommons.org/licenses/by-nd/4.0/

Macrophages

Ageing

Aging

Senescent

Senescence

Senescence-associated Secretory Phenotype

Immune cells

Renal

Kidney

Phagocytosis

Chemotaxis

Immunoevasion

Characterising the influence of resident cell senescence on macrophage phenotype

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy