The molecular mechanisms driving chronic macrophage dysfunction in ageing

Macrophages are key to initiating the early immune response. They have a diverse set of roles in homeostasis that are known to become dysregulated with age. Additionally, macrophages have been implicated in the progression of several age-related diseases. However, the majority of work on macrophages to date has been carried out in mouse models and the underlying molecular mechanisms resulting in their age-related dysregulation are not yet known.
The work presented in this thesis aimed to first comprehensively and critically review the existing literature in the field of macrophage ageing, with the idea of taking this forward into assessing the functioning of human cells. We characterised the functional changes with age in human primary macrophages before setting out to uncover transcriptional networks underpinning these changes. We identified multiple transcription factors potentially driving age-related transcriptional changes and narrowed these down to MYC and USF1 that have key roles in macrophage function, including phagocytosis and chemotaxis, and drive their deregulation with age. We further assessed the contribution of MYC and USF1 to the ageing macrophage phenotype by assessing their expression in human monocytes, finding that MYC but not USF1 was also dysregulated in these precursor cells, that also have reduced phagocytosis and chemotaxis with age.
Lastly we assessed whether macrophage function could be restored in older individuals through modulating expression of key genes and through intervention with senolytic treatments. We found that phagocytosis was restorable in monocyte-derived macrophages isolated from older human donors following modulation of USF1 targets and that MYC expression was restored in bone marrow-derived macrophages isolated from older mice following senolytic treatment.
Overall, this thesis highlights functional and mechanistic changes occurring in human macrophages with age and provides evidence that therapeutically targeting these cells could improve the overall immune response and limit progression of age-related diseases.