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Macrophage aging and rejuvenation

Periodic Reporting for period 2 - MacAGE (Macrophage aging and rejuvenation)

Reporting period: 2018-07-01 to 2019-12-31

Macrophages are immune cells that are present in essentially every organ of the body. Besides classical functions in immunity, they are also important for normal functioning of the surrounding tissue and its regeneration. Recent evidence shows that resident macrophages can originate from embryonic progenitors and be maintained in tissues long term by local proliferation. This self-renewal ability, however, appears to decline with age, with potentially major consequences for the response to infection, the resolution of inflammation and the ability for tissue regeneration. Understanding the decline of self-renewal in the aging macrophage may thus hold key elements for maintaining healthy tissue integrity. Drawing from analogies to stem cell self-renewal we want to decipher the molecular and cellular parameters of macrophage self-renewal and its decline with age.
In the first part of the project we have identified age-associated changes in gene expression and epigenetic identity of tissue macrophage populations and identified transcriptional and epigenetic regulators of age associated changes. We are using several complementary genetic mouse and cell culture models investigating their role in resident macrophage activation and self-renewal.
The ultimate goal will be to rejuvenate macrophage self-renewal capacity and aging related changes using hypothesis driven and unbiased genome wide screens to identify new signalling pathways guiding macrophage self-renewal and aging. Using innovate combinations of genetics and cell transfer protocols we will test whether this knowledge can be employed to reverse macrophage dependent loss of immune competence and failed tissue regeneration with age. Our results will lead to new general insight and potential novel cellular therapies for degenerative diseases.