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Inflammation drives age-induced loss of tissue resident macrophages

Low-grade chronic systemic inflammation, or inflammageing, is a hallmark of ageing and a risk factor for both morbidity and mortality in elderly people. Resident macrophages are tissue homeostasis sentinels that are embedded in their tissue of residence since embryonic development, thus been exposed to cumulative tissue insults throughout life. Therefore, resident macrophages, among other immune cells, emerge as potential key contributors to age-associated tissue dysfunction. Contrary to what is currently postulated, we demonstrate here that the pool of embryo-derived resident macrophages exhibits an age-dependent depletion in liver, and other solid organs and that they are not replaced by Hematopoietic Stem Cell (HSCs)-derived monocytes throughout life. Further, we demonstrate that gradual, cumulative inflammation during ageing induces this specific loss of tissue resident macrophages. Preserving a “youthful” density of resident macrophages attenuates classical hallmarks of liver age-associated dysfunction. Summary The pool of embryo-derived resident macrophages dwindles with age in most tissues, without compensation from Hematopoietic Stem Cell (HSC)-derived cells. This loss is not due to impaired self-renewal in old tissues but rather to increased cell death, which is driven by sustained inflammation. Attenuating inflammation sensing during ageing prevents age-induce macrophage loss and improves hallmarks of liver ageing.