Restoring resident tissue macrophages to combat aging and cancer.

Perturbations to the immune system influence organismal aging, yet identifying effective therapeutic targets that mitigate aging-related tissue decline or the pathogenesis of aging-related diseases, such as cancer, remains challenging. In this Perspective, we focus on the dysfunction and loss of resident tissue macrophages (RTMs) with aging of certain tissues, which promote local inflammation, compromise tissue health and contribute to tumorigenesis. The abnormal genesis of RTMs from the bone marrow is a defining hallmark of both healthy and unhealthy aging. So, we propose that restoring RTMs-either by reshaping their niche and rescuing local self-renewal or by rejuvenating aging-associated myelopoiesis in the bone marrow-should be a major objective of interventions to promote healthy aging. We summarize the body of work supporting this conceptual framework and outline key future directions for the development of versatile myeloid-targeting therapies.