Somatic mutations in oncogene and tumor suppressor genes accumulate in healthy tissues throughout life and delineate clones with limited expansion. Lifestyle‐related toxic insults increase the size and number of these clones that participate to tissue aging. Their identification has blurred the boundaries between clonal expansion and malignant tumor and has drawn more attention to the role of the host environment in tumor emergence and progression. Local tissue factors such as disrupted cell interactions and stromal cell senescence combine with systemic and distant alterations to initiate the reiterative process of clonal expansion, multilayer intrinsic diversification and clonal selection that eventually characterize overt tumor evolution. In turn, tumors remodel their close and distant environments, establishing positive feedback loops that contribute to disease progression. Strategies emerge to preserve the tumor suppressive properties of healthy tissue landscapes and delay age‐induced changes that eventually lead to cancer.

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