The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease

Marongiu, Fabio

First

;DeGregori, James

2022-01-01

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Abstract

Aging represents the major risk factor for the development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones that are frequently driven by cancer-associated mutations in an aging-dependent fashion. Additional studies show how aged tissue microenvironments promote the initiation and progression of malignancies, while young healthy tissues actively suppress the outgrowth of malignant clones. Here, we discuss conserved mechanisms that eliminate poorly functioning or potentially malignant cells from our tissues to maintain organismal health and fitness. Natural selection acts to preserve tissue function and prevent disease to maximize reproductive success but these mechanisms wane as reproduction becomes less likely. The ensuing age-dependent tissue decline can impact the shape and direction of clonal somatic evolution, with lifestyle and exposures influencing its pace and intensity. We also consider how aging- and exposure-dependent clonal expansions of "oncogenic" mutations might both increase cancer risk late in life and contribute to tissue decline and non-malignant disease. Still, we can marvel at the ability of our bodies to avoid cancers and other diseases despite the accumulation of billions of cells with cancer-associated mutations.