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

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.

Ageing as a software design flaw

“…It is largely accepted that, even though multiple processes (including ageing processes) can play a role in tumourigenesis [ 53 ], cancer is primarily driven by damage, specifically random DNA damage and mutations. Recent studies, in fact, show that older people may have billions of cells with oncogenic mutations [ 54 ]. Cancer is also widespread amongst metazoans and mammals [ 55 ].…”

Cell Tree Rings: the structure of somatic evolution as a human aging timer

“…Somatic mutations in a small set of (growth and cancer associated) genes have been shown to propagate clones that become dominant in the hematopoietic system of older individuals [Mitchell et al, 2022] and have been directly linked to increased risk of cancer and other chronic diseases [Marongiu and DeGregori, 2022]. Additionally, somatic mosaicism has been shown, in multiple tissues, to rise with age and to predict disease in animal models [Evans and Walsh, 2022]…”

The role of aging in cancer

“…As noted above, genetic mutations are critical drivers of most cancers [2], and genetic mutations accumulate with age in many tissues, including blood [3][4][5][6], brain [7], skin [8], esophagus [9,10], colon [11], and liver [12,13]. However, as reviewed by James DeGregori and colleagues, the potential response of cells and tissues to accumulated mutations in tissues is complex, ranging from inflammation, suppression of growth or elimination of mutated cells, competitive interactions with neighboring normal cells, tissue functional decline and, in some cases, cancer [41].…”