Of Barriers and Loops—How Evolution Limits Most Cancer Risks to Older Ages

Abstract The risks and health consequences of cancers increase dramatically at older ages. To develop interventions to limit the impact of cancers, from preventative to therapeutic, we must seek both evolutionary and proximate explanations for this age-dependence. Here, we discuss how natural selection has erected barriers to delay malignancy and maximize reproductive fitness. Each barrier need not be perfect, as long as malignant progression is delayed till older ages. With aging, mechanisms ranging from epigenetic deregulation to inflammation to senescence to mutation-driven clonal expansions contribute to increased cancer pathogenesis through mutually enhancing mechanisms, creating tissue contexts more favorable for malignant evolution. Significance: Better understanding of the multiple barriers that we have evolved to limit cancer development and how they can fail at older ages could enable the development of preventative and therapeutic interventions that boost these tumor-suppressive mechanisms.