Peto's paradox: Nature has used multiple strategies to keep cancer at bay while evolving long lifespans and large body masses. A systematic mini-review

Comparative oncology is an understudied field of science. We are far from understanding the key mechanisms behind Peto's paradox, i.e. understanding how long-lived and large animals are not subject to a higher cancer burden despite the longer exposure time to mutations and the larger number of cells exposed. In this work we investigated the scientific evidence on such mechanisms through a systematic mini-review of the literature about the relation of longevity and/or large body mass with physiological, genetic or environmental traits among mammalian species. More than forty thousand articles were retrieved from three repositories and 383 of them were screened using an active-learning-based tool. Of those, 36 articles on longevity and 37 on body mass were selected for the review. Such articles were examined focusing on: number and type of species considered, statistical methods used, traits investigated, and observed relationship with longevity and/or body mass. Where applicable, the traits investigated were matched with one or more hallmarks of cancer. We obtained a list of potential candidate traits to explain the Peto's paradox, related to replicative immortality, cells senescence, genome instability and mutations, proliferative signaling, growth suppression evasion and cells resistance to death. Our investigation suggests that different strategies have been followed to prevent cancer in large and long-lived species. The large number of papers retrieved emphasizes that more studies can be launched in the future, using more efficient analytical approaches, to comprehensively evaluate the convergent biological mechanisms essential for acquiring longevity and large body mass without increasing cancer risk.