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 Peto's paradox related to replicative immortality, cell senescence, genome instability and mutations, proliferative signaling, growth suppression evasion, and cell 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.

The spontaneous immortalization probability of mammalian cell culture strains, as their proliferative capacity, correlates with species body mass, not longevity.

BACKGROUND: The Peto's paradox consists in the observation that individuals from long-lived and large animal species do not experience a higher cancer incidence, despite being exposed for longer time to the possibility of accumulating mutations and having more target cells exposed to the phenomenon. The existence of this paradox has been recently confirmed (Vincze et al., 2022). Concurrently, robust evidence has been published that longevity involves a convergent evolution of cellular mechanisms that prevent the accumulation of mutations (Cagan et al., 2022). It remains unclear which cellular mechanisms are critical to allow the evolution of a large body mass while keeping cancer at bay. METHODS: Adding to existing data linking cellular replicative potential and species body mass (Lorenzini et al., 2005), we have grown a total of 84 skin fibroblast cell strains from 40 donors of 17 mammalian species and analyzed their Hayflick's limit, i.e., their senescent plateau, and eventual spontaneous immortalization escape. The correlation of immortalization and replicative capacity of the species with their longevity, body mass and metabolism has been assessed through phylogenetic multiple linear regression (MLR). RESULTS: The immortalization probability is negatively related to species body mass. The new evaluation and additional data about replicative potential strengthen our previous observation, confirming that stable and extended proliferation is strongly correlated with the evolution of a large body mass rather than lifespan. CONCLUSION: The relation between immortalization and body mass suggests a need to evolve stringent mechanisms that control genetic stability during the evolution of a large body mass.