The Cellular Stress Responses and the Resolution of Peto's Paradox

Peto's paradox (Pp) results from the evidence that in mammals there is no obvious positive correlation between body size, lifespan, and cancer incidence. Posing the question of which mechanisms are responsible for this. Comparative studies searching for specific anticancer mechanisms as putative solutions to Pp have been undertaken in mammals. The result of these efforts are further inconsistencies leading to ad-hoc hypotheses and unnecessary complexity. In contrast to this, we present evidence that the cellular stress responses (CSRs), aimed at curtailing proteotoxic stress and assuring cell survival are necessary for enabling carcinogenesis. Yet, natural selection adjusts the performance of the CSRs according to the life history of each species and because of this, cancer is mostly delayed to the post-reproductive stage in all mammalian species, resulting in a limited impact of cancer on species fitness and viability. From this perspective, the need of evolving anticancer mechanisms, suggested by Pp is weakened or disappears and the paradox is likely resolved.