Longer-lived mammals exhibit greater evolutionary conservatism and epigenetic modification at cancer-associated loci.

Peto's paradox underscores the puzzling disconnect between organismal lifespan, body size, and cancer incidence. Here, we investigate this relationship by examining the evolutionary rates of human cancer-associated sites across 58 mammalian species. While overall evolutionary rates at cancer-associated loci do not differ significantly between long-lived and short-lived species, cancer-associated sites show greater evolutionary conservation relative to non-cancer sites within long-lived mammals but not within short-lived mammals. Furthermore, long-lived species exhibit a pronounced enrichment of m6A at cancer-associated loci (based on m6A modification sites derived exclusively from male samples) despite lower global m6A levels. Notably, tumor suppressor genes in long-lived mammals harbor proportionally more m6A-modified transcripts, suggesting a potential association between mRNA methylation and post-transcriptional regulation at cancer-relevant loci. Together, these results suggest that enhanced sequence conservation at cancer loci, coupled with targeted mRNA modification, may be part of a multilayered molecular strategy that reduces cancer risk in long‑lived mammals.