Mammalian longevity is associated with restricted epithelial plasticity

Abstract

Mammalian maximum lifespan (MLS) varies widely and scales with epigenetic drift and somatic mutation rates. Here, I show that cryptic transcription, a process that compromises transcriptional fidelity, is associated with MLS across 28 mammalian species, particularly in long, highly expressed genes. Genes under differential selection against cryptic transcription are enriched for longevity-related transcriptomic signatures and are co-regulated by transcriptional regulators such as MYC and E2F. Notably, I uncover MLS-linked variation in the transcriptional fidelity of epigenetic regulators, especially Polycomb and MLL/COMPASS complex members, as well as epithelial-mesenchymal transition (EMT) genes, suggesting a close link between longevity and epithelial plasticity. Components of the PRC1.6 complex, which repress germline genes and MYC/E2F/Brachyury targets in somatic cells, show broadly elevated transcriptional fidelity in long-lived species. Conversely, key EMT genes such as ZEB2 and SNAI2 exhibit reduced fidelity. Peripheral tissues in long-lived mammals adopt \"brain-like\" transcriptomic profiles, potentially via derepression of PRC1.6 targets, thereby enhancing somatic maintenance. Reduced fidelity of EMT genes may buffer against maladaptive EMT and preserve epithelial identity. Finally, mouse aging is linked to epithelial plasticity. This study provides insights into the evolution of mammalian longevity and the stochastic components of aging.