Naked mole rats can undergo developmental, oncogene-induced and DNA damage-induced cellular senescence

Abstract

Cellular senescence is an important anticancer mechanism that restricts proliferation of damaged or premalignant cells. Cellular senescence also plays an important role in tissue remodeling during development. However, there is a trade-off associated with cellular senescence as senescent cells contribute to aging pathologies. The naked mole rat (NMR) (Heterocephalus glaber) is the longest-lived rodent that is resistant to a variety of age-related diseases. Remarkably, NMRs do not show aging phenotypes until very late stages of their lives. Here, we tested whether NMR cells undergo cellular senescence. We report that the NMR displays developmentally programmed cellular senescence in multiple tissues, including nail bed, skin dermis, hair follicle, and nasopharyngeal cavity. NMR cells also underwent cellular senescence when transfected with oncogenic Ras. In addition, cellular senescence was detected in NMR embryonic and skin fibroblasts subjected to γ-irradiation (IR). However, NMR cells required a higher dose of IR for induction of cellular senescence, and NMR fibroblasts were resistant to IR-induced apoptosis. Gene expression analyses of senescence-related changes demonstrated that, similar to mice, NMR cells up-regulated senescence-associated secretory phenotype genes but displayed more profound down-regulation of DNA metabolism, transcription, and translation than mouse cells. We conclude that the NMR displays the same types of cellular senescence found in a short-lived rodent.