Naked mole rats are very long-lived in comparison to similarly sized rodents, and exhibit little functional decline until very late life. Along the way, they are also highly resistant to cancer. One aspect of their unusual physiology that likely contributes to both of these outcomes is a lower tendency towards age-related chronic inflammation. Naked mole rat senescent cells are nowhere near as inflammatory as the senescent cells of other mammals, for example, leaving naked mole rats largely unaffected by their accumulation with age. Here, researchers show that necroptosis, an inflammatory form of cell death that is both more common in age-damaged tissues and important in the pharmacological induction of cancer in animal models, operates poorly in naked mole rats.
Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration.
NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.