RNA degradation modulates unique aging-related gene expression in naked mole-rats

Abstract

Gene expression is co-regulated by the rates of RNA synthesis and degradation, and recent evidence has linked their imbalance to the onset of aging. The naked mole-rat (NMR) is a small rodent with an exceptionally long lifespan and markedly delayed aging, yet little is known about its RNA synthesis and degradation characteristics compared to other rodents that age more rapidly. Here, we investigate RNA synthesis and degradation in NMR and mouse skin fibroblasts by monitoring incorporation of a uridine analog, 4-thiouridine. Cross-species analysis showed that the NMR cells have higher overall rates of RNA synthesis and degradation. It further revealed higher RNA degradation rates in aging-related pathways, notably Mtorc1 signaling, likely contributing to reducing the overall expression. Although known aging-associated genes, including Xrcc5, Nudt1, Fen1, and Aptx, were expressed at similar levels in NMR and mouse fibroblasts, the RNA turnover rates were largely altered. To uncover the underlying mechanism enabling differential control of RNA kinetics, we analyzed the transcript feature importance by machine learning and identified key features governing RNA degradation both common and unique in NMR and mouse fibroblasts. Our data highlight a potential role of RNA synthesis and degradation as hidden layers of gene regulation in NMR.