Ravera Silvia, Vigliarolo Tiziana, Bruno Silvia, Morandi Fabio, Marimpietri Danilo, Sabatini Federica, Dagnino Monica, Petretto Andrea, Bartolucci Martina, Muraca Monica, Biasin Eleonora, Haupt Riccardo, Zecca Marco, Fagioli Franca, Cilloni Daniela, Podestà Marina, Frassoni Francesco
Stem Cell Laboratory and Cell Therapy Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy.
Cancers (Basel). 2021 Oct 18;13(20):5214. doi: 10.3390/cancers13205214.
Survival rates of childhood cancer patients have improved over the past four decades, although cancer treatments increase the risk of developing chronic diseases typical of aging. Thus, we aimed to identify molecular/metabolic cellular alterations responsible for early aging in childhood cancer survivors (CCS). Biochemical, proteomic, and molecular biology analyses were conducted on mononuclear cells (MNCs) isolated from peripheral blood of 196 CCS, the results being compared with those obtained on MNCs of 154 healthy subjects. CCS-MNCs showed inefficient oxidative phosphorylation associated with low energy status, and increased lipid peroxidation and lactate fermentation compared with age-matched normal controls. According to a mathematical model based on biochemical parameters, CCS-MNCs showed significantly higher metabolic ages than their real ages. The dysfunctional metabolism of CCS-MNCs is associated with lower expression levels of genes and proteins involved in mitochondrial biogenesis and metabolism regulation, such as CLUH, PGC1-alpha, and SIRT6 in CCS, not observed in the age-matched healthy or elderly subjects. In conclusion, our study identified some biochemical and molecular alterations possibly contributing to the pathophysiology of aging and metabolic deficiencies in CCS. These results identify new targets for pharmacological interventions to restore mitochondrial function, slowing down the aging-associated pathologies in CCS.
在过去的四十年里，儿童癌症患者的存活率有所提高，尽管癌症治疗会增加患典型老年慢性病的风险。因此，我们旨在确定导致儿童癌症幸存者（CCS）过早衰老的分子/代谢细胞改变。对从196名CCS外周血中分离出的单核细胞（MNC）进行了生化、蛋白质组学和分子生物学分析，并将结果与154名健康受试者的MNC结果进行比较。与年龄匹配的正常对照组相比，CCS-MNCs表现出氧化磷酸化效率低下，伴有低能量状态，以及脂质过氧化和乳酸发酵增加。根据基于生化参数的数学模型，CCS-MNCs的代谢年龄显著高于其实际年龄。CCS-MNCs的代谢功能障碍与线粒体生物发生和代谢调节相关基因和蛋白质的表达水平降低有关，如CCS中的CLUH、PGC1-α和SIRT6，在年龄匹配的健康或老年受试者中未观察到。总之，我们的研究确定了一些可能导致CCS衰老病理生理学和代谢缺陷的生化和分子改变。这些结果确定了恢复线粒体功能、减缓CCS衰老相关疾病的药物干预新靶点。
