Identification of Biochemical and Molecular Markers of Early Aging in Childhood Cancer Survivors

Simple Summary: Childhood cancer survivors (CCS) display a higher risk of developing second malignant tumors and chronic diseases compared with aged-matched controls because of chemo/radiotherapy. This early frailty seems associated with accelerated cell aging, a process correlated with altered mitochondrial energy production. Therefore, this work aims to shed light on the mechanisms involved in chemo/radiotherapy-induced early aging, morbidities, and the risk of developing second tumors in CCS through a biochemical and molecular approach. The identification of crucial mechanisms involved in the CCS chemo/radiotherapy-related pathological conditions will allow identifying therapeutic targets to develop appropriate risk-based care and interventions, minimize morbidities, and maximize the quality of life in the cancer survivor population.

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.