IDENTIFICATION OF BIOCHEMICAL AND MOLECULAR MARKERS OF EARLY AGING AND CELLULAR STRESS IN CHILDHOOD CANCER SURVIVORS (CCS) PATIENTS

ABSTRACT: Survival rates of Childhood Cancer Survivors (CCS) have improved tremendously over the past four decades. Unfortunately, treatments are associated with increased risk for developing early onset of chronic diseases, typical of aging, and secondary cancer. Although several studies have described a phenotype of accelerated aging in CCS, the molecular mechanism underlying the “late effects” remain unknown. Evaluating the mitochondrial metabolism in the mononuclear cells (MNC) isolated from peripheral blood of CCS, age-matched control, and healthy elderly subjects, our data demonstrate that CCS-MNC display an altered aerobic metabolism associated with a low expression of genes involved in mitochondrial biogenesis and regulation. In particular, CCS-MNC show an inefficient oxidative phosphorylation and a low level of NAD+, which determine a low energy production and a metabolic switch to lactate fermentation. The alteration of mitochondrial function is also associated with an increment of lipid peroxidation due to an unbalance among the oxidative stress production and the antioxidantdefenses activation. These biochemical alterations seem linked to the lower expression of CLUH, PGC1-, and SIRT6, which play a pivotal role in the mitochondrial biogenesis and metabolism regulation.Finally, predicting the age by a mathematical model based on the glucose metabolism parameters, CCS display an age similar to that of elderly subjects. The early aging is also confirmed by the increment of aging markers evaluated by a proteomic approach. In conclusion, our data suggest that the early aging described in CCS patients could be due to an alteration of mitochondrial function.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bone Marrow

SUBMITTER: Andrea Petretto  

LAB HEAD: Andrea Petretto

PROVIDER: PXD021960 | Pride | 2022-02-16

REPOSITORIES: Pride