ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 9.9 | DOI: 10.1530/ey.17.9.9

ESPEYB17 9. Oncology and Chronic Disease Premature Aging, Cardiometabolic Fitness and Cardiovascular Damage (3 abstracts)

9.9. Advanced glycation end products and chronic inflammation in adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation

Felicetti F , Cento AS , Fornengo P , Cassader M , Mastrocola R , D’Ascenzo F , Settanni F , Benso A , Arvat E , Collino M , Fagioli F , Aragno M & Brignardello E



To read the full abstract: Pediatr Blood Cancer. 2020 Mar;67(3):e28106. ebrignardello@cittadellasalute.to.it

Premature aging has been proposed as a paradigm to explain the early cardiovascular disease (CVD) that affects young-adult childhood cancer survivors (CCS). Protein glycation is recognized as one of the main factors contributing to aging. Advanced glycation end products (AGEs) are a heterogeneous group of compounds that contribute to the development of chronic low-grade inflammation through various mechanisms. Extracellular AGEs accumulation causes an inflammatory response that alters the structure and function of essential proteins as collagen, hemoglobin, myocardial matrix protein, fibrinogen, and low-density lipoproteins. The alteration of protein folding processes impairs mitochondrial function, leading to reduced production adenosine triphosphate (ATP), increased synthesis of reactive oxygen species (ROS), and reduced antioxidant activity. Finally, the interaction of AGEs with their cell-bound receptor (RAGE) increases gene expression and release of proinflammatory cytokines, as well as ROS generation. The stimulation of endothelial proliferative and fibrotic processes induces vascular inflammation and atherosclerosis, leading to myocardial dysfunction and other vascular disruption–related diseases. Interleukin (IL)-1β is considered as the first step of the proinflammatory cytokine chain. It induces the synthesis of multiple inflammatory mediators, as IL-17 that acts on vessel and cardiac cells, leading to inflammation, coagulation, and thrombosis. High-sensitivity C-reactive protein (hs-CRP) has been defined as the downstream biomarker of chronic low-grade inflammation.

Among patients affected by childhood acute lymphoblastic leukaemia (ALL), those who received hematopoietic stem cell transplantation (HSCT) after conditioning regimens involving myeloablative total-body irradiation (TBI) show the highest risk of CVD. This cohort study evaluates AGEs plasma levels in 18 adult survivors of ALL treated with TBI + HSCT; 30 age-matched healthy controls were recruited for comparison. TBI-exposed ALL survivors showed a seven-fold increase of AGEs levels, in comparison with healthy controls. Circulating levels of L-1β, IL-17 and hrCRP, as well as the glutathione/reduced glutathione ratio (expression of antioxidant reserve) in ALL survivors were remarkably higher than in controls. ALL survivors also showed significantly higher levels of triglycerides and apolipoprotein B.

The small sample size represents the major limitation of this study, even if the study group was highly homogeneous. Survivors affected by other conditions, such as diabetes mellitus, chronic graft versus host disease, liver or renal dysfunction, which could potentially influence AGEs accumulation and a chronic inflammatory status, were excluded. If confirmed by larger studies, these findings could lead to development of AGEs-targeted therapeutic strategies in order to prevent late effects related to premature aging. The high circulating levels of AGEs and inflammatory cytokines could contribute to explain not only the increased risk of CVD, but also the pathogenesis of other severe complications including second malignant neoplasms.

References:

1. Ness KK, Kirkland JL, Gramatges MM, et al. Premature physiologic aging as a paradigm for understanding increased risk of adverse health across the lifespan of survivors of childhood cancer. J Clin Oncol. 2018;36:2206–15.

2. Reynaert NL, Gopal P, Rutten EPA, Wouters EFM, Schalkwijk CG. Advanced glycation end products and their receptor in age-related, non-communicable chronic inflammatory diseases: overview of clinical evidence and potential contributions to disease. Int J Biochem Cell Biol. 2016;81:403–18.

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