(P29-011-24) Association Between the Expression of Autophagy-Related Genes in Circulating Leukocytes and Aging: An Exploratory Modulating Effect of the Mediterranean Diet

Objectives: Autophagy is a mechanism that fulfills cellular metabolic needs through the elimination of damaged molecules and organelles. While it is widely acknowledged that autophagy declines with age and that autophagy imbalance promotes pathological aging and disease, the majority of the evidence for this hypothesis comes from animal models; further research on humans is needed to confirm them. Therefore, our objective was to examine the association between the expression of autophagy-related genes and age in humans, as well as explore whether the Mediterranean diet (MedDiet) modulate gene expression of these genes.

Methods: First, a cross-sectional study of 185 subjects, aged 19 -76 y, from a Mediterranean population was undertaken. RNA was isolated from leukocytes. After quality control and array normalization, differential gene expression of selected autophagy-related genes (including genes involved in chaperone-mediated autophagy-CMA, macroautophagy, and lysosomal degradation pathways) associated with chronological age was tested with GeneChip Human Gene 2.0 ST Array. Models were adjusted for sex, BMI, diabetes, and leukocytes. Second, from the same area, selected gene expression was examined in 100 subjects with metabolic syndrome (55-75y). Adherence to MedDiet was assessed by the 17-item score, and its modulating effect on gene expression analyzed.

Results: Regardless of the complexity of the process, significant differences in gene expression (p < 0.05) were found for some autophagy-related genes associated with chronological age. HSP90AB1 (down), RAC1 (down) and AKT2 (up) were the most significantly associated CMA genes. For macro-autophagy, downregulation of FADD, ATG4C, and CASP3 was detected as hits. For lysosomes, consistently with other studies, we detected decreased gene expression for several v-ATPase components, named:  ATP6V1B2 (down), ATP6V1C1 (down), ATP6V1A (down) and ATP6V1E1 (down). Interestingly, when MedDiet was analyzed, gene expression for the ATP6V1B2 (p < 0.01) and ATP6V1A (p=0.04) genes increased significantly with higher adherence.

Conclusions: Age is associated with decreased gene expression of some autophagy-related genes. However MedDiet may play a modulating role.

Funding Sources: AEI-ERDF-PID2019-108858RB-I00, PROMETEO/2021-21 and CIBEROBN