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Immune system function changes during aging, but the molecular mechanisms of this phenomenon are not fully understood. The present study identified pathways that are associated with age-associated changes in human B lymphocytes. Initial in silico analysis of 1355 genes involved in aging revealed the strongest association (p = 4.36E-21) with the gonadotropin-releasing hormone receptor (GnRHR) pathway. Extended analysis of 2736 aging-related genes using updated databases confirmed such association (p = 2.41E-16). Genes involved in both aging and the GnRHR pathway were significantly involved in lymphocyte B and T activation and aging-related phenotypes, including hyperinsulinemia and diabetes, arthritis, cerebrovascular disease, and cancers. We, therefore, examined non-tumorigenic Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines that originated from 12 young subjects (20-31 years old) and 10 centenarians (100-102 years old). Gonadotropin-releasing hormone I (GnRH-I) and GnRHR levels did not depend on the age of the cell donors. Inhibition of the GnRHR pathway age-independently decreased cell proliferation (p < 0.001) and increased apoptosis (p < 0.001). However, the decrease in immunoglobulin G synthesis (p < 0.01) was twice as high in centenarian cells than in young cells. In conclusion, the GnRHR pathway regulated essential properties of B lymphocytes. However, upon EBV transformation, memory class-switched B cells became the dominant cell subpopulation. Therefore, the observed effects of GnRHR inhibition were attributable to this subpopulation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)