Aging-Associated Transcriptional Patterns of Human Endogenous Retroviruses and Epigenetic Regulators in Healthy Individuals

Background/Objectives: Human endogenous retroviruses (HERVs) represent a substantial portion of the human genome and are increasingly recognized as active components of gene regulation and immune modulation. Aging has been associated with alterations in HERV expression; however, data in healthy populations remain limited. The aim of this study was to evaluate age-associated transcriptional patterns of selected HERV elements, and epigenetic regulators in a cohort of healthy individuals. Methods: A total of 269 subjects aged 0.13–89.48 years were enrolled. Transcriptional levels of HERV-H, HERV-K, and HERV-W pol genes, and of Syncytin-1, Syncytin-2, and HERV-W env genes, and the epigenetic regulators SETDB1 and TRIM28 were assessed by real-time PCR. Primary analyses used raw Ct values. Associations with age were evaluated separately in pediatric participants and adults using multivariable linear regression models including sex and the reference gene GAPDH Ct as covariates. Quadratic age terms and alternative approaches to GAPDH adjustment were also examined. Results: GADPH Ct values were positively correlated with age and all target genes. After Benjamini–Hochberg correction, HERV-H-pol, Syncytin-1, and Syncytin-2 showed increasing Ct values with age in pediatric participants, while HERV-K-pol, Syncytin-1, HERV-W-env, SETDB1, and TRIM28 showed increasing Ct values in adults. These associations are compatible with lower transcriptional signals of some HERVs and a few cellular genes over the years within each age group. Separate analyses in pediatric participants and adults provided no significant evidence of quadratic age associations after Benjamini–Hochberg correction for multiple testing. Conclusions: Several age associations depended on the analytical treatment of GAPDH. These findings identify target-specific age-associated transcriptional patterns in peripheral blood from apparently healthy individuals. They highlight the importance of distinguishing developmental from adult age associations and evaluating the reference gene suitability for normalization of target gene expressions. Longitudinal and mechanistic studies are needed to clarify the biological significance of these associations.