Blood-Based Epigenetic Aging Signatures in D3GHR Carriers: An Exploratory Pilot Study of Metabolic Adaptation and Aging-Related Pathways

The exon 3 deletion polymorphism in the growth hormone receptor gene (d3GHR) is associated with altered GH signaling and longevity-related phenotypes, yet its relationship with blood-based epigenetic aging remains unclear. We analyzed whole-blood DNA from 21 unrelated adults recruited at Laniado Medical Center to determine whether the d3GHR genotype was associated with differential DNA methylation in skin-aging-related genes and altered age acceleration across established DNA methylation clocks. Genome-wide methylation was profiled using the Infinium MethylationEPIC v2.0 array, focusing on 1098 CpG sites linked to wrinkling, pigmentation, and extracellular matrix remodeling. No significant single-CpG methylation differences were detected within the targeted panel. However, two promoter-proximal differentially methylated regions (DMRs) were identified near CYP1A1 (FWER = 0.014) and ACAT2 (FWER = 0.026). Notably, only the pan-tissue Horvath clock showed a significant genotype effect, with marked age acceleration in d3/d3 carriers (mean Δ ≈ +14.5 years, p = 0.0179) that persisted after adjustment for chronological age. In contrast, second-generation clocks such as PhenoAge showed a non-significant trend toward deceleration. These findings suggest a preliminary association between d3GHR genotype, clock-specific epigenetic age acceleration and promoter-level methylation signatures near metabolic and stress-response genes. The observed Horvath acceleration may reflect systemic metabolic or immune adaptation rather than direct structural senescence in core skin-aging gene programs in blood. Given the very small d3/d3 subgroup, these findings should be interpreted strictly as exploratory pilot observations and cannot establish reproducible genotype-specific effects without validation in larger independent cohorts.