{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T10:59:45Z","timestamp":1780916385341,"version":"3.54.1"},"reference-count":21,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u0394 \u2248 +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.<\/jats:p>","DOI":"10.3390\/ijms27125181","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T10:04:14Z","timestamp":1780913054000},"page":"5181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood-Based Epigenetic Aging Signatures in D3GHR Carriers: An Exploratory Pilot Study of Metabolic Adaptation and Aging-Related Pathways"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4072-6274","authenticated-orcid":false,"given":"Ori","family":"Berger","sequence":"first","affiliation":[{"name":"Plastic Surgery Department, Barzilai University Medical Center, Ashkelon 7830604, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maayan","family":"Insler","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Natural Sciences, Medical School, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7151-0024","authenticated-orcid":false,"given":"Ghadeer","family":"Falah","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Natural Sciences, Medical School, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Ben David","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Natural Sciences, Medical School, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-1907","authenticated-orcid":false,"given":"Lital","family":"Sharvit","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Natural Sciences, Medical School, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2589-1968","authenticated-orcid":false,"given":"Shmuel","family":"Springer","sequence":"additional","affiliation":[{"name":"The Neuromuscular & Human Performance Laboratory, Department of Physical Therapy, Faculty of Health Sciences, Ariel University, Ariel 4070000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Talisman","sequence":"additional","affiliation":[{"name":"Plastic Surgery Department, Barzilai University Medical Center, Ashkelon 7830604, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6895-3607","authenticated-orcid":false,"given":"Gil","family":"Atzmon","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Natural Sciences, Medical School, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10522-025-10296-x","article-title":"Deciphering the Molecular Clock: Exploring Molecular Mechanisms and Genetic Influences on Skin Ageing","volume":"26","author":"Ng","year":"2025","journal-title":"Biogerontology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/jid.2013.381","article-title":"Identification of Genes Promoting Skin Youthfulness by Genome-Wide Association Study","volume":"134","author":"Chang","year":"2014","journal-title":"J. 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