Lifelong congenital untreated isolated GH deficiency does not alter human leukocyte telomere length

BACKGROUND: Telomere shortening reflects cumulative cell replication and functions as a mitotic clock. It is influenced by age and body mass, as both increase the demand for cell proliferation. The GH/IGF-I axis plays a central role in cell proliferation. The Itabaianinha cohort in Brazil, with severe isolated congenital GH deficiency (IGHD) due to a homozygous mutation in the GHRH receptor gene (GHRHR), represents a unique human model of markedly reduced stature and body mass with preserved lifespan, extended healthspan, and normal brain aging. PURPOSE: To evaluate leukocyte telomere length (LTL) in individuals with untreated congenital IGHD and its association with the GH/IGF axis and metabolic parameters. METHODS: LTL was assessed in 34 IGHD subjects homozygous for the GHRHR c.57 + 1G→A mutation (aged 24-89 years) and 36 controls homozygous for the wild-type allele (aged 26-79 years). LTL was measured by quantitative PCR using the telomere-to-single copy gene (T/S) ratio. T/S ratio Z-scores used the control-group mean and standard deviation. Circulating IGF-I, IGF-II, and metabolic parameters were evaluated. RESULTS: IGHD subjects had markedly reduced height and weight, while BMI was similar between groups. IGF-I and IGF-II levels were significantly lower in IGHD (p < 0.0001 for both). LTL did not differ between IGHD,0.96 (0.3), and controls),1.01 (0.4), and age-related telomere decline was comparable. Z-scores confirmed no deviation from expected values. LTL correlated modestly with IGF-II, but not with IGF-I or HOMA-IR. CONCLUSION: LTL in individuals with untreated IGHD was like that of controls. Age-related LTL decline was also comparable between the groups.