Research Article: Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity

Date Published: September 07, 2016

Publisher: John Wiley and Sons Inc.

Author(s): Evie van der Spoel, Steffy W. Jansen, Abimbola A. Akintola, Bart E. Ballieux, Christa M. Cobbaert, P. Eline Slagboom, Gerard Jan Blauw, Rudi G. J. Westendorp, Hanno Pijl, Ferdinand Roelfsema, Diana van Heemst.


Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle‐aged offspring of long‐living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin‐like growth factor 1 (IGF‐1) and insulin‐like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24‐h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128–216) mU L−1] compared with controls [238 (193–284) mU L−1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39–0.53)] compared with controls [0.66 (0.56–0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF‐1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

Partial Text

Genetic disruption of the insulin/insulin‐like growth factor 1 (IGF‐1) signaling (IIS) pathway can delay aging and promote longevity in a wide variety of species (Longo & Finch, 2003). In mammalian species, growth hormone (GH) plays a pivotal role in the regulation of the IIS pathway and mutations affecting GH action have consistently been shown to alter lifespan (Bartke et al., 2013). Increased longevity in mice can be induced by mutations that result in GH deficiency, including the Prop‐1 and Pit‐1 mutations that cause a combined GH, prolactin, and thyroid‐stimulating hormone deficiency, and by deletion of the GH‐releasing hormone receptor (Brown‐Borg et al., 1996; Flurkey et al., 2001). Likewise, mutations resulting in GH resistance, notably deletion of the GH receptor, were also found to increase longevity (Coschigano et al., 2000). Accordingly, transgenic mice that overexpress GH are short‐lived and show signs of accelerated aging (Wolf et al., 1993). Also in humans, patients with active acromegaly, who have excessive pituitary GH secretion, were found to have a reduced life expectancy (Orme et al., 1998). The results from studies on the association of mutations in the GH pathway that lead to dwarfism in humans with lifespan are contradictory (Sattler, 2013). While Laron syndrome dwarfs with GH receptor gene mutations were found to have relatively long lifespans with reduced risks for cancer and diabetes, patients with untreated GH deficiency had relatively short lifespans (Laron, 2002; Besson et al., 2003; Guevara‐Aguirre et al., 2011).

The two main findings of this study are that GH secretion is lower and more tightly controlled in subjects enriched for familial longevity compared with age‐matched controls.

This research is funded by the European Commission project Switchbox (FP7, Health‐F2‐2010‐259772). Evie van der Spoel is supported by a personal PhD grant from the Leiden University Medical Center.

DvH, FR, RW, and HP designed the study. SWJ, AAA, and EvdS acquired the data. EvdS, SWJ, and FR analyzed the data. EvdS and DvH drafted the manuscript. EvdS, SWJ, AAA, BB, CC, PES, GJB, RW, HP, FR, and DvH interpreted the data and critically revised the manuscript for important intellectual content.

The authors have no conflict of interest.




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