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

Abstract

SummaryReduced 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) ]. 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.

Familial Longevity Is Not Associated with Major Differences in the Hypothalamic–Pituitary–Gonadal Axis in Healthy Middle-Aged Men

“…Indeed, in the same study population, comprising men and women, offspring had a 59.9% higher total TSH secretion and a higher temporal correlation between TSH and fT3 compared to controls (13, 14). Furthermore, GH secretion was lower and tighter controlled in the offspring compared to controls (15). When restricted to men only, which is a sample identical to the sample of men used in the current study, differences of similar magnitude were found in TSH secretion, temporal TSH–fT3 correlation, GH secretion, and GH ApEn.…”

“…It was found that TSH secretion was higher and TSH–fT3 temporal relationship was stronger in the offspring compared to controls (13, 14). Furthermore, we found that GH secretion was diminished and tightly controlled in offspring compared to controls (15). However, we did not find an association between familial longevity and cortisol secretion under resting conditions (16).…”

Impact of Growth Hormone-Related Mutations on Mammalian Aging

“…Thus, exceptional longevity in humans has been associated with reduced IGF-1 levels ( Milman et al, 2014 ) and insulin/IGF-1 composite signaling score ( van Heemst et al, 2005 ). In many populations, shorter people live longer ( Samaras, 2007 ; He et al, 2014 ), and offspring of long-lived families secrete less GH than their spouses ( van der Spoel et al, 2016 ). Moreover, mortality is increased in individuals with pathologic excess of GH ( Baumann, 1987 ).…”

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging

“…Likewise, there are observations that shorter American men of Japanese ancestry live longer than their taller counterparts [60]. Indirect evidence also suggests that there are low IGF-1 levels in the PB of human centenarians [61] and data that people from long living families have lower level of circulating GH [62]. In addition, there have been described functional mutations of IGF-1 receptor lowering its effectiveness in centenarians that as postulated prolongs longevity of these individuals [63].…”