Less Growth Hormone in Long-Lived Families
That lower levels of growth hormone lead to greater longevity in short-lived mammals has been comprehensively established. The longest-lived genetically engineered mice are those in which the growth hormone activity has been suppressed in some way, such as via knockout of the growth hormone receptor. Short-lived species have far more plastic life spans than we do, however: the analogous population of humans with a growth hormone receptor mutation, those with Laron syndrome, certainly don't exhibit the same large increase in life span. So to what degree do natural variations in growth hormone activity impact human longevity? The open access paper here adds more data to the existing evidence:
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. 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. Increased longevity in mice can be induced by mutations that result in GH deficiency. However, little is known about how more subtle differences in GH/IGF-1 secretion would affect human longevity. Interestingly, female centenarians were found to be enriched for rare mutations causing slight IGF-1 resistance and resulting in a somewhat smaller stature. Likewise, we previously observed that a combination of polymorphisms in the GH/IIS pathway, linked to smaller stature in female octogenarians, was associated with better survival in old age. However, to the best of our knowledge, no study has assessed the association of human longevity with GH secretion.
GH secretion by somatotrophic cells in the anterior lobe of the pituitary gland is stimulated by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin, both produced by the hypothalamus. GH exerts its functions by binding to GH receptors located on tissue target cells. A key function of GH is to stimulate production of IGF-1 by the liver, which subsequently inhibits GH secretion via negative feedback. Circulating IGF-1 is mostly bound to binding proteins of which insulin-like growth factor binding protein 3 (IGFBP3) is the most abundant. The IGF-1/IGFBP3 molar ratio is considered an indicator of IGF-1 bioavailability. In humans, many other tissues besides the liver express GH receptors indicating that GH may exert effects independent from IGF-1. To identify determinants of human longevity, the Leiden Longevity Study (LLS) included offspring of long-lived families that are enriched for exceptional longevity and partners thereof, serving as a control group. Indeed, offspring were found to have less age-related diseases and reduced mortality compared with controls. Previously, no differences were observed between offspring and controls in circulating IGF-1 concentrations. However, the magnitude and control of GH secretion have not yet been studied in human familial longevity. Therefore, we aim in this study to compare GH secretion parameters and the strength of GH secretion control signals between offspring of long-lived families and age-matched controls.
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. The observed association between reduced GH secretion and human familial longevity is in line with experimental studies in mice, which found that reduced GH action resulted in extended health and lifespans. Our results implicate the highly conserved GH/IGF-1 signaling pathway, which has been linked to delayed aging and longevity in numerous animal models, is also linked to human longevity. The observed differences in GH secretion between offspring and controls can probably not be explained by a faster clearance of GH from the blood, as the slow half-life was comparable between groups. We hypothesize that the offspring are therefore more efficient in regulating the magnitude and the timing of GH secretion. Our data strengthen the hypothesis that GH/IGF-1 signaling is a conserved mechanism implicated in mammalian longevity.
Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12519/full
It has to be pointed out the difference in age expectancy in the groups was five to ten years - the extremes are at the end of the bell curve of course. Nothing groundbreaking.
It's also known the people with a measurable IGF1 deficiency although seemingly immune to cancer, can suffer from seizures and are more prone to death by infection as seen in the Larons Syndrome cohorts. Also their frailer stature increases accidental death by a significant amount.
So longer maximum lifespan with a trade off of shorter mean lifespan of the cohort and a greater risk for infant death.
Of course these trade offs are always downplayed in these statistical analyses, otherwise it would become apparent how meaningless this type of research is in the grander scheme of things.
This may prove coorelation but it does not prove causation. The shorter lived families may have higher IGF1 levels because they are genetically prone to some unrelated chronic bodily stress that forces the body to produce more growth hormone to overcome the chronic stress, while said stress also causes a shortened life span.