Common Human Growth Hormone Receptor Variant Associated with Greater Longevity

The longest lived laboratory mice, more than a decade after the creation of the first lineage, are still those with impaired growth hormone signaling. That record has yet to be overtaken, and I suspect that it may well stand unbroken until the development of rejuvenation therapies based on damage repair is further advanced, and senescent cell clearance is joined by other types of therapy, their effects adding together. Thus growth hormone and growth hormone receptor genes in humans are one of the places to look for variants and mutations that might improve our understanding of how metabolism influences aging, and as a bonus for those interested in pharmacological or genetic adjustment of metabolism, may lead to ways to modestly slow aging.

With this in mind, attention has fallen on a rare human lineage with a growth hormone receptor mutation that produces dwarfism, the Laron syndrome population. Unfortunately it isn’t yet possible to say whether or not these individuals have any advantage over the rest of us when it comes to longevity. They do appear to be resistant to cancer and type 2 diabetes, though the evidence in support of that conclusion isn’t completely iron-clad at this point. People with Laron syndrome and, separately, people who practice calorie restriction for its health benefits can be compared with the same processes operating in mice. When doing so, we can see that human longevity is not enormously changed, while mouse longevity does increase by up to 70% for growth hormone disruption, and up to 40% for calorie restriction. That degree of gain is certainly not the case in humans. Evolution has delivered a much more plastic life span to short-lived mammals, responsive to environmental circumstances, and with a biochemistry capable of these large changes in the pace of aging.

Putting growth hormone signaling to one side for the moment, considerable effort has been devoted over the years to the broader search for human genetic variants that are associated with longevity. The consensus on genes and longevity is that individual variations in your genome have little influence over aging until later life, and from that point forward, the older and more damaged you get the more that genetic variation matters. Nonetheless, the search has found very few compelling associations. There is solid evidence for APOE and FOXO3A, and less solid evidence for a few other variants such as TXNRD1, but these are not large effects. Beyond this there are scores of other associations that are never replicated, showing up in only one study or one population, and again with small effects – by which I mean maybe you have a 1.5% chance of living to 100 instead of a 1% chance if you held one of these variants. The big picture is of hundreds or thousands of individually tiny effects, and which genes and variants are more or less relevant varies widely between populations and individuals, and very dependent on environmental factors.

That said, there are genetic variants with sizable effects on resistance to specific age-related disease, such as those in ASGR1 or ANGPTL4, both of which reduce cholesterol and cardiovascular disease risk. Nothing is published on their effects on longevity at this time, but give it time. Should we believe that there are human genetic variants that meaningfully increase life expectancy in the carries based on what we’ve seen to date? The association studies with their poor catch of results suggest no. The existence of the variants mentioned above suggest maybe, but equally it is the case that aging has many facets. Being resistant – or even immune – to one thin facet, such as cardiovascular disease, is thought unlikely to do a great deal to overall longevity. It just means that something else gets you in the end, perhaps a couple of years later.

Returning to growth hormone metabolism, I see that researchers are claiming that a common human gene variant of growth hormone receptor, per their statistics, may result in a ten year difference in life expectancy. This is replicated in multiple study populations, but the effect appears only in men. It is interesting, but there is every reason to be cautious with this sort of very statistical genetic association study. I’d say read the paper and put it aside until someone replicates the result. Would a ten year gain from a growth hormone signaling genetic variant be surprising if this turns out in fact be the case? Maybe not, given what we know about the relative sizes of effects in mice and humans. Ten years is about on the outside end of variations that can plausibly exist in some numbers and yet blend in with broader population data, and the effects in mice are considerably larger on a relative basis.

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

Growth hormone (GH) and insulin-like growth factor (IGF) play a central role in development, differentiation, growth, and metabolism among divergent taxa. Dwarf individuals appear to live longer among many species, suggesting a role for the GH/IGF-1 axis in modulating aging and life span. A considerable body of in vitro experimental evidence also suggests an important role for the IGF axis in human longevity and aging-related processes in a tissue-specific manner. Furthermore, several studies in selected human populations lend support on the role of this axis in health and life span.

For instance, we have previously identified a cluster of functional mutations in the IGF-1 receptor in centenarians. We showed that Laron dwarfs, who are naturally short, have decreased prevalence of diabetes, cancer, and stroke, suggesting increased health span although life span in this small sample size cannot be determined accurately. Also, we previously established that centenarians with lower levels of IGF-1 had significantly longer survival. Clearly, individuals with severe GH deficiency have reduced life expectancy, suggesting that some GH is necessary for survival. On the other hand, interventional GH therapy in humans is commonly used to reverse age-related morbidities; hence, the kind of deficiency that will be most beneficial for health span and longevity needs to be further established.

GH production is decreased with age; however, it is never completely diminished. That said, there is accumulating evidence that GH may play a crucial role in modulating aging. Surprisingly, GH deficiency or diminished secretion has been linked to longevity phenotypes both in mice models and in humans with familial longevity. The GH receptor (GHR) gene has nine coding exons and consists of two common isoforms: (i) full-length GHR-flGHR and (ii) a shorter form with a deletion of exon 3, d3-GHR. The allele frequencies of these isoforms among human populations range from 68-90% for flGHR and 10-32% for d3-GHR.

Investigations of the effects of GHR isoforms on human health have provided mixed results. In two Genome Wide Association Studies (GWAS) based on single-nucleotide polymorphisms (SNPs), the GHR locus showed association with final height. However, to our knowledge, the association of d3-GHR with final height has not been examined, possibly because individuals with d3-GHR are expected to maintain normal GH action despite lower GH production. It is reasonable to hypothesize that increased GH sensitivity can also alter IGF-1 secretion and therefore regulate longevity. Given the potential role of the GH/IGF axis in longevity, we hypothesize that low IGF-1 levels will assure longevity of the d3-GHR carriers. To address this hypothesis, we genotyped the d3-GHR locus in four human cohorts with long-lived participants, and we tested its association with longevity-related phenotypes and stature with a relatively common GHR variation.

In Ashkenazi males, but not in females, a marked difference in allele frequency for the exon 3 deletion polymorphism (d3-GHR) was found between centenarian and control, as well as offspring and control groups. Whereas the male control group carried only 4% homozygote deletions, male offspring of centenarians and male centenarians carried 11 and 12%, respectively. We further validated these results in three independent cohorts – the Old Order Amish (OOA), Cardiovascular Health Study (CHS), and the French Long-Lived Study (FLLS). These results demonstrate a consistent relationship between homozygosity for the d3-GHR deletion allele and longevity among the cohorts studied. However, this observation was limited only to males; the frequency of d3-GHR deletion homozygosity among females did not differ with age in any of the cohorts studied. On average, d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers and also showed lower serum IGF-1 levels. Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span.

It appears that deletion of the GHR gene exon 3 might have originated from complex genomic events taking place after the emergence of Old World monkeys, followed by homologous recombination between two retro-elements in Homo sapiens. Thereafter, it spread throughout the human clades to be present now in approximately 25% of Caucasian chromosomes. In centenarians, most IGF-1 regulation seems to respond to caloric and protein nutritional signals, not from GH. IGF-1 is not lower in carriers of d3-GHR during childhood, adolescence, and adulthood despite several reports showing that the GHR genotype may influence circulating IGF-1 under basal conditions. People with d3-GHR or fl-GHR alleles produce comparable amounts of circulating IGF-1. That said, we suspect people with d3-GHR alleles to have a decreased GH secretion.



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