Growth hormone receptor knockout (GHRKO) mice are one of the longest-lived genetically engineered mouse lineages produced to date, and this is one of the few interventions that can slow aging and extend life to a greater degree in mice than is possible via the practice of calorie restriction. It produces dwarf mice with low body temperatures and improved insulin metabolism, alongside a range of other improvements such as greater stress resistance, reduced inflammation, increased reservoirs of pluripotent stem cells, and improved genome maintenance. It is worth recalling, however, that it seems much easier to extend life in short-lived species such as mice. There is a human population with a growth hormone receptor mutation that has a similar impact, people who have inherited Laron-type dwarfism. These individuals do not appear to live any longer than the rest of us, however, though they may be more resistant to some age-related disease.
Pursuing ways to slow down aging through alteration of metabolism is a poor strategy for the future of our health and longevity, and one of the reasons why this is the case is that it is an immensely complex undertaking, and we stand more or less at the beginning of it. The intersection of metabolism and aging is still only just beginning to be cataloged, and even for noted and comparatively well-studied ways to slow aging in mammals in the laboratory - such as GHRKO - it is still an open question as to how it actually works. Just for this one method, one single alteration to a single gene, years of hard work and funding have passed just to get to the point at which I can say "this has barely started." There is enough here in the effects of this single gene to keep teams of researchers occupied for years to come, and at a great cost. We've seen this elsewhere too, in the billion dollars consumed by work on a few sirtuin genes and their possible role in calorie restriction. Yet at the end of the day, we shouldn't expect to see practical results emerge. Knowledge, yes, but not great lengthening of life or reversal of aging. We already know what happens in humans when you disable the function of the growth-hormone receptor, and it isn't anything to write home about.
The knowledge is interesting, however. Just bear in mind that this isn't rejuvenation research: it is exploring how and why the natural pace of aging is somewhat plastic, and detailing the important mechanisms involved. To use an analogy, it tells us how we can marginally affect engine failure rates in cars with choice of oil and driving routes. It says nothing about how to periodically repair wear and damage so as to extend prime operational life far beyond the natural outcome of leaving an engine alone to fail in its own time. If you want repair and reversal of aging, you need to look to the sorts of research approaches detailed in the SENS outline rather than investigations of the details of the progression of aging, most of which deal with operation while being somewhat irrelevant to repair.
Insulin sensitivity, defined as the efficacy and kinetics of glucose clearance from the blood, is highly positively correlated to modifications of longevity, whether induced by genetic or dietary interventions, and many studies of long-lived mutants have investigated their insulin sensitivity and related it to their enhanced survivorship. Although there is a wealth of data showing a clear association between the two, the proffered mechanisms for how insulin sensitivity might engender longevity are few, and those that have been proposed remain untested. Endeavoring to address multiple aging-associated maladies by study of the basic biology of longevity, as outlined in the concept of the Longevity Dividend, we investigated the positive association between insulin sensitivity and retained healthspan.
Increased insulin sensitivity and efficient homeostatic control of blood glucose have been associated with extended survival and retention of good health and functionality in exceptionally long-lived mice and humans (centenarians and long-lived families). Over the past fifteen years, the concept of an endocrinological component to the regulation of longevity has been substantiated by a considerable number of studies integrating endocrinology and gerontology. We have conducted many associative studies of this type with long-lived, somatotrophic signaling-defective mutant mice; we now progress to the first steps in testing the necessity for enhanced insulin sensitivity for the delayed senescence of these mice or the sufficiency of improved blood glucose homeostatic control for delayed aging in their normal counterparts.
The GHR-KO mouse has multiple, gerontologically intriguing characteristics, including increased circulating GH concentration, conversely decreased GH hormonal signaling, decreased circulating IGF-1 concentration, decreased body size, obesity, and altered endocrine function. In order to exclusively test whether the insulin sensitivity due to decreased insulin production/secretion in the GHR-KO mouse is necessary for the delayed and decreased pace of senescence of this mouse, we have used a GHR-KO mouse that carries a transgene driving expression of rat Igf-1 under the potent, β-cell-expression-enriching rat insulin promoter 1 (RIP) (the GHR-KO;RIP::IGF-1 double mutant). This transgene partially corrects the reduction in pancreatic islet cell mass and size present in the GHR-KO mouse, potentially increasing blood insulin levels and thus decreasing insulin sensitivity. If decreased β-cell production and/or secretion of insulin is necessary for the full longevity of the GHR-KO mouse, then a GHR-KO mouse with partially normalized β-cell production of insulin should age sooner/faster than a standard GHR-KO mouse.
The insulin sensitivity-suppressed GHR-KO;RIP::IGF-1 double mutant differs from the GHR-KO mouse in slow-aging-related parameters but in few, if any other, characteristics. This supports the hypothesis that enhanced insulin sensitivity is necessary for the retardation of senescence in the GHR-KO mouse. Lifespan was not assessed as part of our study. Future analyses of whether GHR-KO;RIP::IGF-1 mice live shorter than their standard GHR-KO counterparts, as the data that we have presented would suggest, are clearly required.
The objective of this study was to test the hypothesis that the insulin sensitivity of the GHR-KO mouse is causal in the decreased rate of aging of this long-lived animal. Employing a twenty-fold range of insulin concentrations, we showed that the RIP::IGF-1 transgene normalizes the widely studied insulin sensitivity of slow-aging GHR-KO mice. Although there were other blood glucose regulation-related phenotypes engendered by the transgene, it is this normalization effect on insulin responsiveness that provided the basis for testing the potential effect of the transgene on other slow-aging-associated characteristics.
You'll find a lot of details in this open access paper, but I think the telling one is that the GHRKO mice with additional insulin ate more. The effects of calorie intake on life span in mice are large in comparison to most others, and probably make this work of little value beyond pointing the way to trying again but with calorie controlled diets this time. The hypothesis that insulin metabolism drives alterations in natural longevity is an interesting one, and has a lot of supporting evidence, but if more conclusively proven it just moves the point of investigation one step deeper into the operation of metabolism. One has to again ask "why?" and spend much money and time to make the next step.
Bearing in mind that investigations of insulin, IGF-1, and aging have been ongoing for a couple of decades in earnest, it becomes very clear that this is no way to work effectively on extending human life and addressing the causes of aging in the near term. A better path and more efficient forward is very much needed. Fortunately it exists in the form of SENS, only needing the research community and its extremely conservative funding institutions to buy in to a greater degree.