Despite more than a decade of finding numerous ways to slow aging in mice, the longest-lived genetically altered mice are still those that lack the genes for growth hormone receptor (GHR), one of the earliest demonstrations of a longevity mutation. They are small and have very little body fat, and as a result have to be carefully husbanded because they are vulnerable to cold - they wouldn't do well in the wild, but are otherwise healthy. These mice live 60-70% longer then their unmodified peers. But why?
A decade of research has not produced a definitive answer to that question, but rather a set of plausible contributions and theories proposed with varying amounts of confidence and supporting evidence. This mutation has a sweeping effect on metabolism, altering many areas thought to be important in aging and longevity. Producing any of these individual changes in isolation, so as to evaluate its effect, has proven challenging: metabolism is a web of linked systems and feedback loops, and changing any one item will cause reactions in all linked subsystems and mechanisms. One of the few definitive successes here is the removal of visceral fat: it is possible to surgically remove some of that fat from mice and show extension of life as a result, so we can reasonably conclude that some portion of the GHR knockout effect results from lower levels of visceral fat.
There are other ways to impact growth hormone beyond removing its receptor. Researchers can eliminate the gene for growth hormone itself, for example, or as in the work noted below they can add a gene for a growth hormone receptor antagonist (GHA), producing a protein that to some degree blocks the normal interaction between growth hormone and its receptor. Comparing the results on mouse metabolism and life span produced by these varied approaches might help to identify the importance of different contributing mechanisms to the life extension effect of GHR knockout.
Noteworthy is the fact that GHA mice do not experience significantly longer lifespans as do other mouse lines with a reduction in the GH/IGF-1 axis, such as the aforementioned GHR-/- mice. As a result, GHA mice have not been as extensively studied. Regardless, comparing the phenotype of GHA mice with other long-lived lines, such as GHR-/- mice, should reveal the most important traits caused by reduced GH action that are responsible for lifespan extension. An important distinction between GHA mice and GHR-/- mice is that the GHA does not completely inhibit GH signaling, while inhibition of GH signaling in GHR-/- mice is complete. Thus, we have generated two dwarf mice each with either low or no GH induced intracellular signaling (and each with low levels of IGF-1) yet only one has extended longevity.
Again, what molecular mechanisms account for this difference in lifespan between these two dwarf lines? GHA mice generally have a phenotype intermediate between that of control and GHR-/- mice, especially as it relates to size, readouts of the GH/IGF-1 axis and measures of glucose homeostasis. For example, GHA mice are dwarf, but not as dramatic as seen in GHR-/- mice. As compared to controls, circulating IGF-1 are reduced in both lines but by only ~25-40% in GHA mice as opposed to more than 80% in GHR-/- mice. While GHR-/- mice are extraordinarily insulin sensitive, glucose homeostasis is moderately improved in young GHA mice with low to normal plasma levels of glucose and insulin. However, insulin levels deteriorate with advancing age in male GHA mice. Perhaps the more marginal decreases in IGF-1 or the lack of dramatic alterations in glucose metabolism are sufficient in GHA mice to curb significant gains in longevity.
Interestingly, while dwarf throughout life, the body weight of male GHA mice gradually catches up to that of control mice with advancing age [due to] marked increases in adipose tissue. Where do GHA mice deposit their adipose tissue and could that be relevant to longevity? Like GHR-/- mice, GHA mice display dramatic increases in the subcutaneous fat depot. However, unlike GHR-/- mice, intra-abdominal fat pads (including visceral depots) become enlarged with advancing age in GHA mice, which may contribute to their deterioration in glucose homeostasis over time.
So here again is something to point to the accumulation of visceral fat as a bad thing for health and longevity. This is one of the few aspects of our biochemistry that we can reliably do something about today, and some portion of the demonstrated long-term health benefits of exercise and calorie restriction probably stems from the presence of lesser amounts of visceral fat tissue. Studies show that maintaining even a modest excess of body fat has a detrimental effect on future health and life expectancy.