Growth Hormone Receptor Knockout in Adipose Tissue Extends Life in Mice
The record for mouse life span is held by growth hormone receptor knockout lineages, approaching a 70% gain, but a lot of that increase is due to early life effects. These animals are very small in comparison to their peers. In comparison, growth hormone receptor knockout in adulthood has a greater impact on female mice than on male mice, and the gain in life span is much reduced. In today's open access paper, researchers demonstrate another approach, generating a lineage of mice in which growth hormone receptor is only disabled in fat tissue. Again, the outcomes are different in male and female mice, and smaller than those produced by full knockout.
While the effect size of full growth hormone knockout in mice is larger than that produced by most other interventions, this seems unlikely to be a viable approach to greatly extend human life span. The life span of short-lived species is more plastic in response to changes in environment and metabolism than is the case for long-lived species such as our own.
We can make direct comparisons between mice and humans for the practice of calorie restriction, and see that while mouse life span can be extended by up to 40%, adding more than a few years of human life span is just not in the cards. We can also directly compare interference in growth hormone receptor function, as a human lineage analogous to the growth hormone receptor knockout mice exists. Those individuals born with Laron syndrome inherit a loss-of-function mutation in growth hormone receptor. They may be resistant to some age-related conditions, but don't appear to live longer than the rest of us.
Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity.
To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages.
Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these two tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.
It's disheartening to see this sort of dead end research still ongoing when there are clearly better avenues to explore that have a real chance of making a difference to human lifespan.