The Merits of Late Life Suppression of Growth Hormone Signaling
The longest lived mice are those in which growth hormone or growth hormone receptor are knocked out, a gain of 70% or so in life span. They exhibit dwarfism, like the human population with the analogous inherited Laron syndrome, caused by a loss-of-function mutation in growth hormone receptor. The Laron syndrome population may be somewhat more resistant to some age-related diseases, that data still to be rigorously confirmed, but do not appear to live any longer than the rest of us. Studies on growth hormone metabolism and longevity conducted in mice should be read with that in mind, particularly when used to advocate therapeutic approaches.
One of the most potent interventions used to extend lifespan in laboratory mice is targeted disruption of the growth hormone (GH) receptor (GHR). In fact, the current record holder for the Methuselah Mouse Prize for Longevity - a mouse that lived one week shy of five years - is the GHR "knockout" (GHRKO) mouse. A new study by our laboratory suggests that partial knockdown of the GHR beginning at 6 months of age can also extend median and maximal lifespan in female mice. GH secretion decreases with age (referred to as somatopause), causing some to consider the use of GH replacement as a means to counteract aging-related conditions. Counterintuitively, diminished GH action in model organisms, either by way of natural mutations or inactivation of the GH or GHR genes, increases lifespan and slows the aging process through reducing IGF-1, mTOR signaling, and cellular senescence while simultaneously enhancing insulin sensitivity and stress resistance.
GHRKO mice (as well as most other mouse lines with reduced GH action) and humans with Laron syndrome experience the effects of the inactivated GHR gene mutations from conception; thus, the specific impact of GH on longevity in later life required further investigation. The first study was published in 2016 where we suppressed GH action at 1.5 months of age - just prior to sexual development in mice. As might be expected with GHR disruption at this younger age, mouse growth is impacted with both body weight and length significantly decreased relative to controls. Despite only partial disruption of the GHR, female 1.5mGHRKO mice have a significant increase in maximal lifespan.
We conducted a second study recently published in which GHR disruption was initiated at 6 months of age - a mature adult age in mice. Like the first study, female 6mGHRKO mice exhibit a significant extension in lifespan, but this time with mean, median, and maximal lifespan increased compared to controls. Additionally, although 6mGHRKO males did not have a significant increase in lifespan, they did have multiple signs of improved healthspan (e.g., decreased cancer, improved insulin signaling, decreased oxidative damage). Importantly, unlike the 1.5mGHRKO mice, both male and female 6mGHRKO mice have no significant changes in bodyweight and minimal impact on body length. Thus, extension in lifespan and healthspan can be achieved with GHR disruption in adult life without major changes in growth.
Collectively, these results suggest that pharmacologic modalities that block GH action later in life, even as somatopause proceeds, could have therapeutic benefit for aging and aging-related diseases. While gene disruption in humans is not viable, approved pharmacological strategies to reduce GH action exist and include somatostatin receptor ligands, dopamine agonists, and GH receptor antagonists (GHRAs). Of the options, the one that exclusively targets GH action is the GHRA, pegvisomant. This GHRA, which was discovered in our laboratory with a transgenic mouse line (GHRA mice) and approved by the FDA in 2003, is now used world-wide as a highly effective drug to antagonize GH action in the treatment of patients with acromegaly. Importantly, in a workshop convened to assess development of safe interventions to slow aging and increase healthy lifespan in humans, GHRA is cited as a promising therapeutic. Thus, when considering whether drugs designed to specifically antagonize or inhibit GH action have potential as gerotherapeutics, the current mouse study would suggest "yes".