Genetic engineering of mouse lineages to produce life-long disruption of growth hormone metabolism, either growth hormone itself or growth hormone receptor, extends life. Animals are smaller, more challenged in maintaining body temperature, have more fat tissue, yet enhanced insulin sensitivity, and exhibit as much as a 70% longer life span. The present record for engineered mouse longevity has been held since 2003 by growth hormone receptor knockout (GHRKO) mice. That this record still stands in 2021 might be taken as a sign that the research and development community are not yet trying hard enough to produce therapies capable of meaningful rejuvenation and extension of healthy life span.
It is an interesting question as to how much of the longevity of GHRKO and similar mice results from the disruption of growth hormone metabolism during development. To pick just one example, a smaller body size can produce a broad range of effects, such as lowered risk of cancer. In today's open access paper, researchers report on their use of an inducible gene knockout mouse lineage to remove growth hormone receptor expression at six months of age, roughly equivalent to a mid-30s human. The mice thus had a normal development, allowing for a better assessment of growth hormone metabolism as a target for therapies intended to slow the progression of aging.
I am not that optimistic that meaningful therapies will result from this line of work. Changes in metabolism that operate for short periods of time have smaller effects than those that operate for longer periods of time. Further, the usual approach of small molecule treatments that interfere in growth hormone metabolism will likely do so only partially, not producing the full effect of a gene knockout. Further, alterations to growth hormone metabolism have much smaller effects on aging in long-lived mammals than is the case for short-lived mammals. The human Laron syndrome population has loss of function mutations in growth hormone receptor, and they do not appear to live significantly longer than the rest of us.
Several mouse lines with germline growth hormone (GH) axis disruptions have shown extensions in lifespan. As a result, it has been proposed that targeted inhibition of the GH axis could be a promising pharmacological intervention to extend healthy aging. Notably, except for the GHRKO mice, the aforementioned mouse lines have reduced action of at least one additional hormone such as prolactin, thyroid-stimulating hormone, or GHRH, that may contribute to their extended longevity phenotype. Therefore, the GHRKO mouse line was established as a model to study the specific effects of reduced GH action in vivo.
Importantly, due to their exceptional longevity, the GHRKO mice hold the Methuselah mouse prize for the world's longest-lived laboratory mouse with a lifespan a week short of 5 years of age. The GHRKO mice also exhibit improved healthspan, showing improved cognition and insulin sensitivity, resistance to diabetes, reduced neoplasia, and decreased markers of aging such as adipose tissue (AT) senescence and mTORC1 signaling in liver, kidney, heart, and muscle.
Our laboratory recently reported that some of the benefits of congenital GH deficiency, such as enhanced insulin sensitivity and extended lifespan in females could be achieved if GHR is disrupted during puberty at 1.5 months of age. In light of such promising results, the present study sought to answer if it is possible to attenuate GH action further in life and attain the benefits obtained in mice with congenital GHR ablation. Clinically relevant interventions to extend healthy lifespan should be given at an adult age. Therefore, here, we disrupted the GHR at 6 months of age in mice.
In the present study, we tested how adult-onset reductions in GH action affect health and lifespan, using a mouse line of inducible ablation of the GHR starting at 6 months of age (6mGHRKO). These mice exhibited GH resistance (reduced IGF-1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects.