Disrupting the growth hormone receptor gene in adipose tissue leads to longer lifespans in mice, study finds

A mouse study led by Ohio State University College of Osteopathic Medicine and Edison Biotechnology Institute researchers found that stopping the activity of growth hormone (GH) in fat cells can improve health and increase lifespan.

Growth hormone is best known for regulating growth; however, its presence has both beneficial and detrimental effects. It is found in many body tissues and plays an important role in many biological functions, including aging.

The concept behind the study was partly inspired by a mouse that set the record for the longest-lived animal in the laboratory. This long-lived mouse does not exert growth hormone on any cell or tissue, resulting in mice which were small in size and obese, but with much longer life spans than normal laboratory mice. The researchers wanted to know if there was selective removal of the GH receptor from fat cells (adipocytes), rather than completely removing it from the body, will preserve the beneficial aspects of GH insensitivity, limiting the more harmful effects.

“This study expands our knowledge of the actions of GR and how it can affect different tissues with different physiological outcomes,” said John Kopczyk, Ph.D., who collaborated on the study with Ohio State University researchers Edward List, Ph.D. and Darlene Berryman, Ph.D., along with researchers at Dalhousie University in Nova Scotia. “Even though the mice in this study had more body fat, they were metabolically healthy and lived longer than their littermates in the control group, which means we can apply this to our own lives, helping the general public understand that not every fat is harmful.’

The results, which were recently published in the journal Endocrinologywhere he received the title of Selected Article, showed that disruption of the growth hormone receptor (GHR) gene in fat cells improved insulin sensitivity in old age and increased lifespan in male mice. The mice also had increased fat mass, decreased levels of circulating insulin, C-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength in adulthood. The researchers found that the roughly 23% increase in lifespan in male GH-deficient mice was due to disruption of GHR in fat cells. In a previous report, they determined that approximately 19% of the increase in lifespan was due to the effects of growth hormone in muscle, and that women benefited less from disruption of the GHR.

The study was conceived when researchers looked at a line of mice developed in Kopczyk’s lab here at Ohio State University that has been used for more than 25 years to study healthy aging. This line of mice, no growth hormone receptor knockout (GHRKO) mice have no GH action in their bodies. They live longer, have increased sensitivity to insulin and are protected from many age-related diseases.

“In fact, this mouse, which is completely insensitive to GH because it lacks the GH receptor (GHR), holds the record as the longest-lived laboratory mouse, living one week shy of five years compared to control mice that live about two years . up to two and a half years,” List said. “We also know that GH acts on fat cells so we wanted to find out what would happen if we took away the GHR in just these cells, leaving the GHR intact in all the other cells and tissues.”

After removing the GH receptor in adipocytes in mice, the researchers allowed the mice to live normally and analyzed whether this change affected their metabolism and lifespan, looking at obesity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging mice of both sexes. .

According to the study, the evidence demonstrates that abrogating the action of GH, even in a single tissue, is sufficient for the observed health benefits that promote long-term health, reduce frailty and increase longevity.

“This study is important because it tells us that some of the not-so-beneficial health effects of GH occur in adipose tissue and that GH is not an anti-aging drug; if anything, it contributes to aging,” List said.