Growth hormone activates gene involved in healing damaged tissue

December 03, 2003

Growth hormone is known to increase lean body mass and bone density in the elderly, but it does something else, too.

It activates a gene critical for the body's tissues to heal and regenerate, says Robert Costa, professor of biochemistry and molecular genetics at the University of Illinois at Chicago and a member of the UIC Cancer Center.

That discovery could help explain why we age.

"Growth hormone levels decline as we grow older; as a result, the Foxm1b gene stops working and our bodies are less capable of repairing damage," Costa said.

In a paper published in the December issue of Hepatology, Costa and his colleagues report the results of studies on liver regeneration in aged (12-month-old) and young (2-month-old) mice -- a model system for studying the molecular mechanisms the body enlists to restore tissue damaged by injury or age. The liver is the only organ in the body capable of completely regenerating from mature cells.

The scientists focused on the Foxm1b gene, which is involved in the entire life cycle of the mammalian cell -- its proliferation, maturation and death. The gene's activity is elevated in dividing cells in young mammals but diminishes in old age.

In previous studies, the researchers inserted the human Foxm1b gene in aged mice whose livers had been partially removed (the two species have virtually identical forms of the gene). The experiments showed that the gene restored levels of Foxm1b proteins and induced the animals' livers to grow back at a rate typical of young mice. Further research detailed how the gene directs the busy molecular traffic inside cells to make them divide and multiply.

In the present study, the scientists tested the effects of human growth hormone because of its purported role in stimulating cell proliferation. Growth hormone, a substance secreted by the pituitary gland in the brain, is responsible for growth in children and young adults, but its levels decline during aging.

"The literature had suggested that growth hormone therapy in elderly men stimulates cells to divide," said Costa, leading to increases in muscle mass and skin thickness and greater bone density in the spine, while decreasing body fat.

"We wanted to find out how the hormone worked at a molecular level."

When aged mice whose livers had been partially removed were injected with human growth hormone, histological and other tests showed that the activity of the Foxm1b gene increased dramatically, as did levels of various enzymes and proteins that cause cells to divide. At the same time, the livers of these animals regenerated at a pace found in young mice. Cell proliferation peaked at just two days, and the liver was fully restored within a week.

By comparison, in aged mice that did not receive hormone injections, complete regeneration took a month or longer. Without growth hormone to turn on Foxm1b, the gene remained stuck at the low level of activity found in old age, and liver cells failed to multiply rapidly enough for a quick recovery.

Further tests were done with genetically engineered mice in whose liver cells the Foxm1b gene had been disabled. In these mice, growth hormone injections failed to stimulate recovery when the liver was partially removed.

"These results clearly demonstrate that Foxm1b is essential for growth hormone to spur liver regeneration," Costa said.

The study is apt to provide impetus for high-end clinics and spas already offering growth hormone injections to "treat" old age, but Costa is cautious about drawing any conclusions from his research about the merits of the therapy.

"Our liver regeneration studies tell us a great deal about how growth hormone works at a molecular level, but the injections occurred only over short periods of time, giving us no information about any long-term consequences," Costa said.

While several studies have shown that prolonged growth hormone therapy has dangerous side effects ranging from diabetes to carpal tunnel syndrome, Costa believes that short-term treatment with growth hormone could be used to speed repair after injuries or surgery in the elderly, shortening recovery time.
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The National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging provided funding for the study. Other UIC scientists involved in the research were Katherine Krupczak-Hollis, Xinhe Wang and Margaret Dennewitz.

For more information about UIC, visit www.uic.edu.

University of Illinois at Chicago

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