Genetically low GH activity linked to diabetes, cancer protection in unique population
Results of a long-term study of growth hormone receptor-deficient people living in the Andes Mountains suggest that growth-stunting mutations may protect against cancer and diabetes.
These findings raise the potential for achieving similar protection in full-grown adults with the use of medications or controlled diets, researchers said.
For 22 years, an international team of researchers followed a remote community of residents living in the Loja province of southern Ecuador. The community consisted of about 100 people with Laron syndrome, a deficiency in a gene that prevents the body from using GH, compared with 1,600 relatives of normal stature.
Effect of GH activity on disease
During the study period, there were no cases of diabetes and only one non-lethal case of cancer in those with Laron syndrome. Among relatives living in the same towns during the same time period, 5% were diagnosed with diabetes and 17% with cancer.
“The GH receptor-deficient people don’t get two of the major diseases of aging. They also have a very low incidence of stroke, but the number of deaths from stroke is too small to determine whether it’s significant,” Valter Longo, PhD, associate professor at the University of Southern California, said in a press release.
Overall lifespan for both groups was about the same; those with Laron syndrome died more often from substance abuse and accidents. The study did not include psychological assessments that could have helped explain the difference.
“Although all the GH-deficient subjects we met appear to be relatively happy and normal and are known to have normal cognitive function, there are a lot of strange causes of death, including many that are alcohol-related,” Longo said.
Because other environmental and genetic risk factors are assumed to be the same for both groups, Longo and his team concluded that GH activity has many downsides, at least for adults past their growing years.
Animal studies have shown health benefits of blocking GH. Specifically, groups led by John Kopchick, PhD, of Ohio University, and Andrzej Bartke, PhD, of Southern Illinois University, achieved a 40% lifespan extension with growth factor-deficient mice in studies published in 2000 and 1996. Later, the researchers linked growth factor deficiency to reduced tumor risk.
According to Longo, any treatment for preventive reduction of GH would have to show fewer and milder adverse effects compared with drugs that are used against a confirmed disease. However, any preventive treatment would target adults with high GH activity to bring levels down to average and not to the extremely low and potentially riskier state observed in people who have Laron syndrome.
If high growth factor levels “become a risk factor for cancer as cholesterol is a risk factor for cardiovascular diseases,” drugs that reduce the growth factor could become the new statins, Longo said. To start, such drugs would be used only for families with a very high incidence of cancer or diabetes. In addition, any preventive treatment would be appropriate only until the effects of advanced age took over because of the natural decrease of GH activity with age.
GH receptor agonists, such as pegvisomant (Somavert, Pharmacia and Upjohn Company), are currently FDA-approved for the treatment of acromegaly. According to Longo, he and his team would initially seek approval for a clinical trial to test such drugs for the protection of patients undergoing chemotherapy based on evidence demonstrating that GH deficiency protects mouse and human cells against some chemical damage. However, the ways in which GH deficiency may protect a person are not fully understood.
In test tube studies, Longo’s team found that serum from patients with Laron syndrome had a double protective effect: It protected DNA against oxidative damage and mutations but promoted the suicide of cells that became highly damaged, according to the press release.
In joint experiments with a group at the National Institute on Aging, human cells exposed to the Laron syndrome serum also showed changes in the activity of genes linked to life extension in yeast and other model organisms. Although Longo and colleagues had identified such genes 15 years ago, they had not been shown to be important for disease prevention in humans.
Artificial hormone blocking is not the only way to reduce these hormones in humans; restricting calories or specific components of the diet, such as proteins, seems to have the same effect, according to the researchers. In particular, patients with Laron syndrome tend to have very low insulin levels and low insulin resistance, which may explain the absence of diabetes.
Studies to assess the effect of dietary restriction in humans and other primates are ongoing, but a recent study by Longo’s group showed that fasting induces rapid changes in growth factors similar to those caused by the Laron mutation.
However, Longo said more data are needed because of the risk for anorexia, hypotension and immunosuppression caused by long-term fasting or short-term fasting in those with rare genetic mutations.
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Disclosure: The researchers report no relevant financial disclosures.
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