Projects Ger Strous
Major topics in today’s research field are health, cancer and ageing. Most Dutch people spend 20-30% of their income to be fit as a fiddle a long life long. Thanks to antibiotics, vaccinations and life style improvements, life span has increased during the last 50 years. Despite the effort of health industry to make health issues central, if not obsessive, for many people, science has been able to solve neither cancer nor ageing.
During the first 45 years of human life growth hormone (GH) is important and beneficial for growth, body composition, fitness and immunity. In the second half of our life science shows that GH activity is unfavorable. People without GH activity live longer, without cancer, diabetes, arthritis, stroke, and neurodegeneration. They enjoy both a longer life and health span.
It is not known how GH contributes to cancer and ageing. GH activity is at the top of the hierarchy in both the DNA damage theory as in its role in protein synthesis via Foxo. All cells produce GHR, pituitary cells, but also some other cells, produce GH. Cells precisely control their GH sensitivity by complex mechanisms that exist thanks to an unusual high degradation rate of the GHR: if no stressor is present every 50 minutes new receptors replace the old ones. If the body is stressed e.g. due to illness cells degrade their GHRs fast and people become GH-insensitive. This condition contributes to severe weight loss. After the age of 45, GH also plays an important role in cancer, diabetes and ageing: e.g. women that growth fast in puberty, most likely due to high levels of GH, have a 50% higher risk of cancer.
For the last 20 years my group has been working on the cell biology of the GH receptor (GHR). We now understand the basic principles of how cells control their sensitivity for GH. It turns out that the balance between ubiquitylation (SCF(TrCP)) and phosphorylation (Jak2) regulates the GH activity. Inhibition of the SCF(TrCP)-GHR interaction increases the GH sensitivity of cells, which would be beneficial in youth and cachectic conditions, while inhibition of the Jak2-GHR function would cure cancer and increase health span. The next step is to develop drugs that either increase or decrease the GH activity in humans.
Figure legend: GHR is a major controller of human health span