Grant: Operating Grant

In the present grant application I propose to use an animal model to understand why some of the risk factors that lead to cardiovascular diseases develop preferentially in aged individuals. These risk factors, which often occur together, are obesity, diabetes, elevated blood cholesterol, and hypertension. One characteristic that several of these risk factors have in common is an association with elevated levels of toxic free radicals produced by mitochondria. Mitochondria are the part of the cell in which energy is generated from nutrients. This is why it has often been suggested that these pathological conditions could be treated with antioxidants, which neutralize free radicals. This may also be why these risk factors develop in an age-dependent manner, because aging is accompanied by a continuous increase in the production of free radicals. We are using the nematode roundworm C. elegans to study the effects of elevated free radical production on bile acids. These are hormone-like substances that regulate the storage and consumption of fats, cholesterol and sugars in the body. In this model animal we have found that mitochondrial free radicals deregulate the normal mechanisms of synthesis of bile acids in such a way that the animals are taking up more cholesterol than is normal. This was fully unexpected and provides a new hypothesis of how and why free radical generation is linked to the risk factors for cardio-vascular diseases.