With age, metabolic disorders occur. These disorders often change the content of dissolved substances in the blood, which can increase the susceptibility to different diseases. As American researchers have now discovered, the blood of older people has increased concentrations of an organic acid that is produced as an intermediate when proteins and fats break down. Cancer cells respond to this by increasing metastases and becoming insensitive to certain cancer drugs.
This link could be one of the reasons why cancers are more likely to be fatal in old age than in younger people, the scientists report in Nature. Anti-acid preventive therapy could thus prevent the development of aggressive forms of cancer and improve the effectiveness of chemotherapy.
“Our results show that deregulation of metabolism in the elderly plays a central role in the development of aggressive tumors,” write John Blenis of the Weill Cornell Medical College in New York and his colleagues. They first investigated whether blood serum of old and young people differ in their effect on cancer cells. They also used blood serum from 30 healthy individuals, either younger than 30 years or older than 59 years, in cultures of human cancer cells. The majority of the serum of old people caused a change in the cell shape and the production of special proteins, both of which are also typical for the development of metastases. In addition, the cells became resistant to the cancer drugs carboplatin and paclitaxel. The blood serum of young people did not trigger such effects. Breast cancer cells treated with serum in old humans formed more lung metastases after injection in mice than after treatment with serum in young people.
To find out which ingredient of the blood caused the increased aggressiveness of the cancer cells, the researchers examined both types of serum for the content of 179 different compounds. Relevant differences were only found for ten substances. Three of these were present in the blood of old people in significantly higher concentrations. However, only methylmalonic acid (MMS) had a similar effect on the cultures of cancer cells as the complete serum. Dicarboxylic acid MMS is a normal intermediate of metabolism, which is produced by the breakdown of proteins and fatty acids. It is usually processed quickly, so that it is only present in low concentrations in the blood of young people. One possible cause of the higher MMS blood level in old age would be that the activity of special enzymes decreases over the course of life.
Molecular biological analyses have shown that MMS alters the activity of more than 400 genes, several of which are also important in cancer spread or resistance formation. The gene of the transcription factor SOX4, which plays an important role in the development of metastases, was particularly strongly activated. Cancer cells whose SOX4 gene had been eliminated no longer responded to MMS. Further studies now need to examine whether the results obtained with cell cultures and animal experiments can be applied to metastasis in humans, Hai Wang and Xiang Zhang of Baylor College of Medicine in Houston write in an accompanying commentary. The optimal time at which MMS-blocking agents could be used for preventive therapy as soon as they become available should then be determined.