Metabolism: Tumour-promoting metabolite found in ageing blood

A by-product of protein and fat metabolism that is elevated in people aged 60 years and over induces aggressive traits such as drug resistance and metastasis in cancer cells. The findings, reported in Nature this week, suggest that ageing-related deregulation of metabolism may have a role in the increased risk of cancer development and death in older people.

John Blenis and colleagues treated human cancer cell lines with serum from 30 healthy donors who were 30 years old or younger and 30 more who were 60 years old or older. The authors found that cancer cells treated with serum from the older donors gained the ability to migrate, invade, survive and metastasize. The cells also showed increases in levels of proteins associated with aggressive cancer, as well as resistance to widely used chemotherapeutic drugs.

Analysing the metabolites in the sera from old and young donors, the authors found significantly higher concentrations of methylmalonic acid (MMA), a metabolite of proteins and fats, in samples from older donors. Subsequent genetic analyses revealed that higher concentrations of MMA were associated with increased expression of the SOX4 gene, which contributes to tumour progression and metastasis formation and is present at high levels in aggressive cancers. When SOX4 activity was blocked, MMA did not increase migratory and invasive properties or resistance to chemotherapeutic drugs in cancer cells.

Taken together, the findings suggest that ageing promotes increased MMA levels in the blood, which in turn enables cancer cells to migrate, invade, survive and metastasize. Accumulation of MMA represents a novel link between ageing and cancer progression, and is a potential target for new cancer therapies.