Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness

Summary From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher 1-3 . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy 4 . For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging 5-8 . Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.