Age-induced accumulation of methylmalonic acid promotes tumour progression

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards 1 – 6 . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy 2 , 3 , 7 , 8 . For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing 9 – 12 . Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.