As we get older, the risk that we will develop cancer increases, because we accumulate genetic mutations and are continually exposed to cancer-causing substances1. Most cancer-causing agents are found in the environment, but some are produced by our own bodies. Writing in Nature, Gomes et al.2 report that methylmalonic acid (MMA) — a by-product of protein and fat digestion — can accumulate in the blood with age, and might promote the spread of tumours.
Methylmalonic acid is produced in cells in very small amounts3. Usually, it becomes linked to the molecule coenzyme A to form methylmalonyl-CoA, and is converted to succinyl-CoA in a reaction that involves vitamin B12 as a cofactor. Succinyl-CoA subsequently enters the TCA cycle — a series of chemical reactions that are a key part of energy production in the cell.
In some diseases, the body fails to metabolize MMA efficiently, leading to its toxic accumulation in the blood. For instance, the metabolic disorder methylmalonic acidaemia is characterized by the failed conversion of methylmalonyl-CoA to succinyl-CoA, owing to genetic defects in key enzymes (such as methylmalonyl-CoA mutase) or to vitamin B12 deficiency1.
Gomes et al. report that MMA levels are significantly higher in the blood of healthy people over the age of 60 than in those under 30. The elevated level of MMA had not caused ill health in the individuals studied. However, the authors found that treating human cancer cells with serum from the blood of the older group, or with high concentrations of MMA, led them to adopt characteristics of metastatic cancer cells — those that can spread from a primary tumour to seed cancers elsewhere in the body. These characteristics include a loss of cell–cell attachment and an increase in mobility. When injected into mice, the cells formed metastatic tumours in the lungs.
The researchers demonstrated that the presence of large lipid structures in ‘old’ blood serum was also key to its ability to induce metastatic characteristics in cells. Removing these structures from blood prevented MMA from entering cells, indicating that MMA is in complex with a large lipid. The identity of this lipid structure, and the mechanism by which it helps MMA to enter cells, remains to be determined.
Gomes and colleagues next asked what molecular changes MMA triggers in cells. The authors examined the gene-expression profiles of cells treated with MMA, and compared them with those of untreated cells. One of the genes most highly upregulated in response to MMA was SOX4, which encodes a transcription factor involved in the regulation of embryonic development and cancer progression4. The authors demonstrated that repressing SOX4 expression blocked the cancer-cell response to MMA, and prevented the formation of metastatic tumours in mice that received injections of cancer cells treated with old serum. Thus, MMA indirectly induces an increase in the expression of SOX4, which in turn elicits broad reprogramming of gene expression and subsequent transformation of cells into a metastatic state (Fig. 1).
Gomes and colleagues’ work implies that lipids have dual roles in MMA-driven metastases: first, in the form of the fatty acids from which MMA derives; and second, as large lipids that help MMA to cross cell membranes. Levels of the lipid cholesterol increase between puberty and the age of 50 or 605 — overlapping with the rise in MMA levels in the blood. It is possible that the lipidic structures observed in the current study involve cholesterol. If so, anti-cholesterol treatments might reduce levels of MMA and slow its entry into cells.
Why does MMA increase with age? Levels of vitamin B12 decrease with age, and deficiency in that vitamin is linked to an accumulation of MMA. However, the authors found no reverse correlation between levels of these two molecules in their study participants. Therefore, B12 deficiency is unlikely to be the main reason for MMA accumulation. Another potential culprit is protein. A low-protein diet can reduce the substrates for MMA formation6, and might enhance anticancer immune responses7. In addition, high protein intake significantly increases the risk of death from cancer in people aged 50 to 65 (although the opposite correlation is seen in people over 65)8. Given these previous observations, Gomes and colleagues’ work should stimulate more interest in the relationship between protein intake and age-associated cancer risks.
All the people in this study who had high plasma levels of MMA seemed to be cancer-free, suggesting that the effects of MMA are specific to cancer spread in the body, rather than to initial cancer formation. Cancer initiation and spread are distinct processes that involve different molecular mechanisms9. If future studies can confirm that MMA specifically affects metastasis in humans in the same way that Gomes et al. have demonstrated it does in vitro and in mice, this molecule will stand apart from many previously known ageing-related causes of cancer, including environmental factors and genetic mutations. Further investigation into the timing of MMA‘s effects could then inform the optimal timing for therapeutic use of MMA-blocking agents, if they become available.
A final question is how MMA stimulates gene-expression changes associated with metastasis at a molecular level. The authors hypothesized that MMA activates transcription of the gene TGF-β2; this gene is part of a TGF-β signalling pathway that, in turn, promotes SOX4 expression. But how MMA enhances the transcription of TGF-β2 remains to be seen.
Answers to these questions will further our understanding of metabolic changes and their roles in cancer development. Regardless of the answers, Gomes and colleagues’ study has broadened our view of cancer risk factors, by drawing attention to the role of metabolism in ageing-associated cancer progression.
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