Reason for lower cancer risk in old age discovered

How ageing induces iron insufficiency, reduces stem cell renewal and tumour formation has been discovered.

The risk of developing cancer increases until around 80 years of age. This is thought to be associated with the accumulation of mutations within different cells of the body, including stem cells and pluripotent cells. However, as we age, these cells lose their ability to regenerate and divide effectively which offsets any amassed tumour-promoting mutations. Now, researchers studied the effects of stem cells in the lungs of older mice that had lung cancer mutations introduced via an adenovirus.

'As with many types of cancer, lung cancer is diagnosed in most people around age 70... But once you get to 80 or 85, the incidence rate starts to come down again,' said Dr Xueqian Zhuang from Memorial Sloan Kettering Cancer Centre in New York, and first author of the study. 'Our research helps show why... Ageing cells lose their capacity for renewal and therefore for the runaway growth that happens in cancer.'

Mice at around two years old were used as they resembled the age of 65-70 year old people; the most common age that lung cancer is diagnosed. The lung stem cells were isolated from the mice to measure their self-renewal capacities and gene expression was analysed using single-cell RNA sequencing. DNA methylation patterns were also studied to determine any epigenetic changes linked to ageing.

Publishing their findings in Nature, the researchers have shown that ageing suppresses the ability of lung stem cells to form tumours. The aged mouse stem cells had increased gene expression of Nupr1, through age-accumulated epigenetic modifications to their DNA, resulting in high amounts of the NUPR1 protein, a specific transcription factor involved in iron insufficiency.

'The ageing cells actually have more iron, but for reasons we don't yet fully understand, they function like they don't have enough,' Dr Zhuang said.

NUPR1 makes the cells function as if they are iron deficient, and subsequently have a reduced ability for regeneration, which is directly linked to the older mice developing fewer tumours. However, this effect could be reversed, which the researchers achieved by giving the older mice additional iron or by reducing the amount of NUPR1 in their cells.

Furthermore, the researchers discovered that disrupting this pathway in young cells induced cell death caused by too much iron. Thus, reinforcing the age-specific role of Nupr1.

'What our data suggests in terms of cancer prevention is that the events that occur when we're young are probably much more dangerous than the events that occur later,' said Dr Tuomas Tammela from Memorial Sloan Kettering Cancer Centre, and senior author of the study. 'So, preventing young people from smoking, or from tanning, or from other obvious carcinogenic exposures are probably even more important than we thought.'