Researchers from EMBL and Heidelberg University unveil the molecular mechanisms of ageing in human adult stem cells
Getting older means a few more wrinkles and grey hairs. Deep down, ageing also entails a functional decline of your cells and especially of stem cells. A research team from EMBL and Heidelberg University has studied the molecular features of ageing in human blood stem cells. The most prominent finding is that the sugar metabolism of stem cells increases with age – a change similar to that observed in cancer cells. This is coupled with a decline in stem cell functionality and in immune defense. Resulting, for example, in an increased susceptibility to infection. Their results, published in Nature Communications on 1st October 2018, serve as an important reference for further studies on the molecular mechanisms of ageing in humans.
The team recruited 59 healthy people aged between 20 and 60, who donated bone marrow for the research. Similar studies have been performed in blood stem cells of ageing mice in recent years. In this study, the team examined all protein changes not only in human blood stem cells, but also in five other bone marrow cell types that function as stem cell niche. These datasets are therefore unique and act as a model for other stem cell systems.
“We looked at proteomes: the collections of proteins that are expressed by each cell, and how they changed over time,” says Anne-Claude Gavin, the EMBL group leader who led the project together with Anthony Ho, Professor and previously Head of Hematology at Heidelberg University. Ho: “Our most exciting finding is that ageing stem cells show changes in their metabolism, and especially an increase in their sugar metabolism. These changes are reminiscent of what we observe in cancer cells.”
This heightened sugar metabolism is linked to a shift in the types of blood cells generated by blood stem cells. For our immune defense, blood cells in the myeloid and subsequently granulocytic lineages are the foot soldiers, whereas those in the lymphoid lineages represent the commanders. The latter coordinate the efforts of myeloid lineages and granulocytes – a category of white blood cells – to battle invaders such as infections and cancer cells. With ageing, the balance between the production of these two lineages gets skewed: more granulocytic cells (foot soldiers) and less lymphoid cells (commanders) are generated. With the gradual loss of functional lymphoid cells, the white blood cells’ efforts to fight against infections or recognize cancer cells is reduced. The body tries to compensate for this with a higher rate of cell division in the myeloid lineages. This increase in cell division needs both fuel and building blocks for DNA, and both come from the glucose molecules.
“While your body is trying to cope with this skewed balance, it’s more likely to get exhausted,” explains Gavin. “And therefore the risk for a failure is higher.”
“Our discovery implies that we might be able to influence the changes associated with ageing by intervening in sugar metabolism,” says Ho. “Controlled inhibition of glucose metabolism might restore the balance between the myeloid and lymphoid cells.”
Moreover, these rare human datasets will serve as an important reference for further studies on the molecular mechanisms of ageing, especially in studies on age-related diseases. The team has been working, for example, on differences between mechanisms in ageing versus those associated with MDS: myelodysplastic syndrome, typically a disease of the elderly.
The project was a collaboration between clinicians, experimentalists and computational scientists in the Molecular Medicine Partnership Unit (MMPU), established by EMBL and the Medical Faculty of Heidelberg University. The paper’s first authors are Marco L. Hennrich, mass spectrometrist at EMBL, Natalie Romanov, predoctoral fellow in bioinformatics at EMBL, and Patrick Horn, cell biologist at Heidelberg University.
This image is a composite of lateral pentascolopidial organs, a wing imaginal disc pouch, and an epithelial wound in a Drosophila larva. The organs are arranged here like eyelashes. Cells surrounding an epidermal wound appear as the iris and pupil of this artistic eye.