New insights into ageing revealed

The way in which blood stem cells evolve over a lifespan differs greatly between humans and mice, new research reveals. The findings provide a new understanding of the critical factors that influence tissue ageing.

Scientists from Baylor College of Medicine and the Wellcome Sanger Institute, as well as their collaborators, show that the drastic changes seen in human blood in old age do not occur in old mice. 
The research, published in the current edition of Nature, raises important questions about ageing and stem cell research models used in the lab and provides a better understanding of the breadth of factors that contribute to tissue ageing. 

All cells accumulate genetic changes throughout life, known as somatic mutations. In humans, these somatic mutations result in dramatic changes in blood after the age of 70 years. Young individuals have up to 200,000 stem cells producing blood, while in older individuals, over half of blood production comes from a drastically reduced set of stem cell clones, which have expanded over the individual’s lifetime. These stem cell clones in older individuals can develop into cancer and drive other diseases. One theory is that they may even underlie features of human ageing and explain why our tissues become less resilient with age. 

It has remained unknown if what is observed in humans is a universal pattern of ageing, and thus, mirrored over the lifespan of other species as they age, including shorter lived animals, such as mice.

To investigate this, Sanger Institute researchers and their collaborators studied how mouse blood stem cells develop, produce blood and change over the mouse’s lifespan. By sequencing the whole genomes of 1,305 blood stem cells from young and old mice, they were able to identify all the mutations present in each cell.

These data were used to reconstruct ‘family trees’ of blood production, gaining unprecedented insights into stem cell formation and evolution over life.

The researchers observed a stark contrast to patterns of human ageing in blood. Mice maintain diverse blood stem cells throughout their lives, without the same collapse into a few dominant clones that occurs in longer lived humans. This may help explain why age-related blood disorders are far less common in older mice.

Generally, mice accumulate mutations 20 times faster than humans and it has been hypothesised that this might in some way be linked to why their lifespan is shorter. However, the team showed that in blood from mice, the rate of accumulation of mutations was much lower than expected – only three times higher than humans. This suggests that blood stem cells have special protection from mutation accumulation in both humans and mice.

Additionally, the researchers found that while humans rely on a pool of 20,000 to 200,000 stem cells for blood production, mice have a surprisingly large number too – around 70,000 blood stem cells – despite their vastly smaller body size and shorter lifespan. This raises intriguing questions about why such small animals require so many stem cells and whether this is an evolutionary adaptation that enables rapid response to environmental challenges. 

In humans, key mutations are often detectable in older individuals that drive blood stem cells to outgrow into clones. The team found that these same mutations were also observed in mice, but at incredibly low levels, meaning that they were rarely at significant levels to cause any issues in older mice, unlike in humans. 

In humans, a healthy blood stem cell might divide once or twice a year, undergoing roughly 100 divisions over its lifetime. The team showed that in mice, healthy blood stem cells divide every six weeks, which did not allow for as many total cell divisions over their much shorter lifespan. The findings suggest that factors other than mutational damage, such as stem cell numbers and rates of cell division, are also critical for influencing patterns of ageing over an organism’s lifetime.  

With the behaviour and evolution of blood stem cells in mice being different to humans, this suggests that what is seen in mice cannot simply be translated to humans. This has implications for the way researchers might use mice as laboratory models in the future and provides a new framework for how we interpret study findings when mouse cells are used in stem cell biology or ageing research. 

Dr Chiraag Kapadia, first author of the study, visiting researcher at the Wellcome Sanger Institute, and a MD-PhD student at Baylor College of Medicine, said: “Expansions of cells are a ubiquitous feature of ageing human tissue. It’s seen in both healthy and diseased organs. It’s like Darwinian selection as some cells outcompete their neighbours and expand over life. Understanding how blood stem cells develop over time in species with a different lifespan to humans is invaluable knowledge that we can use when considering the evolution of human blood cells and associated diseases.”

Professor Margaret Goodell, a co-supervising author and Chair of Molecular and Cellular Biology at Baylor College of Medicine, said: “In humans, we know that there has been a lifetime of different exposures to stressors and injury that may shape observed patterns of ageing. With this study, we now have a better understanding of how environmental exposures shape patterns of ageing through stem cell adaptation. This knowledge will inform future studies of stem cell research and ageing.”

Dr. Jyoti Nangalia, Group Leader at the Wellcome Sanger Institute and University of Cambridge, and senior author of the study, said: “This work gives us a more complete understanding of the factors that come together to determine how a tissue ages over an organism’s lifetime. Some biological processes, such as rates at which DNA mutations accumulate in cells, were thought to scale to animal time. Blood stem cells have evolutionary protection against this, with age related changes only playing out over much longer lifespans. This understanding opens new avenues to explore how we might optimise the ageing process.”

For a full list of collaborators and funding information click here.