Decreasing Clonal Diversity with Age in Human Hematopoiesis

In today's research materials, scientists present data on clonal hematopoiesis with age in humans. Hematopoiesis is the creation of blood and immune cells, taking place in the bone marrow. Clonal hematopoiesis of indeterminate potential (CHIP) is the name given to one of the age-related changes taking place in the populations of stem cells and progenitor cells that carry out hematopoiesis. Stochastic mutations occur constantly in the body. In the dynamic hematopoietic cell populations of the bone marrow, some of these mutations allow the mutated cells to outcompete their undamaged peers to make up a much larger fraction of the population than would otherwise be the case. Thus, with advancing age, an increasing proportion of the immune cells in the body originate from just a few clonally expanded, mutated hematopoietic populations.

Where these mutations predispose cells to cancerous behavior, then this is clearly an issue. CHIP is a known precursor to leukemia and similar conditions. It is less clear as to why CHIP is associated with other aspects of aging, such as atherosclerosis and consequent cardiovascular disease. Arguments based on mutations increasing predisposition to inflammatory behavior in immune cells seem reasonable, but, as ever, more data is needed.

What to do about all of this? The research community is heading in the direction of restoring disrupted hematopoiesis in older people as a part of improving immune function in the elderly. Some approaches, such as transplantation of new hematopoietic cells, may effectively address CHIP if carried out in the right way. Approaches that involve restoration of function in the existing population by adjusting cell behavior, such as CD42 inhibition, have been shown to produce benefits in animal models, but they could also make CHIP worse if they give further advantage to a mutated hematopoietic population. With that in mind, it would be advantageous to be able to avoid the need to outright replace stem cell populations, given the challenges involved, and focus on small molecule and similar, easier modes of treatment. Unfortunately, cell replacement may turn out to be necessary in this context.

Cellular secrets of ageing unlocked by researchers

Researchers studied the production of blood cells from the bone marrow, analysing 10 individuals ranging in age from new-borns to the elderly. They sequenced the whole genomes of 3,579 blood stem cells, identifying all the somatic mutations contained in each cell. The team used this to reconstruct 'family trees' of each person's blood stem cells, showing, for the first time, an unbiased view of the relationships among blood cells and how these relationships change across the human lifespan.

The researchers found that these 'family trees' changed dramatically after the age of 70 years. The production of blood cells in adults aged under 65 came from 20,000 to 200,000 stem cells, each of which contributed in roughly equal amounts. In contrast, blood production in individuals aged over 70 was very unequal. A reduced set of expanded stem cell clones - as few as 10 to 20 - contributed as much as half of all blood production in every elderly individual studied. These highly active stem cells had progressively expanded in numbers across that person's life, caused by a rare subset of somatic mutations known as 'driver mutations'.

These findings led the team to propose a model in which age-associated changes in blood production come from somatic mutations causing 'selfish' stem cells to dominate the bone marrow in the elderly. This model, with the steady introduction of driver mutations that cause the growth of functionally altered clones over decades, explains the dramatic and inevitable shift to reduced diversity of blood cell populations after the age of 70. Which clones become dominant varies from person to person, and so the model also explains the variation seen in disease risk and other characteristics in older adults.

Clonal dynamics of haematopoiesis across the human lifespan

Age-related change in human haematopoiesis causes reduced regenerative capacity, cytopenias, immune dysfunction, and increased risk of blood cancer, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production.

Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.