Clonal dynamics: A potential contributor to aging and longevity

The mortality curve of modern humans displays an abrupt increase in death rates after the age of 70. Research has shown that molecular damage accumulation across the lifespan is gradual. Examples include telomere attrition, epigenetic changes, oxidative stress, and others. The abrupt increase in mortality rates after the seventh decade of life due to molecular changes remains to be resolved.

Blood sample sequencing has shown an age-driven increase in acquired mutations (called driver mutations) in genes that cause myeloid neoplasms (a group of diseases characterized by the production of high levels of red blood corpuscle, white blood cells, or platelets). This phenomenon is known as clonal hematopoiesis (hematopoiesis is the formation of blood cellular components. Clonal hematopoiesis is the process in which hematopoietic stem cells make cells with a genetic mutation). The prevalence of clonal hematopoiesis in the elderly could reach up to 20%, but driver mutations typically account for less than 5% of cells. Also, research indicates that some elderly display clonal expansion without driver mutations. Deep sequencing of large blood samples has difficulties detecting mutations present in a low proportion (1-5%). Utilizing whole-genome sequencing could overcome the said challenge.

Mitchell et al. sequenced more than 3500 single cell-derived hematopoietic colonies from 10 healthy individuals using the abovementioned technique. The subjects' ages ranged from 0 to 81 years, making the sample representative of the human lifespan.

Results revealed that the sampled hematopoietic stem cells or multipotent progenitors (cells with a capacity to differentiate into different types of cells) (HSC/MPPs) accumulated ~17 mutations per year throughout life. Also, telomere attrition occurred at a rate of about 31 base pairs (bp) per year. Further analysis revealed that young and middle-aged adults below 65 years had polyclonal hematopoiesis. On the contrary, hematopoiesis in individuals over 75 showed profoundly lower clonal diversity (a measure of how much clones are distinct from each other). The researchers found that in the elderly, there is an abrupt increase in the frequency of the expanded clones and the total fraction of hematopoiesis they produce. In addition to the previous, the investigators found that loss of the Y chromosome was more frequent in older males. The said chromosome was linked to all-cause mortality, and its loss was linked to clonal expansion (an increase in the numbers of specific clones).

The investigators concluded that qualitative, lifelong accumulation of molecular damage could abruptly change tissue composition due to clonal structure changes. In other words, clonal expansion with the abrupt collapse of stem cell diversity could be an aging feature.

Source: Mitchell E, Spencer Chapman M, Williams N, Dawson KJ, Mende N, Calderbank EF, Jung H, Mitchell T, Coorens TH, Spencer DH, Machado H. Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022 Jun 1:1-8.