Researchers have established a new theory for aging, demonstrating that genetic defects that manifest gradually over a lifetime result in significant changes in how blood is produced after the age of 70.
Recent studies suggest that genetic changes that slowly accumulate in blood stem cells over the course of life are likely responsible for the sharp decline in blood output after the age of 70.
A novel idea on aging has been presented in a paper that was published in the journal Nature by researchers from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, among other institutions.
All human cells undergo somatic mutations, or changes to the genetic code, over the course of a lifetime. One theory is that the accumulation of somatic mutations leads cells to gradually lose functional reserve, and it is most probable that aging is caused by the accumulation of many types of cell damage over time. It is still unclear, though, how such slowly accumulating molecular harm may lead to the abrupt reduction in organ function at the age of 70.
In order to better understand how the body ages, researchers from the Wellcome Sanger Institute, Cambridge Stem Cell Institute, and other institutions looked at the creation of blood cells from the bone marrow in 10 individuals ranging in age from infants to the elderly.
Researchers sequenced the whole genomes of 3,579 blood stem cells, allowing them to identify every somatic mutation that exists in each cell. The team was able to construct “family trees” of each person’s blood stem cells using this data, offering for the first time an unbiased viewpoint of the relationships between blood cells and how these relationships change over the course of a person’s lifetime.
The researchers found that these “family trees” experienced considerable modification after 70 years. 20,000 to 200,000 stem cells produced roughly equal amounts of blood cells in adults under the age of 65. In contrast, blood output in those beyond the age of 70 was incredibly unequal.
A small number of larger stem cell clones—as few as 10 to 20 in each elderly subject examined—contributed as much as half of the overall blood production. These highly active stem cells have gradually increased in number over the course of that person’s life due to a rare class of somatic mutations known as “driver mutations.”
These results prompted the researchers to develop a model in which somatic mutations cause’selfish’ stem cells to predominate in the bone marrow of the elderly, resulting in age-associated alterations in blood output. The dramatic and unavoidable change to lower variety of blood cell populations after the age of 70 is explained by this model, which features the gradual introduction of driving mutations that result in the creation of functionally altered clones over decades. The model also explains the variation in disease risk and other traits seen in older adults because which clones become dominant varies from person to person. Another research, also in Nature, investigates the temporal evolution of cell growth rates as a function of distinct individual driver mutations.
The study’s principal investigator, Dr. Emily Mitchell, a Haematology Registrar at Addenbrooke’s Hospital and a Ph.D. candidate at the Wellcome Sanger Institute, stated: “Our results demonstrate that the diversity of blood stem cells is lost in older age as a result of positive selection of faster-growing clones with driver mutations.
The faster-growing clones are “outcompeted” by these ones. This enhanced fitness at the stem cell level frequently has a trade-off since it impairs the capacity of the cells to form mature blood cells that are functional, which would explain the observed age-related decrease of function in the blood system.
Dr. Elisa Laurenti, co-senior researcher on this study and assistant professor and Wellcome Royal Society Sir Henry Dale Fellow at the University of Cambridge’s Wellcome-MRC Cambridge Stem Cell Institute, stated: “Factors like chronic inflammation, smoking, infection, and chemotherapy cause earlier growth of clones with cancer-causing mutations. We anticipate that these variables will hasten the aging-related reduction in blood stem cell diversity. There may be elements that additionally delay this process down. The intriguing job now is to determine how these recently revealed mutations influence blood function in the elderly in order to develop ways to reduce illness risk and encourage healthy aging.
We have demonstrated for the first time how slowly accumulating mutations throughout life result in a catastrophic and unavoidable change in blood cell populations after the age of 70, according to Dr. Peter Campbell, Head of the Cancer, Ageing, and Somatic Mutation Programme at the Wellcome Sanger Institute and senior researcher on the study. The possibility that this approach may also be applied to other organ systems is what makes it so interesting. We observe the expansion of these selfish clones with driver mutations with aging in several different bodily tissues; we are aware that this might raise the risk of cancer, but it may also be a factor in other functional alterations brought on by aging.
References include the article “Clonal dynamics of haematopoiesis across the human lifespan” by Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily F. Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H. H. Coorens, David H. Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A. Fabre, Krishnaa Mahbubani, Federico
“The longitudinal dynamics and natural history of clonal haematopoiesis” by Margarete A. Fabre, José Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, Michael Spencer Chapman, M. S. Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas
The William B. Harrison Foundation and Wellcome provided funding for the study.