Researchers have discovered how genetic mutations accumulated slowly over a lifetime lead to dramatic changes in how blood is formed after the age of 70, providing a new theory for aging. A novel hypothesis of aging is proposed in the study, which was conducted by researchers from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and other institutions.

All human cells acquire genetic changes throughout life, known as somatic mutations. One notion is that the accumulation of somatic mutations leads cells to gradually lose functional reserve. Aging is likely to be brought on by the accumulation of many types of cell damage over time. It is still unknown, though, how such a slow-moving accumulation of molecular harm could result in the sudden decline in how our organs work around the age of 70.

The Wellcome Sanger Institute, the Cambridge Stem Cell Institute, and associates examined the creation of blood cells from the bone marrow in 10 people ranging in age from newborns to the elderly in order to study this aging process. 3,579 blood stem cells had their entire genomes sequenced, allowing researchers to determine every somatic mutation present in each cell. In order to illustrate, for the first time, an unbiased view of the relationships among blood cells and how these relationships vary across the human lifespan, the scientists used this to reconstruct "family trees" of each person's blood stem cells.

The researchers discovered that after the age of 70 years these "family trees" underwent significant change. In persons under the age of 65, 20,000 to 200,000 stem cells, each contributed about similar numbers to the creation of blood cells. In contrast, blood production was exceedingly uneven in people above the age of 70. In every elderly person investigated, a small number of enlarged stem cell clones—as few as 10 to 20—contributed as much as half of the total blood production. Because of an uncommon class of somatic mutations known as "driving mutations," these highly active stem cells have gradually increased in number throughout that person's life.

These results prompted the team 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 a 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 approach also explains the heterogeneity in illness risk and other traits reported in older adults since which clones become dominant differs from person to person. Another study investigates the evolution of cell growth rates as a result of different individual driver mutations.

The study's principal investigator, Dr. Emily Mitchell, a Ph.D. candidate at the Wellcome Sanger Institute, said: "Our results demonstrate that positive selection of faster-growing clones with driver mutations causes the diversity of blood stem cells to decline with age. The slower-growing clones are "outcompeted" by these fast-growing ones. When stem cells become fitter, it probably comes at a price since they are less able to develop mature blood cells that are functional, which would account for the observed age-related loss of function in the blood system."

"Clones with cancer-causing mutations proliferate more quickly when conditions like long-term inflammation, smoking, infection, and chemotherapy are present. We anticipate that these variables will hasten the aging-related reduction in blood stem cell diversity. There may be elements that additionally slow this process down. We now have the fun task of determining how these recently discovered mutations impact blood function in the elderly in order to discover how to reduce disease risk and encourage healthy aging "said Dr. Elisa Laurenti, a co-senior researcher on this study and assistant professor at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge.

"For the first time, we have demonstrated how gradually accumulating mutations over the course of a person's life cause blood cell populations to inevitably and catastrophically shift after the age of 70. The possibility that this approach could also apply to other organ systems is what makes it so interesting. We observe these self-centered clones with driver mutations growing with age in many other bodily tissues; we are aware that this can increase the risk of cancer, but it may also be causing other functional changes related to aging." Dr. Peter Campbell, senior researcher on the study and director of the Wellcome Sanger Institute made the statement.

(Written by Dr. Thiago and Reshma Bhasker)