What causes rapid health decline after age 70? Research shows it’s due to poor blood production

Aug 1, 2022 | 11 comments

By Wellcome Institute staff

A new explanation for aging has been developed by researchers who have discovered that genetic abnormalities that develop gradually over a lifetime cause substantial alterations in how blood is generated beyond the age of 70.

According to the research, the drastic reduction in blood production beyond the age of 70 is likely caused by genetic alterations that steadily accumulate in blood stem cells throughout life.

Researchers from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and others have published a study that offers a new theory of aging in the journal Nature.

Somatic mutations, or alterations to the genetic code, occur in all human cells during the course of a lifetime. Aging is most likely caused by the accumulation of numerous sorts of damage to our cells over time, with one hypothesis proposing that the accumulation of somatic mutations causes cells to gradually lose functional reserve. However, it is still unknown how such slow-building molecular damage may result in the rapid decline in organ performance after the age of 70.

The Wellcome Sanger Institute, the Cambridge Stem Cell Institute, and collaborators examined the production of blood cells from the bone marrow in 10 people ranging in age from newborns to the elderly in order to better understand how the body ages.

More than 3,500 blood stem cells had their whole genomes sequenced, allowing researchers to determine every somatic mutation present in each cell. Using this information, the team was able to create “family trees” of each person’s blood stem cells, providing for the first time an impartial perspective of the connections between blood cells and how these ties develop over the course of a person’s lifetime.

New research shows that the human aging process, especially after 70, is the result of organ deterioration from reduced blood production.

After the age of 70 years, the researchers discovered that these “family trees” underwent significant change. In adults under the age of 65, 20,000 to 200,000 stem cells contributed roughly equal amounts to the creation of blood cells. In contrast, blood production was exceedingly uneven in those 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 output. Because of an uncommon class of somatic mutations known as “driver mutations,” these highly active stem cells have gradually increased in number during that person’s life.

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. A second study, also published in Nature, explores how different individual driver mutations affect cell growth rates over time.

Dr. Emily Mitchell, Haematology Registrar at Addenbrooke’s Hospital, a Ph.D. student at the Wellcome Sanger Institute, and lead researcher on the study, said: “Our findings show that the diversity of blood stem cells is lost in older age due to positive selection of faster-growing clones with driver mutations.

These clones ‘outcompete’ the slower-growing ones. In many cases this increased fitness at the stem cell level likely comes at a cost – their ability to produce functional mature blood cells is impaired, so explaining the observed age-related loss of function in the blood system.”

Dr. Elisa Laurenti, Assistant Professor and Wellcome Royal Society Sir Henry Dale Fellow at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, and joint senior researcher on this study, said: “Factors such as chronic inflammation, smoking, infection, and chemotherapy cause earlier growth of clones with cancer-driving mutations. We predict that these factors also bring forward the decline in blood stem cell diversity associated with aging. It is possible that there are factors that might slow this process down, too. We now have the task of figuring out how these newly discovered mutations affect blood function in the elderly, so we can learn how to minimize disease risk and promote healthy aging.”

Dr. Peter Campbell, Head of the Cancer, Ageing and Somatic Mutation Programme at the Wellcome Sanger Institute, and senior researcher on the study said: “We’ve shown, for the first time, how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70. What is super exciting about this model is that it may well apply to other organ systems too. We see these selfish clones with driver mutations expanding with age in many other tissues of the body – we know this can increase cancer risk, but it could also be contributing to other functional changes associated with aging.”

Campbell adds that the new findings help explain the failure of life-extension therapies and supplements. “We’ve known for years that these things don’t work and now we know why. The prescription for a long life hasn’t really changed in decades: It’s good genes and a healthy, active lifestyle.”


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