The secrets of cellular aging unlocked

New research has revealed how genetic changes that slowly accumulate in blood stem cells throughout life are likely to be responsible for the dramatic change in blood production after the age of 70.

The study, conducted by scientists at the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute and collaborators, was published today (June 1) in the journal. temper natureHe proposes a new theory of aging.

All human cells acquire genetic changes throughout life, known as somatic mutations. Aging is likely caused by the accumulation of multiple types of damage to our cells over time, with one theory being that the accumulation of somatic mutations causes cells to gradually lose functional reserve. However, it is currently unclear how this gradual accumulation of molecular damage can translate into a sudden deterioration in how our organs function after the age of 70.

To investigate this aging process, a team from the Wellcome Sanger Institute, the Cambridge Stem Cell Institute and collaborators studied the production of blood cells from the bone marrow, analyzing 10 individuals ranging in age from newborns to the elderly. They sequenced the complete genomes of 3,579 blood stem cells, identifying all the somatic mutations present in each cell. The team used this to reconstruct the ‘family tree’ of each person’s blood stem cells, showing, for the first time, an unbiased view of the relationships between blood cells and how those relationships change across the human lifespan.

The researchers found that these “family trees” changed dramatically after age 70. The production of blood cells in adults younger than 65 years was 20,000-200,000 stem cells, each contributing approximately equal amounts. In contrast, blood production in individuals over 70 years of age was highly uneven. A reduced set of expanded stem cell clones – as many as 10 to 20 – contributed up to half of the total blood production in each elderly individual studied. These highly active stem cells gradually expanded in numbers throughout that person’s life, due to a rare subset of somatic mutations known as “driver mutations.”

These findings led the team to propose a model in which age-related changes in blood production come from somatic mutations that cause “selfish” stem cells to take over the bone marrow of older adults. This model, with the continuous introduction of driver mutations causing the growth of functionally altered clones over decades, explains the dramatic and inevitable shift of reduced diversity of blood cell populations after the age of 70. The types that become prevalent differ from person to person, and so the model also explains the variation observed in disease risk and other traits in older adults. A second study, also published today in temper natureexplores how different mutations of a single driver affect cell growth rates over time.

“Our findings show that blood stem cell diversity is lost in old age due to positive selection of faster-growing clones with driver mutations. These clones ‘outperform’ the slower-growing ones. In many cases, this fitness is likely to come Growing at the stem cell level comes at a cost – their ability to produce mature, functional blood cells is impaired, which explains the age-related loss of function in the blood system.” – Dr. Emily Mitchell, Principal Investigator from Addenbrooke’s Hospital and Sanger Institute.

Factors such as chronic inflammation, smoking, infection, and chemotherapy cause premature growth of clones with cancer-causing mutations. We speculate that these factors may also lead to the decrease in blood stem cell diversity associated with aging. It is possible that there are factors that may slow down this process as well. We now have the exciting task of discovering how these newly discovered mutations affect blood function in the elderly, so that we can learn how to reduce disease risks and promote healthy aging. Dr Elisa Llorente, a joint senior researcher from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge.

“We have shown, for the first time, how mutations accumulating steadily throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70. What is very exciting about this model is that it may well apply to other organ systems as well. We see these selfish clones With driver mutations expanding with age into many other tissues of the body – we know this can increase the risk of cancer, but it may also contribute to other functional changes associated with ageing. In the study.

Reference: Mitchell E, Spencer Chapman M, Williams N et al. Clonal dynamics of hematopoiesis across human lifespan. temper nature. 2022: 1-8. doi: 10.1038/s41586-022-04786-y

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