Cellular secrets discovered by researchers lead to a new theory on aging

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Genetic mutations accumulated slowly over a lifetime lead to dramatic changes in blood formation as we age.

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 age 70.

The study, led by scientists from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute and collaborators, was published in the journal Nature.

Longevity.Technology: Has our understanding of one of the mechanisms of aging made a leap forward? Molecular damage accumulates throughout our lives, gradually increasing year by year as we suffer from telomere attrition, mutations, epigenetic changes, and oxidative and replicative stress. It’s a double whammy because our ability to repair this damage also declines with age, but given the gradual nature of these processes, why, as the authors of the paper themselves put it, “y there a sudden increase in mortality after 70? » [1]

All human cells acquire genetic changes throughout life, called somatic mutations, and aging is likely caused by the accumulation of several types of damage to our cells over time. One theory of aging is that the accumulation of somatic mutations causes cells to gradually lose their functional reserve, however, it is not currently known how such a gradual accumulation of molecular damage could result in the abrupt deterioration in the functioning of our organs which often occurs after the age of about 70 years.

To study this aging process, the team from the Wellcome Sanger Institute, Cambridge Stem Cell Institute and collaborators studied the production of blood cells from the bone marrow, analyzing 10 individuals whose ages ranged from newborns to the elderly.

The research team sequenced the entire genomes of 3,579 blood stem cells and identified all the somatic mutations contained in each cell. The researchers then used it to reconstruct ‘family trees’ 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 throughout life. human life.

Scientists have found that these family trees change dramatically after age 70. Blood cell production in adults under 65 increased from 20,000 to 200,000 stem cells, each contributing in roughly equal amounts. In contrast, blood production in individuals over the age of 70 was very uneven. A reduced set of expanded stem cell clones – as few as 10 to 20 – contributed up to half of all blood production in each elderly person studied. These highly active stem cells gradually multiplied throughout that person’s lifetime, due to a rare subset of somatic mutations called “motor mutations.” [1].

Send the clones

These findings led the team to propose a model in which age-associated changes in blood production stem from somatic mutations causing ‘selfish’ stem cells to dominate in the bone marrow of the elderly.

This pattern, along with the regular introduction of motor mutations that cause functionally impaired clones to grow over decades, may explain the dramatic and inevitable shift to reduced diversity in blood cell populations after age 70. Which clones become dominant varies from person to person. , and thus the model also explains the observed variation in disease risk and other characteristics among older adults. A second study, also published in Natureexplores how different individual motor mutations affect cell growth rates over time [2].

Dr Emily Mitchell, lead researcher of the study, said: ‘Our results 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” slower growing clones. 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, thus explaining the observed age-related loss of function in the blood system. [3].”

“Factors such as chronic inflammation, smoking, infection and chemotherapy cause clones carrying carcinogenic mutations to grow earlier,” added Dr. Elisa Laurenti, assistant professor and co-principal investigator on this study.

“We predict that these factors also advance the decline in blood stem cell diversity associated with aging. It is possible that certain factors also slow down this process. We now have the exciting task of understanding how these newly discovered mutations affect blood function in the elderly, so that we can learn how to minimize disease risk and promote healthy aging. [3].”

Dr. Peter Campbell, head of the Cancer, Aging and Somatic Mutations program at Welcome Sanger Instituteand principal investigator of the study, said: “We have shown, for the first time, how mutations that accumulate steadily throughout life lead to a catastrophic and inevitable change in blood cell populations after 70 years old.

“What’s super exciting about this model is that it could apply to other organ systems as well. We’re seeing these selfish clones with driver mutations develop with age in many other tissues. of the body – we know this can increase the risk of cancer, but it could also contribute to other functional changes associated with aging. [3].”

[1] https://www.nature.com/articles/s41586-022-04786-y
[2] https://www.nature.com/articles/s41586-022-04785-z
[3] https://www.sanger.ac.uk/news_item/cellular-secrets-of-aging-unlocked-by-researchers/

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