Cellular Secrets of Aging Unlocked by Researchers

Cellular Secrets of aging unlocked by Researchers

There are many theories about the cause of aging. Telomere shortening, cellular senescence, Loss of hormones, a weakened immune system, uncontrolled inflammation, mitochondrial damage, The Information Theory of Aging, DNA damage, free radicals, loss of stem cells, a distorted Wnt signaling pathway, environmental toxins, and just plain old wear-and-tear.

However, there is another theory of aging: Genetics

New research has uncovered how genetic changes that accumulate slowly in blood stem cells throughout life might cause dramatic changes in blood production in elderly people. The study, by scientists at the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and collaborators, points to a new theory of aging.

Human cells experience genetic changes throughout life. These changes are called somatic mutations. Aging is probably caused by the accumulation of several types of damage to our cells, with one theory being that the accumulation of somatic mutations causes cells to lose functional reserve gradually.

But, it is currently unclear how such a slow accumulation of molecular damage could translate into the rapid degeneration of our organs' operations after age 70.

To test this theory, the team studied the production of blood cells from the bone marrow, analyzing ten individuals ranging in age from new-born to the elderly.

They sequenced the entire genomes of 3,579 blood stem cells, identifying all the somatic mutations in each cell. The team used this to reconstruct 'family trees' of each person's blood stem cells, illustrating, for the first time, an unbiased view of the relationships among blood cells and how these relationships change during the human lifespan.

The researchers determined that these 'family trees' changed dramatically after the age of 70 years. The blood cell production in adults under 65 came from 20,000 to 200,000 stem cells, each of which contributed in around equal amounts.

By contrast, blood production in individuals aged over 70 was unequal. A lower set of expanded stem cell clones (as little as 10 to 20) contributed almost half of all blood production in each elderly individual studied.

These highly active stem cells had steadily increased during that person's life, caused by a rare subset of somatic mutations known as driver mutations.

These conclusions led the team to suggest a model in which age-associated changes in blood production come from somatic mutations causing 'selfish' stem cells to influence 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 unavoidable shift to reduced diversity of blood cell populations after age 70.

Which clones become dominant varies by each individual, so the model also explains the variation seen in disease risk and other developments in older adults. A second study, also published today in Nature, explores how various driver mutations affect cell growth.

Dr. Emily Mitchell, Hematology Registrar at Addenbrooke's Hospital, Ph.D. A 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 exciting 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, Aging, 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 in 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."

Wellcome and the William B Harrison Foundation funded this research. (ANI)

https://www.devdiscourse.com/article/health/2266212-cellular-secrets-of-aging-unlocked-by-researchers