DNA Replication Difficulty May Be Key to Immune System Aging

People over 60 are not donor candidates for bone marrow transplantation; the immune system ages and weakens with time, making the elderly predisposed to life-threatening infection and other disorders. US researchers have now have found a reason.

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies,” said Emmanuelle Passegué, PhD, a professor of medicine and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco (UCSF; USA). Dr. Passegué, a stem cell specialist, led a team that published their findings online July 30, 2014 in the journal Nature.

Blood and immune cells no not live long, and not like most tissues, must be continually replenished. The cells that must keep generating them throughout a lifetime are called hematopoietic stem cells. Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that replenish replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division, Dr. Passegué’s lab team determined.

Particularly susceptible to the degradation, the researchers discovered in their new study of older mice, are transplanted, aging, blood-forming stem cells, which no not have the ability to produce B cells of the immune system. These B cells generate antibodies to help treat many types of microbial infections, including bacteria that cause pneumonia, a leading killer of the older people.

In old blood-forming stem cells, the researchers found a lack of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell’s genetic material can be duplicated and assigned to daughter cells later in cell division. In their study, the stem cells were stressed by the loss of activity of this machine, and as a result, were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells. “Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated,” Dr. Passegué said.

The older surviving stem cells still had problems. The molecular tags accumulated on genes required to generate the cellular factories known as ribosomes. Dr. Passegué will further examine the concerns of reduced protein production as part of her ongoing research. “Everybody talks about healthier aging,” he added. “The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning.”

Dr. Passegué hopes that it might be possible to prevent declining stem-cell populations by developing a medicine to prevent the loss of the helicase components required to effectively unwind and replicate DNA, thereby avoiding immune-system failure.

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