in the bone marrow
A new study helps explain how blood production declines with age and why older individuals are not suitable donors for hematopoietic stem cell (HSC) transplant.
The research also reveals a potential approach for mitigating
the negative effects of aging on the blood, which can lead to anemia,
bone marrow failure, and myeloid malignancies.
The study, conducted in mice, suggests HSCs falter with age because they lose the ability to replicate their DNA accurately and efficiently during cell division.
Emmanuelle Passegué, PhD, of the University of California San Francisco, and her colleagues reported this discovery in Nature.
The researchers analyzed old HSCs in mice and found a scarcity of protein components needed to form the mini-chromosome maintenance helicase. This molecular machine unwinds double-stranded DNA so the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division.
The HSCs were stressed by the loss of this machine’s activity. As a result, they had an increased risk for DNA damage and death when forced to divide.
On the other hand, the cells tended to survive unless they were confronted with a “strong replication challenge” like transplantation.
The researchers also discovered that even after the stress associated with DNA replication, old HSCs retained molecular tags on histones, a feature often associated with DNA damage.
However, 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.
Of course, not all was well in the old, surviving HSCs. The molecular tags accumulated on genes needed to make ribosomes.
Dr Passegué said she will further explore the consequences of reduced protein production as part of her ongoing research. She hopes it might be possible to prevent declining stem cell populations by developing a drug to prevent the loss of the helicase components needed to unwind and replicate DNA, thereby avoiding immune system failure.
