Key to aging immune system: Discovery of DNA replication problem
July 31, 2014
University of California, San Francisco (UCSF)
The immune system ages and weakens with time, making the elderly
prone to life-threatening infection and other maladies, and
scientists have now discovered a reason why.
Molecular tags of DNA damage are highlighted in green in blood-
There’s a good reason people over 60 are not donor candidates for
bone marrow transplantation. The immune system ages and weakens
with time, making the elderly prone to life-threatening infection
and other maladies, and a UC San Francisco research team now has
discovered a reason why.
“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
UCSF. Passegué, an expert on the stem cells that give rise to the
blood and immune system, led a team that published the new findings
online July 30, 2014 in the journal Nature.
Blood and immune cells are short-lived, and unlike most tissues,
must be constantly replenished. The cells that must keep producing
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 give rise to
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,
Passegué’s lab team determined.
Especially vulnerable to the breakdown, the researchers discovered
in their new study of old mice, are transplanted, aging, blood-
forming stem cells, which lack the ability to make B cells of the
immune system. These B cells make antibodies to help us fight all
sorts of microbial infections, including bacteria that cause
pneumonia, a leading killer of the elderly.
In old blood-forming stem cells, the researchers found a scarcity
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 allocated 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” Passegué said.
But not all was well in the old, surviving stem cells. The
molecular tags accumulated on genes needed to make the cellular
factories known as ribosomes. The ribosomes make all the cell’s
proteins. Passegué will further explore the consequences of reduced
protein production as part of her ongoing research.
“Everybody talks about healthier aging,” Passegué 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
Passegué hopes that it might be possible to prevent declining stem-
cell populations by developing a drug to prevent the loss of the
helicase components needed to faithfully unwind and replicate DNA,
thereby avoiding immune-system failure.
Among the additional study authors are graduate student Johanna
Flach and postdoctoral fellow Sietske Bakker, PhD, who performed
the experiments in Passegué’s lab at the Eli and Edythe Broad
Center of Regeneration Medicine and Stem Cell Research at UCSF.
International collaborators included Juan Méndez, PhD, of the
Spanish National Cancer Research Center, in Madrid, and Ciaran
Morrison, PhD, of the National University of Ireland, in Galway.
The research was funding by the California Institute for
Regenerative Medicine and the National Institutes of Health.
The above story is based on materials provided by University of
California, San Francisco (UCSF). The original article was written
by Jeffrey Norris. Note: Materials may be edited for content and
1.Johanna Flach, Sietske T. Bakker, Mary Mohrin, Pauline C. Conroy,
Eric M. Pietras, Damien Reynaud, Silvia Alvarez, Morgan E.
Diolaiti, Fernando Ugarte, E. Camilla Forsberg, Michelle M. Le
Beau, Bradley A. Stohr, Juan Méndez, Ciaran G. Morrison, Emmanuelle
Passegué. Replication stress is a potent driver of functional
decline in ageing haematopoietic stem cells. Nature, 2014; DOI:
University of California, San Francisco (UCSF). “Key to aging
immune system: Discovery of DNA replication problem.” ScienceDaily.
ScienceDaily, 31 July 2014.