and Medicine for Seniors
Aging Immune System May Get Kick-Start from
Discovery of Molecular Defect
‘Old stem cells are not just sitting there with
damaged DNA ready to develop cancer, as it has long been postulated’
"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."
Emmanuelle Passegué, PhD
July 31, 2014 - There's a good reason seniors 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
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
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.
Molecular tags of
DNA damage are highlighted in green in blood-forming stem cells.
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"
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 optimal
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.
Additional study authors include 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. Passegué recently was recognized for the research with a
prestigious Glenn Award for Research in Biological Mechanisms of Aging.
UC San Francisco (UCSF), now celebrating the 150th
anniversary of its founding, reports to be a leading university
dedicated to promoting health worldwide through advanced biomedical
research, graduate-level education in the life sciences and health
professions, and excellence in patient care.