Scientists Discover New Causes of Cellular Decline in Prematurely Aging Kids
In a recent paper published in Cell Reports, Saint Louis University researchers have uncovered new answers about why cells rapidly
age in children with a rare and fatal disease. The data points to cellular replication
stress and a mistaken innate immune response as culprits, and the team found success
in the laboratory in blocking these processes with vitamin D.
Susana Gonzalo, Ph.D., associate professor of biochemistry and molecular biology at
SLU, and her lab examined human and animal cells connected to a rare disease called
Hutchinson-Gilford Progeria Syndrome (HGPS).
HGPS is caused by the random mutation of a single gene that causes children to age
rapidly. Children with the condition develop many of the typical changes and illness
associated with aging, including hair loss, aging skin, joint abnormalities, and bone
loss. The disease causes atherosclerosis -- fatty deposits that clog arteries -- and
patients with the illness die from cardiovascular complications such as stroke or
myocardial infarction in their teens.
Thanks to genetic mapping, scientists now know that HGPS is caused by a mutation in
the LMNA gene, which encodes for lamin A protein. Lamin A serves as a scaffold that
keeps the cell’s nucleus organized and in shape. The shortened, mutated version of
this protein is called progerin, and it causes the nucleus and cell to become unstable,
leading to premature aging of the cells.
“Those with progeria have a mutation in their DNA that codes for these proteins,”
Gonzalo said. “The presence of progerin makes a mess in the nucleus.”
This is a problem because the nucleus houses our DNA. Cell health and reproduction
are closely tied to our genome integrity -- the ability of a cell to faithfully transmit
its DNA information on to new cells. Mistakes or obstacles in the replication of our
DNA cause breaks and mutations, which are linked to both cancer and aging.
Research in Gonzalo’s lab revealed that replication stress is a key cause of the underlying
DNA damage accumulation found in the cells of those with HGPS. Replication stress
occurs when the machinery that replicates DNA encounters obstacles along the way that
makes replication to stall until the obstacle is removed.
Normally, our cells have in place a number of strategies to address these obstacles
and then successfully continue with DNA replication. In the case of those with HGPS,
however, Gonzalo found that progerin causes these strategies to falter. Replication
stress can derail a cell’s ability to reproduce.
Gonzalo and her team discovered two new mechanisms by which progerin causes damage.
First, progerin induces the stalling of the replication machinery, and at the same
impedes the proper protection of the newly replicated DNA. This results in DNA being
preyed upon by nucleases, which degrade the newly synthesized DNA with the consequent
loss of genetic material.
They also found another way that progerin causes cell toxicity.
Scientists know that DNA damage and replication stress not only underlie the genomic
instability that drives aging and cancer, but that they also contribute to activate
“When DNA fragments leak outside the nucleus into the cytoplasm, the cell recognizes
that material as something foreign,” Gonzalo said. “This activates a series of immune
responses. In particular, a signaling cascade known as the interferon response is
activated when the cell thinks it senses a viral or bacterial infection that needs
to be fought.
“We found that this is happening in progeria cells, and it is contributing to cellular
After demonstrating that progerin elicits replication stress and nuclease-mediated
degradation of newly replicated DNA, and that it activates an interferon pathway,
the team wanted to see if they could reverse these problems. They found that when
they used compounds, including vitamin D, to reduce replication stress and interferon
response, cellular fitness improved.
“When we block this pathway with vitamin D, it rejuvenates the cells,” Gonzalo said.
“The immune response is activated by progerin and then it is brought back down by
“We saw that vitamin D reduces significantly the toxicity of progerin in cells from
Gonzalo hopes that her research not only will help in the eventual development of
new therapies for those with HGPS, but that it also will explain many of the processes
that underlie normal human aging.
Other authors on the study include Ray Kreienkamp, Simona Graziano, Nuria Coll-Bonfill,
Gonzalo Bedia-Diaz, Emily Cybulla, Alessandro Vindigni, Dale Dorsett, Nard Kubben
and Luis Francisco Zirnberger Batista.
Saint Louis University School of Medicine
Established in 1836, Saint Louis University School of Medicine has the distinction
of awarding the first medical degree west of the Mississippi River. The school educates
physicians and biomedical scientists, conducts medical research, and provides health
care on a local, national and international level. Research at the school seeks new
cures and treatments in five key areas: cancer, liver disease, heart/lung disease,
aging and brain disease, and infectious diseases.