|Changes in Adult Stem Cells May Underlie Rare
Genetic Disease Associated with Accelerated Aging
Adult stem cells may provide an explanation for the cause of Hutchinson-Gilford
Progeria Syndrome (HGPS), a rare disease that causes premature
aging in children, according to researchers at the National Cancer
Institute (NCI), part of the National Institutes of Health (NIH).
These findings, the first to indicate a biological basis for the
clinical features of HGPS, also known as progeria, may also provide
new insights into the biological mechanisms of normal aging. The
results were published in the March, 2008, issue of Nature
"Studies like this of the biology of HGPS hold the potential
to benefit children suffering from this terrible illness and enlighten
us as to the medical changes we all experience as we grow older," said
NCI Director John E. Niederhuber, M.D. "As our population
ages, we have an increasing need for greater understanding of the
biology of aging and age-related illness, such as cancer."
HGPS is an extremely rare hereditary genetic disease of children
characterized by signs of premature aging. Children with HGPS generally
experience the first symptoms by the age of one, and on average
succumb around the age of 15, almost exclusively from premature,
progressive heart disease. HGPS occurs in one out of four to eight
million births; only 100 patients have been documented in the medical
literature. Because its striking cardiovascular effects and other
clinical features are so closely associated with the normal aging
process, HGPS holds great interest for researchers studying age-related
biological changes and disease.
The cause of HGPS, a mutated protein called progerin, was identified
in 2003. However, the mechanism by which progerin causes the widespread
clinical effects of HGPS has been unclear. To forge this link between
molecular biology and medical outcome, Tom Misteli, Ph.D., head
of the Cell Biology of Genomes Group at NCI's Center for Cancer
Research (CCR), and CCR staff scientist Paola Scaffidi, Ph.D.,
examined the effects of progerin on gene expression in a laboratory
model of HGPS. They found that progerin activates genes involved
in the Notch signaling pathway, a major regulator of stem cell
differentiation — the process by which stem cells give rise
to the mature cells that make up different tissues.
Because most of the tissues affected by HGPS (e.g., skin, fat,
muscles, bone, and blood vessels) arise from a common developmental
pathway, Misteli and Scaffidi looked at the effects of progerin
on adult mesenchymal stem cells, the common cellular ancestor of
these tissue types. An adult stem can renew itself,
and can differentiate to yield the major specialized cell types
of the tissue or organ. Their experiments revealed that
progerin profoundly affects the fate of these stem cells, greatly
skewing the rate at which they mature into different tissues. For
instance, progerin-producing stem cells showed accelerated maturation
into bone but failed to develop into fat. This could explain two
of the distinguishing clinical features of HGPS: abnormal bone
growth and an almost complete loss of the fatty tissues normally
found just beneath the skin. The researchers were able to mimic
the progerin's effects in these stem cells by experimentally activating
the same components of the Notch pathway targeted by progerin.
Taken together, the results of these experiments provide a new
window into the biology behind the clinical features of HGPS. They
may also hold relevance for understanding the biology of normal
aging. "Progerin is present at low levels in the cells of
healthy people," said Misteli. "One could envision a
scenario in which progerin's effects on the Notch pathway and,
by extension, on adult stem cells could, over time, lead to many
of the tissue changes we commonly associate with the aging process."
For more information on Misteli's laboratory, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5819.
For more information about cancer, please visit the NCI Web site
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Scaffidi P and Misteli T. Lamin. A-dependent misregulation of adult
stem cells associated with accelerated aging. Nature Cell Biology,