X-Message-Number: 30580
Date: Wed, 5 Mar 2008 10:14:55 -0800 (PST)
From: 
Subject: Stem cell differentiation may underlay normal aging

**SPECULATION**
[Even if progerin turns out not to be the main cause of normal aging,
other evdence still points to stem cell depletion as potentially being
the main mediator of much of the deterioration we term "aging".]

http://www.sciencedaily.com/releases/2008/03/080302150715.htm

Adult Stem Cell Changes Underlie Rare Genetic Disease Associated With
Accelerated Aging
ScienceDaily (Mar. 2, 2008) - Adult stem cells may provide an explanation
for the cause of a 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.

"Studies like this of the biology of HGPS hold the potential to benefit
children suffering 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."

Journal reference: Scaffidi P and Misteli T. Lamin A-dependent
misregulation of adult stem cells associated with accelerated
aging. Nature Cell Biology, March 2008.

Adapted from materials provided by NIH/National Cancer Institute, via
EurekAlert!, a service of AAAS.

http://www.nature.com/ncb/journal/vaop/ncurrent/abs/ncb1708.html

Letter abstract
Nature Cell Biology Published online: 2 March 2008 | doi:10.1038/ncb1708

Lamin A-dependent misregulation of adult stem cells associated with
accelerated ageing
  Paola Scaffidi1 & Tom Misteli1 National Cancer Institute, NIH,
Bethesda, Maryland, 20892
  The premature-ageing disease Hutchinson-Gilford Progeria Syndrome
(HGPS) is caused by constitutive production of progerin, a mutant form of
the nuclear architectural protein lamin A1, 2. Progerin is also expressed
sporadically in wild-type cells and has been linked to physiological
ageing3. Cells from HGPS patients exhibit extensive nuclear defects,
including abnormal chromatin structure4, 5 and increased DNA damage6. At
the organismal level, HGPS affects several tissues, particularly those of
mesenchymal origin7. How the cellular defects of HGPS cells lead to the
organismal defects has been unclear. Here, we provide evidence that
progerin interferes with the function of human mesenchymal stem cells
(hMSCs). We find that expression of progerin activates major downstream
effectors of the Notch signalling pathway. Induction of progerin in hMSCs
changes their molecular identity and differentiation potential. Our
results support a model in which accelerated ageing in HGPS patients, and
possibly also physiological ageing, is the result of adult stem cell
dysfunction and progressive deterioration of tissue functions.

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