Effects Of Aging In Stem Cells
Date: July 24, 2007
Science Daily — There is little disagreement that the body's
maintenance and repair systems deteriorate with age, even as there is
plenty of disagreement as to why. Stem cells combat the aging process
by replenishing old or damaged cells--particularly in the skin, gut,
and blood--with a fresh supply to maintain and repair tissue.
Aging HSCs exhibit a functional decline (yet an increase in cell
number) and display a heightened stress and inflammatory response
along with signs of epigenetic erosion. (Credit: S. M. Chambers, PLoS
Biology, article authors)Ads by Google Advertise on this site
Unfortunately, new evidence published in the open-access journal PLoS
Biology suggests that this regenerative capacity also declines with
age as stem cells acquire functional defects.
Stuart Chambers, Margaret Goodell, and their colleagues investigated
the molecular mechanisms underlying aging of stem cells by looking at
the gene expression profiles of aging hematopoietic stem cells
(HSCs), the precursors of blood cells. They found that genes involved
in the inflammatory and stress response became more active with age,
while genes important for regulating gene expression and genomic
integrity became less active. These results lend strong support to
the notion that HSCs succumb to the wear and tear of aging, just like
other cells, and shed light on the mechanisms of aging.
To study HSCs' regenerative capacity over time, Chambers et al.
isolated HSCs from young (aged 2 months) and old (aged 21 months)
mice and then transplanted either young or old cells into mice whose
bone marrow cells had been destroyed by radiation. The young and old
HSCs gave rise to new marrow cells at roughly the same pace 4 weeks
after transplantation. But at 8 and 16 weeks after transplantation,
the old HSCs' contributions had dropped considerably, suggesting that
aging HSCs lose their repopulating capacity. Yet, because HSCs
increased in number, overall blood production from HSCs remained
stable.
The finding that genes involved in the inflammatory response are
expressed more (called up-regulation) as HSCs age fits with evidence
linking inflammation and aging in the kidney, brain, and arteries. It
may also help explain why HSCs lose function. One of the up-regulated
genes, P-selectin, encodes a cell surface adhesion molecule. Because
transplanted HSCs depend on cell adhesion to colonize bone marrow
properly, the researchers explain, inappropriate up-regulation of
genes encoding P-selectin may interfere with this process.
The markedly reduced expression (or down-regulation) of genes
involved in chromatin remodeling, an "epigenetic" regulator of gene
expression, suggested that transcriptional activity might be
dysregulated across the genome.
Though the dominant model attributes the physical effects of aging to
an accretion of isolated genetic insults, these results link age-
related decline to global mechanisms operating across the genome. In
the researchers' "epigenetic view of aging," chromatin dysregulation
provides a logical explanation for the numerous and diverse age-
related changes observed at the molecular, cellular, and organismal
levels.
Over the normal course of aging, chromatin dysregulation leads to
dysregulation of many genes, which in turn leads to a loss of normal
cellular functions and a loss of growth regulation. These changes
ultimately increase the risk of cancer, which, in many of its forms,
increases dramatically with age. Future studies can investigate how
epigenetic regulation, inflammation, and the stress response interact
to better understand the molecular mechanisms of aging, and why so
many of us face a high risk of cancer in our later years.
Reference: Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, et
al. (2007) Aging hematopoietic stem cells decline in function and
exhibit epigenetic dysregulation. PLoS Biol 5(8): e201.
doi:10.1371/
Note: This story has been adapted from a news release issued by PLoS
Biology
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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