http://findarticles.com/p/articles/mi_m1200/is_6_173/ai_n24320926/
Faulty fountains of youth: adult stem cells may contribute to aging
by Patrick Barry
Skin sags. Hair grays. Organs don't work quite like they used to. A gradual
wearing out and running down of the body's tissues seems an inherent part of
growing older. Rejuvenation of skin, muscles, and other body parts naturally
declines with the passing years.
Scientifically speaking, however, this observation is much less self-evident.
Some cells in a person's body can resist the tide of aging. Consider the
reproductive cells a person carries that will become the cells of newborn
children who have 80-plus years of life to look forward to. Generation after
generation, these reproductive cells form an unbroken line stretching for
millennia.
The reason that an otherwise healthy person grows old and dies remains a
mystery. Scientists have suggested several suspects for why people's bodies wear
out with age, including accumulated damage to DNA, free radicals, and the
shortening of telomeres--the caps on the ends of chromosomes. While each of
these factors may play a part, biologists acknowledge that their understanding
of aging is incomplete.
Enter stem cells. Scientists have long known that people have small reservoirs
of stem cells in some of their tissues, such as bone marrow. These stem cells
are distinct from those found in newly fertilized embryos--the more
controversial embryonic stem cells. The embryonic type can become any type of
cell in the body.
Adult stem cells, in contrast, can normally generate new cells only for the
tissue in which they're found: blood cells for blood, intestinal cells for the
intestines. As old cells in these tissues are damaged or wear out, nearby stem
cells can manufacture new ones to take their place. At the same time, the stem
cells produce more copies of themselves, maintaining a seemingly indefinite pool
of cells capable of churning out a stream of replacement cells.
Until recently, most scientists thought that adult stem cells existed only in
tissues that need to constantly replace their cells, such as skin, blood, and
the lining of the intestine. But over the past few years, researchers have found
stem cells in many, perhaps most, of the body's organs and tissues. Even the
brain, which scientists once thought never replaced its nerve cells during
adulthood, is now known to have stem cells that make new nerve cells throughout
life (SN: 6/16/07, p. 376).
With the realization that so much of the body contains self-renewing stem cells,
scientists began wondering whether changes in these stem cells over time might
contribute to aging.
Imagine that, as a person ages, these fountains of cellular youth might start to
run dry. As the supply of fresh cells dwindles, tissues would gradually decline
and show signs of age. "That was the initial model" of how stem cells could be
involved in aging, says Norman E. Sharpless, a stem cell expert at the
University of North Carolina in Chapel Hill. And some data support this idea.
Graying of hair, for example, could be caused by a decline in melanocyte stem
cells that accompanies aging, as observed by Emi K. Nishimura and her colleagues
at Dana-Farber Cancer Institute in Boston. Melanocytes make the hair pigment
melanin, so depleting these stem cells eventually causes loss of hair color, the
team reported in Science in 2005.
Elderly people also have diminished resistance to disease because their immune
systems make fewer of the disease-fighting white blood cells known as
lymphocytes. In mice, bone marrow stem cells produce fewer lymphocytes as the
mice get older, Derrick J. Rossi, now at Harvard Stem Cell Institute in
Cambridge, reported in 2005 in the Proceedings of the National Academy of
Sciences.
Yet evidence is mounting that the connection between adult stem cells and aging
is more complex. Some kinds of stem cell actually grow more abundant with age.
And just as stem cells affect aging, the aging body affects stem cells.
TINKERING WITH TIME To untangle these effects, scientists led by Thomas A. Rando
of Stanford University surgically joined pairs of mice like reconnected Siamese
twins. The team linked the animals' circulatory systems so that blood from each
member of a pair flowed through both mice. One mouse in each pair was old; the
other was young.
Scientists knew that the ability of muscle stem cells (also called satellite
cells) to repair damaged muscles declines substantially with age. Rando's team
wanted to find out whether such declines should be attributed to changes in the
satellite cells themselves or to changes in the cells' environment as the
animals aged.
"There clearly is an effect of aging on stem cells," Rando says. "But I think
the other question is ... are those changes reversible or irreversible?"
Amazingly, the blood of the young mice completely restored the tissue-healing
powers of the satellite cells in the older mice, Rando's team reported in 2005
in Nature. Exposure to the young blood reactivated a system of proteins inside
the cells called the Notch signaling pathway, which is crucial for triggering
the cells' muscle-repair functions. Notch signaling in satellite cells normally
declines in old age, but Rando's experiment showed that this decline is a
response to changes in the blood, not the result of an inherent wearing out of
the satellite cells themselves.
This influence of the cells' environment is possible because all cells receive
signals--including hormones and other messenger proteins--from their
surroundings, and these signals allow the cells to behave appropriately for
their context. So a change in these external messengers in aging mice could
diminish the satellite cells' muscle-repair activity.
Stem cells' surroundings also wield an influence in fruit fly testes. Changes in
the stem cell-harboring niche inside the testes contribute to a decline in the
number of sperm-making stem cells with age, according to research by D. Leanne
Jones of the Salk Institute for Biological Studies in La Jolla, Calif., and her
colleagues. As the flies grew old, the niche produced less of a protein that
activates a gene in the stem cells called unpaired, which triggers self-renewal
of the cells, the team reported in the Oct. 11, 2007 Cell Stem Cell.
"We definitely see changes in the environment long before we start to see" signs
of intrinsic aging, Jones says. In mice testes as well, "there seems to be
evidence for the environment aging instead of the stem cells themselves."
In other cases, though, stem cell aging seems independent of context.
Blood-forming stem cells from bone marrow age in an unusual way. When scientists
transplant blood stem cells from an old mouse into a young mouse, allow the
young mouse to grow old, and then repeat the process for several generations,
the stem cells lose none of their ability to make copies of themselves. In fact,
in some mouse strains, blood stem cells become even more numerous with age.
But that's not necessarily a good thing. While old age doesn't appear to affect
blood stem cells' power of self-renewal, it does gum up their ability to make
specialized offspring cells. Ideally, each time a stem cell divides, one of the
daughter cells would remain a stem cell, and the other would continue dividing
to produce a fresh crop of specialized cells to replenish the tissue. That way,
the stem cell's lineage always contains only one stem cell at a time to replace
the original, keeping the total number of stem cells constant.
For that number to increase, daughter cells must sometimes both become stem
cells, decreasing production of tissue-replenishing cells.
Even when these elderly stem cells do spawn new lines of specialized cells, the
process goes awry. Blood stem cells must give rise to a whole family of
specialized cells: red blood cells, lymphocries, monocytes, macrophages, and
others. As the stem cells age, something goes wrong in this specialization
process, skewing it away from making lymphocytes. So the old-age slump in
germ-fighting lymphocytes happens not because the stem cells peter out but
because they charge ahead with their specialization machinery slightly broken.
In mice, this misbehaving of blood stem cells occurs even when scientists
repeatedly transplant the cells into young animals, leading them to conclude
that the stem cells themselves become damaged with time.