X-Message-Number: 28181
Date: Thu, 6 Jul 2006 13:09:07 -0700 (PDT)
From: Doug Skrecky <>
Subject: stem cells versus aging

[Stem cell function drops off with age. Is this due to intrinsic aging of
the stem cells themselves, or due to adverse changes in the stem cell
niche environment? In other words is aging driven mostly by stem cells, or
by niche cells? At least with regards to short lived mouse strains, (see
below) it the niche cells themselves that appear to be the determining
factor in the rate of aging. Whether this conclusion applies to humans is
an open question.]

Nature. 2006 Jun 29;441(7097):1080-6. Stem cells, ageing and the quest
for immortality.
  Adult stem cells reside in most mammalian tissues, but the extent to
which they contribute to normal homeostasis and repair varies
widely. There is an overall decline in tissue regenerative potential with
age, and the question arises as to whether this is due to the intrinsic
ageing of stem cells or, rather, to the impairment of stem-cell function
in the aged tissue environment. Unravelling these distinct contributions
to the aged phenotype will be critical to the success of any therapeutic
application of stem cells in the emerging field of regenerative medicine
with respect to tissue injury, degenerative diseases or normal functional
declines that accompany ageing.

[Acetylcysteine and caloric restriction have extended lifespan in
some but not all rodent models. They may act via different mechanisms,
and so may exert additive effects if used in combination.]

Exp Gerontol. 2006 Jun 24; [Epub ahead of print] Long-term treatment with
N-acetylcysteine, but not caloric restriction, protects mesenchymal stem
cells of aged rats against tumor necrosis factor-induced death.
  The survival of mesenchymal stem cells (MSCs) to tumor necrosis factor
alpha (TNFalpha) stimulation was evaluated after a long-term antioxidant
treatment, or caloric restriction, in aged rats. MSCs were isolated from
bone marrow of 30-month-old rats which orally received N-acetylcysteine
in the last 18 months. The necrotic cell death-induced in vitro by
TNFalpha, determined by trypan blue exclusion, was markedly attenuated in
MSCs obtained from treated vs. control aged rats (percent
mean+/-SEM: 10.9+/-2.17 vs. 17.8+/-0.53; p<0.05). Also, the proliferation
rate of MSCs from control, but not N-acetylcysteine-treated, aged rats
evaluated up to 2 weeks was significantly higher than that of MSCs from
younger (4-month-old) rats. No significant effect was observed relative
to the parameters investigated when the aged rats were previously
subjected to a hypocaloric diet for 18 months. In conclusion, a prolonged
supplementation with N-acetylcysteine in rats can increase resistance to
necrotic death of MSCs and may also counteract an excessive rate of MSC
proliferation.

Ann N Y Acad Sci. 2006 May;1067:436-42. Stem cells: potential therapy for
age-related diseases.
  Aging is associated with a progressive failing of tissues and organs of
the human body leading to a large number of age-related
diseases. Regenerative medicine is an emerging clinical discipline that
aims to employ cellular medicines (normal cells, ex vivo expanded cells,
or tissue-engineered organs) to restore the functions of damaged or
defective tissues and organs and thus to "rejuvenate" the failing aging
body. One of the most important sources for cellular medicine is
embryonic and adult (somatic) stem cells (SSCs). One example of SCCs with
enormous clinical potential is the mesenchymal stem cells (MSCs) that are
present in the bone marrow and are able to differentiate into cell types
such as osteoblasts, chondrocytes, endothelial cells, and probably also
neuron-like cells. Because of the ease of their isolation and their
extensive differentiation potential, MSCs are among the first stem cell
types to be introduced in the clinic. Some recent studies have
demonstrated the possible use of MSCs in systemic transplantation for
systemic diseases, local implantation for local tissue defects, as a
vehicle for genes in gene therapy protocols, or to generate
transplantable tissues and organs in tissue-engineering
protocols. However, several challenges confront the use of these cells in
the clinic, ranging from biological challenges (e.g., how to isolate a
homogenous populations of the cells with specific criteria from the bone
marrow and how to expand them ex vivo without affecting their
differentiation potential) to biotechnological challenges (e.g., how to
develop easy methods for quality control of the cellular-based
products). While it is expected that cellular medicines will decrease the
burden of several age-related diseases, it is not clear whether they can
change the course of the aging process itself and thus prolong human life.

[Stem niche cells appear to critically important in limiting lifespan in
short lived mouse strains.]

Ann N Y Acad Sci. 2006 May;1067:235-42. Aging of murine mesenchymal stem
cells.
  Mesenchymal stem cells (MSCs) are able to differentiate into distinct
lineages such as adipo-, osteo-, and chondrocytes. MSCs were isolated
from three mouse strains, which are short- (SAMP6, 9.7 months), medium-
(SAMR1, 16.3 months), or long-lived (C57BL/6, 28 months). We investigated
primary colony-forming units with regard to bone marrow stroma and found
differences that correlate with mean life expectancies of the particular
genetic backgrounds. However, MSC derived from the various mouse strains
behaved equivalently in vitro with respect to growth rate. By genomic
means, we analyzed the cellular milieu in vivo and found considerable
differences among the various mouse strains. This implies that, although
individual MSCs show an equivalent differentiation potential in vitro,
the primary stem cells are greatly influenced by their molecular
environment.

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