X-Message-Number: 24070
Date: Sat, 8 May 2004 10:16:21 -0700 (PDT)
From: Doug Skrecky <>
Subject: stem cells and aging

Am Heart J. 2003 Oct;146(4 Suppl):S5-12
Loss of bone marrow-derived vascular progenitor cells leads to
inflammation and atherosclerosis.
BACKGROUND: Aging represents the most powerful risk for the development
of atherosclerosis and atherosclerotic thromboembolic complications. Yet,
the mechanism by which aging affects the arterial wall and its
deterioration has remained essentially uncharacterized. FINDINGS: Chronic
injuries to the arterial wall contribute to the development of
atherosclerosis. However, it is important to note that a complex repair
system that involves both local and bone marrow-derived cells maintains
arterial homeostasis and integrity. With this review, we explain how the
age-dependent failure of the bone marrow to produce vascular progenitor
cells responsible for such arterial repair--an inability that results
from the impact of a lifetime of risk factors such as
hyperlipidemia--drives atherosclerosis and its thromboembolic
complications. As a consequence of such failure, the normal processes of
arterial wall repair and rejuvenation are impaired. The disequilibrium
that ensues between injury of the arterial wall and repair leads to
atherosclerotic inflammation and consequent thromboembolic complications.
CONCLUSION: The bone marrow and derived progenitor cells represent key
regulators of atherosclerosis, and progress in the prevention and
treatment of atherosclerosis and its thromboembolic complications will
need to take into account this new dimension for the disease process.

Circulation. 2003 Jul 29;108(4):457-63. Epub 2003 Jul 14
Aging, progenitor cell exhaustion, and atherosclerosis.
BACKGROUND: Atherosclerosis is largely attributed to chronic vascular
injury, as occurs with excess cholesterol; however, the effect of
concomitant vascular aging remains unexplained. We hypothesize that the
effect of time in atherosclerosis progression is related to obsolescence
of endogenous progenitor cells that normally repair and rejuvenate the
arteries. METHODS AND RESULTS: Here we show that chronic treatment with
bone marrow-derived progenitor cells from young nonatherosclerotic
ApoE-/- mice prevents atherosclerosis progression in ApoE-/- recipients
despite persistent hypercholesterolemia. In contrast, treatment with bone
marrow cells from older ApoE-/- mice with atherosclerosis is much less
effective. Cells with vascular progenitor potential are decreased in the
bone marrow of aging ApoE-/- mice, but cells injected from donor mice
engraft on recipient arteries in areas at risk for atherosclerotic injury.
CONCLUSIONS: Our data indicate that progressive progenitor cell deficits
may contribute to the development of atherosclerosis.

J Clin Invest. 2004 Jan;113(1):4-7.
Do tumor-suppressive mechanisms contribute to organism aging by inducing
stem cell senescence?
Stem/progenitor cells ensure tissue and organism homeostasis and might
represent a frequent target of transformation. Although these cells are
potentially immortal, their life span is restrained by signaling pathways
(p19-p53; p16-Rb) that are activated by DNA damage (telomere dysfunction,
environmental stresses) and lead to senescence or apoptosis. Execution of
these checkpoint programs might lead to stem cell depletion and organism
aging, while their inactivation contributes to tumor formation.

EMBO J. 2003 Aug 15;22(16):4212-22.
Reversal of human cellular senescence: roles of the p53 and p16 pathways.
Telomere erosion and subsequent dysfunction limits the proliferation of
normal human cells by a process termed replicative senescence.
Replicative senescence is thought to suppress tumorigenesis by
establishing an essentially irreversible growth arrest that requires
activities of the p53 and pRB tumor suppressor proteins. We show that,
depending on expression of the pRB regulator p16, replicative senescence
is not necessarily irreversible. We used lentiviruses to express specific
viral and cellular proteins in senescent human fibroblasts and mammary
epithelial cells. Expression of telomerase did not reverse the senescence
arrest. However, cells with low levels of p16 at senescence resumed
robust growth upon p53 inactivation, and limited growth upon expression
of oncogenic RAS. In contrast, cells with high levels of p16 at
senescence failed to proliferate upon p53 inactivation
or RAS expression, although they re-entered the cell cycle without growth
after pRB inactivation. Our results indicate that the senescence response
to telomere dysfunction is reversible and is maintained primarily by p53.
However, p16 provides a dominant second barrier to the unlimited growth of
human cells.

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