X-Message-Number: 25786
Date: Sun, 13 Mar 2005 12:12:35 -0800 (PST)
From: Doug Skrecky <>
Subject: bone marrow may regulate the greater part of aging

[In addition to osteoporosis, bone marrow also may be primarily
responsible for the development of sarcopenia as well as
atherosclerosis. Could oxidized low density lipoprotein be a
connecting factor?]

Nature. 2005 Feb 17;433(7027):760-4.
Rejuvenation of aged progenitor cells by exposure to a young
systemic environment.
    The decline of tissue regenerative potential is a hallmark of
ageing and may be due to age-related changes in tissue-specific
stem cells. A decline in skeletal muscle stem cell (satellite
cell) activity due to a loss of Notch signalling results in
impaired regeneration of aged muscle. The decline in hepatic
progenitor cell proliferation owing to the formation of a complex
involving cEBP-alpha and the chromatin remodelling factor brahma
(Brm) inhibits the regenerative capacity of aged liver. To examine
the influence of systemic factors on aged progenitor cells from
these tissues, we established parabiotic pairings (that is, a
shared circulatory system) between young and old mice (heterochronic
parabioses), exposing old mice to factors present in young serum.
Notably, heterochronic parabiosis restored the activation of Notch
signalling as well as the proliferation and regenerative capacity
of aged satellite cells. The exposure of satellite cells from old
mice to young serum enhanced the expression of the Notch ligand
(Delta), increased Notch activation, and enhanced proliferation in
vitro. Furthermore, heterochronic parabiosis increased aged
hepatocyte proliferation and restored the cEBP-alpha complex to
levels seen in young animals. These results suggest that the
age-related decline of progenitor cell activity can be modulated
by systemic factors that change with age.

Clin Exp Pharmacol Physiol. 2004 Jul;31(7):407-13.
Oxidized low-density lipoprotein induces endothelial progenitor
cell senescence, leading to cellular dysfunction.
   1. Recent studies have revealed an association between
coronary risk factors and both the number and function of bone
marrow-derived endothelial progenitor cells (EPC). We
investigated the effect of oxidized low-density lipoprotein
(ox-LDL) on the senescence of EPC, leading to cellular
dysfunction. 2. Endothelial progenitor cells were isolated from
human peripheral blood and characterized. The exposure of
cultured EPC to ox-LDL (10 microg/mL) significantly accelerated
the rate of senescence compared with control during 20 days in
culture as determined by acidic beta-galactosidase staining.
Oxidized LDL-induced EPC senescence was significantly inhibited
by pretreatment with either lectin-like ox-LDL receptor-1 (LOX-1)
antibody (Ab) or atorvastatin (P < 0.01). 3. Because cellular
senescence is critically influenced by telomerase, which
elongates telomeres, we measured telomerase activity using a
polymerase chain reaction-ELISA-based assay. Oxidized LDL
significantly diminished telomerase activity to approximately
50%, an effect that was significantly abolished by pretreatment
with either LOX-1 Ab or atorvastatin (P < 0.01). 4. We examined
whether ox-LDL-induced EPC senescence translates into EPC
dysfunction. An MTS assay disclosed an inhibitory effect of
ox-LDL on EPC proliferation. In a Matrigel assay, EPC treated
with ox-LDL were less likely to participate in network formation
compared with controls. 5. In conclusions, ox-LDL accelerates
the onset of EPC senescence, which may be related to telomerase
inactivation. Oxidized LDL-induced EPC senescence leads to the
impairment of proliferative capacity and network formation.

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.

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