X-Message-Number: 27820
Date: Thu, 6 Apr 2006 21:43:13 -0700 (PDT)
From: Doug Skrecky <>
Subject: SB203580 might rejuvenate aged humans

[It all depends on how important P38 is in normal human aging.]

J Gerontol A Biol Sci Med Sci. 2005 Nov;60(11):1386-93.
Prevention of accelerated cell aging in Werner syndrome using a p38
mitogen-activated protein kinase inhibitor.
  We investigated the role of p38 mitogen-activated protein kinase
(MAPK) signalling in the accelerated aging of Werner Syndrome
(WS) fibroblasts by use of SB203580, a cytokine-suppressive
anti-inflammatory drug that targets p38 activity. SB203580 treatment
reverts the aged morphology of young WS fibroblasts to that seen in young
normal fibroblasts. In addition, SB203580 increases the life span and
growth rate of WS fibroblasts to within the normal range. In young WS
cells, p38 is activated coincident with an up-regulation of p21(WAF1),
and a reduction in the levels of both activated p38 and p21(WAF1) are seen
following treatment with SB203580. As these effects are not seen in young
normal cells, our data suggest that the abbreviated replicative life span
of WS cells is due to a stress-induced, p38-mediated growth arrest that
is independent of telomere erosion. With some p38 inhibitors
already in clinical trials, our data suggest a potential route to drug
intervention in a premature aging syndrome.

[SB203580 might also cure osteoarthritis.]

Mech Ageing Dev. 2005 May;126(5):591-7. Epub 2005 Jan 9.
Inactivation of p38 kinase delays the onset of senescence in rabbit
articular chondrocytes.
  Replicative senescence limits cellular proliferation in vivo and in
vitro. Recently, other groups and we reported that p38 kinase plays a key
role on the onset of senescence. In this study, we demonstrated that
replicative senescence can be delayed in rabbit chondrocytes in vitro by
that p38 kinase inactivation. We found that the activity of p38 kinase is
elevated in senescent chondrocytes as compared to pre-senescent
counterparts. To examine the role of p38 kinase on the onset of
senescence, we inactivated the kinase pharmacologically or genetically
using either a chemical inhibitor, SB203580, or dominant negative mutant
forms of MKK6 and p38 (MKK6A and p38dn, respectively). We show that the
inactivation of p38 kinase leads to the stimulation of proliferation, the
extension of life span, and a delay in the onset of senescence, thus
implying that p38 kinase limits the life span of rabbit articular
chondrocytes in vitro

[TNF-alpha levels are good predictors of mortality in human centenarians.]

Circulation. 2005 Mar 8;111(9):1184-91.
p38 mitogen-activated protein kinase downregulates endothelial progenitor
cells.
  BACKGROUND: Transplantation of endothelial progenitor cells
(EPCs) improves neovascularization after ischemia, but patients with
coronary artery disease (CAD) or diabetes mellitus show a reduced number
of EPCs and impaired functional activity. Therefore, we investigated the
effects of risk factors, such as glucose and TNF-alpha, on the number of
EPCs in vitro to elucidate the underlying mechanisms. METHODS AND
RESULTS: EPCs of patients or healthy subjects were isolated from
peripheral blood. Incubation with glucose or TNF-alpha dose-dependently
reduced the number of EPCs (79.9+/-1.3% and 74.3+/-8.1% of
control; P<0.05, respectively). This reduction was not caused by
apoptosis. TNF-alpha and glucose induced a dose- and time-dependent
activation of the p38 MAP kinase, the downstream kinase mitogen- and
stress-activated kinase 1, and the transcription factor cAMP-responsive
element-binding protein (CREB), in EPCs. Moreover, EPCs from CAD patients
had significantly higher basal p38-phosphorylation levels
(1.83+/-0.2-fold increase; P<0.05) compared with healthy subjects. The
inhibition of the p38-kinase by SB203580 or infection with a dominant
negative p38 kinase adenovirus significantly increased basal number of
EPCs (136.7+/-6.3% and 142.9+/-18% versus control,
respectively). Likewise, ex vivo cultivation of EPCs from patients with
CAD with SB203580 significantly increased the number of EPCs and
partially reversed the impaired capacity for neovascularization of EPCs in
vivo (relative blood flow: 0.40+/-0.03 versus 0.64+/-0.08, P<0.05). The
increased numbers of EPCs by SB203580 were associated with an
augmentation of EPC proliferation and a reduction of cells expressing the
monocytic marker proteins CD14 and CD64, suggesting that p38
regulates proliferation and differentiation events. CONCLUSIONS: These
results demonstrate that p38 MAP kinase plays a pivotal role in the
signal transduction pathways regulating the number of EPCs ex
vivo. SB203580 can prevent the negative effects of TNF-alpha and glucose
on the number of EPCs and may be useful to improve the number of EPCs for
potential cell therapy.

[P38 is implicated in human immunosenescence.]

Mech Ageing Dev. 2004 Aug;125(8):539-46.
Role of defective ERK phosphorylation in the impaired GM-CSF-induced
oxidative response of neutrophils in elderly humans.
  GM-CSF-induced oxidative responses are defective in neutrophils of
elderly humans. In the present study we evaluated whether this phenomenon
might be related to alterations in cytokine-dependent MAPK
signalling. Neutrophils obtained from elderly humans and stimulated with
GM-CSF showed a significant reduction in phosphorylated ERK1/2 levels and
an even higher decrease in ERK1/2 activation with respect to baseline. No
changes in GM-CSF-induced p38 MAPK phosphorylation were observed. Cell
pretreatment with the MEK inhibitor PD98059 determined a marked
suppression of GM-CSF-induced O2-release. Interestingly, under the above
experimental condition, there was no longer any difference in O2-
production observed between elderly and young subjects. Furthermore,
despite the fact that the p38 MAPK pathway was activated less strongly by
GM-CSF, the p38 MAPK inhibitor SB203580 reduced GM-CSF-induced O2-
production in the neutrophils of the elderly to levels similar to those
obtained with PD98059. TNF-alpha-triggered O2- production was not altered
by ageing and in fact, a similar ERK1/2 or p38 MAPK activation was found
in TNF-alpha-stimulated neutrophils from elderly and young individuals. In
accordance with the different potency of TNF-alpha in activating ERK1/2
and p38 MAPK, the TNF-alpha-induced oxidative responses were more
sensitive to the inhibitory effects of SB203580 than to those of PD98059
in young as well as elderly subjects. These results suggest that, along
the GM-CSF-dependent ERK signalling pathway, a step proximal to MEK1/2
but distal to the connection with the p38 MAPK module likely becomes
defective as a feature of age. The consequent decline in ERK1/2
activation could potentially account for the GM-CSF-dependent impairment
of the neutrophil respiratory burst that occurs with ageing.

[Eicosapentaenoic acid is a component of fish oil.]

J Biol Chem. 2002 Sep 13;277(37):34239-46. Epub 2002 Jun 28.
Apoptotic changes in the aged brain are triggered by
interleukin-1beta-induced activation of p38 and reversed by treatment
with eicosapentaenoic acid.
  Among the several changes that occur in the aged brain is an increase
in the concentration of the proinflammatory cytokine interleukin-1beta
that is coupled with a deterioration in cell function. This study
investigated the possibility that treatment with the polyunsaturated
fatty acid eicosapentaenoic acid might prevent interleukin-1beta-induced
deterioration in neuronal function. Assessment of four markers of
apoptotic cell death, cytochrome c translocation, caspase-3 activation,
poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end
staining, revealed an age-related increase in each of these measures, and
the evidence presented indicates that treatment of aged rats with
eicosapentaenoate reversed these changes as well as the accompanying
increases in interleukin-1beta concentration and p38 activation. The data
are consistent with the idea that activation of p38 plays a significant
role in inducing the changes described since interleukin-1beta-induced
activation of cytochrome c translocation and caspase-3 activation in
cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The
age-related increases in interleukin-1beta concentration and p38
activation in cortex were mirrored by similar changes in
hippocampus. These changes were coupled with an age-related deficit in
long term potentiation in perforant path-granule cell synapses, while
eicosapentaenoate treatment was associated with reversal of age-related
changes in interleukin-1beta and p38 and with restoration of long term
potentiation.

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