X-Message-Number: 32568
Date: Sat, 24 Apr 2010 20:51:57 -0700 (PDT)
From:
Subject: acrolein as a driver of human aging Part 1
[The free radical theory of aging is a bust, due to the fact that
oxygen derived free radicals such as superoxide or hydrogen peroxide are
very mild toxins, which do little damage by themselves. However if the
free radical theory of aging is generalized to the "Toxin Theory of
Aging", then this broader theory does have a lot of data to support
it. Here I will briefly discuss acrolein as a putative driver of human
aging.
The leading cause of premature death in humans is believed to be due
to smoking. Acrolein in turn is believed to be the main driver of smoking
induced damage. Acrolein is also upregulated with aging and is believed
to be an independant contributor to many of the diseases associated with
aging such as atherosclerosis, cancer, and neurodegeneration. Diverse
sources of flavonoids can scavenge acrolein, with apple derived
phloretin being most effective. Cysteamine offers outstanding protection
against acrolein, and is more effective in extending mouse lifespan than
N-acetylcysteine. The cysteamine precursor pantethine lowers lipids in
humans.]
[Human blood vessels are very vulnerable to acrolein, but not to hydrogen
peroxide.]
Toxicol Appl Pharmacol. 2006 Dec 15;217(3):277-88. Epub 2006 Sep 29.
Acrolein generation stimulates hypercontraction in isolated human blood vessels.
Conklin DJ, Bhatnagar A, Cowley HR, Johnson GH, Wiechmann RJ, Sayre LM, Trent
MB, Boor PJ. Institute of Molecular Cardiology, Department of Medicine,
University of Louisville, Louisville, KY 40202, USA.
Abstract
Increased risk of vasospasm, a spontaneous hyperconstriction, is associated
with atherosclerosis, cigarette smoking, and hypertension-all conditions
involving oxidative stress, lipid peroxidation, and inflammation. To test
the role of the lipid peroxidation- and inflammation-derived aldehyde,
acrolein, in human vasospasm, we developed an ex vivo model using human
coronary artery bypass graft (CABG) blood vessels and a demonstrated
acrolein precursor, allylamine. Allylamine induces hypercontraction in
isolated rat coronary artery in a semicarbazide-sensitive amine oxidase
activity (SSAO) dependent manner. Isolated human CABG blood vessels
(internal mammary artery, radial artery, saphenous vein) were used to
determine: (1) vessel responses and sensitivity to acrolein, allylamine, and
H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of
allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL
72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the
vasoactive effects of two other SSAO amine substrates, benzylamine and
methylamine, and (4) the contribution of extracellular Ca(2+) to
hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or
methylamine stimulated spontaneous and pharmacologically intractable
hypercontraction in CABG blood vessels that was similar to clinical
vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO
activity were abolished by pretreatment with semicarbazide or MDL 72274-E
but not by MDL 72274-Z. Allylamine-induced hypercontraction also was
significantly attenuated in Ca(2+)-free buffer. In isolated aorta of
spontaneously hypertensive rat, allylamine-induced an SSAO-dependent
contraction and enhanced norepinephrine sensitivity but not in
Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood
vessel wall increases human susceptibility to vasospasm, an event that is
enhanced in hypertension.
PMID: 17095030
[To no great surprise, acrolein is beleived to be a major driver of
atherosclerosis.]
Ann N Y Acad Sci. 2008 Apr;1126:185-9.
Acrolein induces inflammatory response underlying endothelial dysfunction: a
risk factor for atherosclerosis.
Park YS, Taniguchi N. Department of Microbiology and MRC for Bioreaction to ROS,
Kyung Hee University School of Medicine, Seoul, Korea.
Abstract
Endothelial dysfunction by proinflammatory stimuli represents an important
link between risk factors and the pathologic mechanisms underlying
atherosclerosis. Thus, control of the inflammatory status of endothelial
cells is crucial to limiting the disease. Tobacco smoking induces
inflammatory reactions and promotes atherosclerosis; however, the mechanism
that links cigarette smoking to an increased incidence of atherosclerosis is
poorly understood. Our study demonstrates that acrolein, a known toxin in
tobacco smoke, elevates oxidative stress via inactivation of thioredoxin
reductase and stimulates expression of cyclooxygenase-2 through activation
of the protein kinase C, p38 mitogen-activated protein kinase, and cAMP
response element-binding protein pathway in endothelial cells. Our finding
suggests that acrolein may play a role in the progression of
atherosclerosis.
PMID: 18448814
[Acrolein levels can predict the pathogensis of Alzheimer's disease.]
Neurobiol Aging. 2006 Aug;27(8):1094-9. Epub 2005 Jul 1.
Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid
peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer's
disease.
Williams TI, Lynn BC, Markesbery WR, Lovell MA. Department of Chemistry,
University of Kentucky, 135 Sanders-Brown Center on Aging, Lexington, KY 40506,
USA.
Abstract
Previous studies show increased levels of lipid peroxidation and neurotoxic
by-products of lipid peroxidation including 4-hydroxynonenal (HNE) and
acrolein in vulnerable regions of the Alzheimer's disease (AD) brain. To
determine if lipid peroxidation occurs early in progression of AD, we
analyzed levels of HNE and acrolein in the hippocampus/parahippocampal gyrus
(HPG), superior and middle temporal gyrus (SMTG) and cerebellum (CER) of 7
subjects with Mild Cognitive Impairment (MCI), six subjects with early AD
(EAD) and sevem age-matched control subjects using liquid chromatography
electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS). Our data
show that there is a statistically significant (P<0.05) increase in HNE in
HPG, SMTG and CER in MCI compared to age-matched control subjects. Specimens
of SMTG also showed a significant increase in levels of acrolein in MCI.
Comparison of EAD and control subjects showed a statistically significant
increase in HNE in HPG and SMTG and a significant increase in acrolein in
all three brain regions studied. We did not observe any statistically
significant differences between MCI and EAD specimens. These results suggest
that lipid peroxidation occurs early in the pathogenesis of AD.
PMID: 15993986
[Acrolein appears to be a major driver of telomere shortening.]
J Cell Biochem. 2007 Oct 15;102(3):689-703.
Age-dependent telomere-shortening is repressed by phosphorylated
alpha-tocopherol together with cellular longevity and intracellular
oxidative-stress reduction in human brain microvascular endotheliocytes.
Tanaka Y, Moritoh Y, Miwa N. Laboratory of Cell-Death Control BioTechnology,
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima,
Nanatsuka, Shobara, Hiroshima 727-0023, Japan.
Abstract
Cellular life-span of neonatal human brain microvascular endotheliocytes
(HBME) was estimated by population doubling levels (PDLs) for serial
subcultivations until spontaneous proliferation stoppage, and was 2.4-fold
longer for continuous administration with the 6-O-phosphorylated derivative
(TocP) of alpha-tocopherol (Toc), being bio-available owing to its
water-solubility, or TocP plus 2-O-phosphorylated ascorbate (Asc2P), and
1.3-fold longer with Asc2P, at a dose of 150 microM, than for the
non-administered control. Enlarged cell diameters indicative of cellular
aging were repressed for TocP-administered cells as analyzed with a
channelizer. Age-dependent shortening of telomeric DNA length (291 bp/PDL)
was slowed markedly for TocP (165 bp/PDL) or TocP plus Asc2P, but slightly
for Asc2P. Telomerase activity as assessed by the PCR-based TRAP method was
detectable slightly at younger ages but no longer at middle ages for the
non-administered cells, but, for TocP-administered cells, was intensely
detected at younger ages and appreciably until middle ages. Intracellular
TocP amounts were not changed age-dependently in contrast to a marked
decrease in Toc which accrued from TocP esterolysis. This may be partly
attributed to age-dependent changes in the lipid peroxidation product
acrolein (ACR), which was abundant at older ages in non-administered cells,
but scarcely in TocP-administered cells. Furthermore, intracellular reactive
oxygen species (ROS) such as H(2)O(2) and hydroperoxides as detected using
the redox indicator CDCFH-DA was less abundant in TocP-administered cells
than in non-administered cells. Thus the telomeric-DNA retention,
concurrently with retained telomerase activity, was shown to be correlated
with cellular longevity, and may be supported by diminished oxidative
stress, in hydrophobic microenvironment, which can be achieved by TocP
rather than AscP. (c) 2007 Wiley-Liss, Inc.
PMID: 17407150
[Acrolein is a carcinogen.]
Free Radic Res. 2010 May;44(5):497-504.
Lipid peroxidation product acrolein as a predictive biomarker of prostate
carcinoma relapse after radical surgery.
Custovic Z, Zarkovic K, Cindric M, Cipak A, Jurkovic I, Sonicki Z, Uchida K,
Zarkovic N. Department of Urology, General Hospital Dubrovnik, Croatia.
Abstract
Cancer recurrence after radical surgery might happen even in the case of
patients with localized prostate carcinoma treated by radical prostatectomy.
Therefore, identifying predictive markers of tumour recurrence is very
important, so this study evaluated the presence of lipid peroxidation
product acrolein in primary prostate carcinomas, assuming that acrolein
could be involved in prostate carcinogenesis as was recently shown for colon
cancer. Samples obtained by radical prostatectomy of 70 patients were
analysed, out of which 27 patients suffered afterwards from tumour
recurrence, while 43 patients were disease free. Immunohistochemistry using
genuine monoclonal antibodies against acrolein-protein adducts revealed the
association of acrolein with progression of carcinoma. The logistic
regression combining clinical parameters together with the biochemical
markers of disease and acrolein immunohistochemistry has shown that the
relapse might be predicted with 90% accuracy if tumour-positive surgical
margins, stage of disease and the intensity of acrolein presence in tumour
stroma were taken together.
PMID: 20166882
Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=32568