X-Message-Number: 30730
Date: Thu, 8 May 2008 10:19:07 -0700 (PDT)
Subject: insulin induced aging claimed to be mediated by oxidative str...

[Or maybe it isn't - see below.]

J Exp Biol. 2008 Mar;211(Pt 5):741-8.
Insulin regulates aging and oxidative stress in Anopheles stephensi.
    Kang MA, Mott TM, Tapley EC, Lewis EE, Luckhart S. Department of Medical
Microbiology and Immunology, 3146 Tupper Hall, One Shields Avenue,
University of California at Davis, School of Medicine, Davis, CA 95616, USA.
    Observations from nematodes to mammals indicate that
insulin/insulin-like growth factor signaling (IIS) regulates lifespan. As in
other organisms, IIS is conserved in mosquitoes and signaling occurs in
multiple tissues. During bloodfeeding, mosquitoes ingest human insulin. This
simple observation suggested that exogenous insulin could mimic the
endogenous hormonal control of aging in mosquitoes, providing a new model to
examine this phenomenon at the organismal and cellular levels. To this end,
female Anopheles stephensi mosquitoes were maintained on diets containing
human insulin provided daily in sucrose or three times weekly by artificial
bloodmeal. Regardless of delivery route, mosquitoes provided with insulin at
1.7x10(-4) and 1.7x10(-3) mumol l(-1), doses 0.3-fold and 3.0-fold higher
than non-fasting blood levels, died at a faster rate than controls. In
mammals, IIS induces the synthesis of reactive oxygen species and
downregulates antioxidants, events that increase oxidative stress and that
have been associated with reduced lifespan. Insulin treatment of mosquito
cells in vitro induced hydrogen peroxide synthesis while dietary
supplementation reduced total superoxide dismutase (SOD) activity and
manganese SOD activity relative to controls. The effects of insulin on
mortality were reversed when diets were supplemented with manganese (III)
tetrakis (4-benzoic acid) porphyrin (MnTBAP), a cell-permeable SOD mimetic
agent, suggesting that insulin-induced mortality was due to oxidative
stress. In addition, dietary insulin activated Akt/protein kinase B and
extracellular signal-regulated kinase (ERK) in the mosquito midgut,
suggesting that, as observed in Caenorhabditis elegans, the midgut may act
as a ;signaling center' for mosquito aging.
PMID: 18281336

[MnTBAP does not in fact scavenge superoxide, although some of its
impurities do. This all goes to illustrate, that just because peer
reviewed journals publish a fact, drug manufacturers and distributors
claim a fact, and many scientists believe in a fact, does make that fact
true. The claimed fact that MnTBAP itself is a SOD mimic is false.]

J Biol Inorg Chem. 2008 Feb;13(2):289-302. Epub 2007 Nov 29.
Pure manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP) is
not a superoxide dismutase mimic in aqueous systems: a case of
structure-activity relationship as a watchdog mechanism in experimental
therapeutics and biology.
    Rebou as JS, Spasojevic I, Batinic-Haberle I. Department of Radiation
Oncology, Duke University Medical School, Durham, NC 27710, USA.
    Superoxide is involved in a plethora of pathological and physiological
processes via oxidative stress and/or signal transduction pathways.
Superoxide dismutase (SOD) mimics have, thus, been actively sought for
clinical and mechanistic purposes. Manganese(III)
5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP) is one of the most
intensely explored "SOD mimics" in biology and medicine. However, we show
here that this claimed SOD activity of MnTBAP in aqueous media is not
corroborated by comprehensive structure-activity relationship studies for a
wide set of Mn porphyrins and that MnTBAP from usual commercial sources
contains different amounts of noninnocent trace impurities (Mn clusters),
which inhibited xanthine oxidase and had SOD activity in their own right. In
addition, the preparation and thorough characterization of a high-purity
MnTBAP is presented for the first time and confirmed that pure MnTBAP has no
SOD activity in aqueous medium. These findings call for an assessment of the
relevance and suitability of using MnTBAP (or its impurities) as a
mechanistic probe and antioxidant therapeutic; conclusions on the
physiological and pathological role of superoxide derived from studies using
MnTBAP of uncertain purity should be examined judiciously. An unequivocal
distinction between the biological effects due to MnTBAP and that of its
impurities can only be unambiguously made if a pure sample is/was used. This
work also illustrates the contribution of fundamental structure-activity
relationship studies not only for drug design and optimization, but also as
a "watchdog" mechanism for checking/spotting eventual incongruence of drug
activity in chemical and biological settings.
PMID: 18046586

[MnTBAP plus impurities can rejuvenate endothelial function in aged normal
mice, but not in aged growth hormone transgenic mice.]

Clin Sci (Lond). 2006 Feb;110(2):217-25.
Endothelial dysfunction in growth hormone transgenic mice.
    Andersson IJ, Johansson ME, Wickman A, Bohlooly-Y M, Klintland N,
Caidahl K, Gustafsson M, Bor n J, Gan LM, Bergstr m G. Department of
Physiology, Institute of Physiology and Pharmacology, Sahlgrenska Academy,
G teborg University, G teborg, Sweden.
    Acromegaly [overproduction of GH (growth hormone)] is associated with
cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH)
develop hypertension and hypercholesterolaemia and could be a model for
cardiovascular disease in acromegaly. The aims of the present study were to
investigate the effects of excess GH on vascular function and to test
whether oxidative stress affects endothelial function in bGH transgenic
mice. We studied the ACh (acetylcholine)-induced relaxation response in
aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female
bGH transgenic mice and littermate control mice, without and with the
addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic
acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial
nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase).
Intracellular superoxide anion production in the vascular wall was estimated
using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had
an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with
69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas
endothelial function in aorta was intact in young but impaired in aged bGH
transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP
in carotid arteries from young mice and in aortas from aged mice; however,
MnTBAP did not correct endothelial dysfunction in carotid arteries from aged
bGH transgenic mice. There was no difference in intracellular superoxide
anion production between bGH transgenic mice and control mice, whereas mRNA
expression of EC-SOD and eNOS was increased in aortas from young bGH
transgenic mice compared with control mice (P < 0.05). We interpret these
data to suggest that bGH overexpression is associated with a time- and
vessel-specific deterioration in endothelial function, initially caused by
increased oxidative stress and later by other alterations in vascular
PMID: 16185195

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