X-Message-Number: 30624
Date: Tue, 18 Mar 2008 08:37:27 -0800 (PST)
From: 
Subject: reductive hotspot hypothesis has been falsified

**SPECULATION**

[At least, I think it has been falsified. One prediction of de Grey's
reductive hotspot hypothesis of aging is increasing levels of oxidized LDL
with age. This does not happen in humans, so this hypothesis is
falsified.]

Arch Gerontol Geriatr. 2006 May-Jun;42(3):265-76. Epub 2005 Oct 7.
Oxidation of serum low-density lipoprotein (LDL) and antioxidant status in
young and elderly humans.
  Nakamura YK, Read MH, Elias JW, Omaye ST. Department of Nutrition, Mail
Stop 142, University of Nevada, Reno 89557, USA.
  The incidence of atherosclerosis increases with age, as do various indices
of free-radical mediated damage, e.g., lipid peroxidation. Because lipid
peroxidation plays a prominent role in lipoprotein oxidation, likely a
prelude to atherosclerosis, we compared the susceptibility of lipoproteins
to oxidation in young (19-30 years) and elderly (59-86 years) groups.
Although we found no significant differences in serum malondialdehyde (MDA)
or oxidized LDL antibodies (OLAB) between young and elderly lipoproteins,
MDA was directly related to OLAB regardless of age (r = 0.322, p = 0.005)
and there was a trend for lower OLAB levels (30.5%, p = 0.079) in the
elderly compared to the young population. Overall, serum antioxidant status
was either similar or greater in the elderly group compared to the young
group, likely reflecting antioxidant supplementation by the elderly group.
OLAB was inversely related to Vitamin C (r = -0.310, p = 0.008) and Vitamin
E intake (r = -0.277, p = 0.018) from foods and supplements. Serum levels of
Vitamin C and Vitamin E were significantly higher (18.5%, p = 0.021 and 58.1
%, p < 0.001, respectively) in the elderly group compared to the young group
and the ratio of Vitamin E to Vitamin C was significantly higher (30.4%, p =
0.042) in the serum of the elderly group. Oxidation of serum LDL and
antioxidant status were not affected by age; however, the ratio of serum
Vitamin E to Vitamin C was higher in the elderly group which may affect
Vitamin E recycling.
PMID: 16214244

Eur J Biochem. 2002 Apr;269(8):2003-9.
  Comment in: Eur J Biochem. 2002 Apr;269(8):1995.
The reductive hotspot hypothesis of mammalian aging: membrane metabolism
magnifies mutant mitochondrial mischief.
  de Grey AD. Department of Genetics, University of Cambridge, UK.
  A severe challenge to the idea that mitochondrial DNA mutations play a
major role in the aging process in mammals is that clear loss-of-function
mutations accumulate only to very low levels (under 1% of total) in almost
any tissue, even by very old age. Their accumulation is punctate: some cells
become nearly devoid of wild-type mitochondrial DNA and exhibit no activity
for the partly mitochondrially encoded enzyme cytochrome c oxidase. Such
cells accumulate in number with aging, suggesting that they survive
indefinitely, which is itself paradoxical. The reductive hotspot hypothesis
suggests that these cells adjust their metabolism to use plasma membrane
electron transport as a substitute for the mitochondrial electron transport
chain in the reoxidation of reduced dinucleotides, and that, like
mitochondrial electron transport, this process is imperfect and generates
superoxide as a side-effect. This superoxide, generated on the outside of
the cell, can potentially initiate classical free radical chemistry
including lipid peroxidation chain reactions in circulating material such as
lipoproteins. These, in turn, can be toxic to mitochondrially nonmutant
cells that import them to satisfy their cholesterol requirements. Thus, the
relatively few cells that have lost oxidative phosphorylation capacity may
be toxic to the rest of the body. In this minireview, recent results
relevant to this hypothesis are surveyed and approaches to intervening in
the proposed process are discussed.
PMID: 11985576

Arch Biochem Biophys. 2000 Jan 1;373(1):295-301.
The reductive hotspot hypothesis: an update.
  de Grey AD. Department of Genetics, University of Cambridge, Downing
Street, Cambridge, CB2 3EH, United Kingdom.
  The mitochondrial free radical theory of aging is seriously challenged by
the finding that mutant mtDNA never becomes abundant in vivo, a result
disputed only in experiments using novel PCR variants whose quantitative
accuracy is widely doubted. However, evidence continues to mount that
mitochondria are the crucial site of free radical damage in vivo, most
notably that mice lacking the nonmitochondrial isoforms of superoxide
dismutase are healthy. It is thus important to determine whether a low level
of mutant mtDNA could have serious systemic effects. This possibility exists
because of the observed mosaic distribution of mutant mtDNA: some cells (or
muscle fiber segments) lack any aerobic respiration. Such cells are presumed
to satisfy their ATP needs by glycolysis. In vitro, however, NADH recycling
by transmembrane pyruvate/lactate exchange does not suffice: cells only
survive if they can up-regulate the plasma membrane oxidoreductase (PMOR).
The PMOR's physiological electron acceptor is unknown. It was proposed
recently (de Grey, A. D. N. J. (1998) J. Anti-Aging Med. 1(1), 53-66) that a
prominent in vivo acceptor from these mitochondrially mutant cells may be
oxygen, forming extracellular superoxide. The mosaic ("hotspot")
distribution of this superoxide would limit its dismutation by extracellular
superoxide dismutase; it may thus reduce transition metals leading to
oxidation of circulating material, such as LDL. This would raise systemic
oxidative stress, greatly amplifying the damage done by the originating
mitochondrially mutant cells. This model, now known as the "reductive
hotspot hypothesis," has recently gained much indirect experimental support;
several direct tests of it are also feasible. Copyright 2000 Academic Press.
PMID: 10620352

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