Drug extends fruit fly lifespan by 50%
James
Florian Siebzehnruebl
James wrote:
> http://www.eurekalert.org/pub_releases/2002-01/ns-kya012302.php
>
Sounds quite interesting, but i think the difference between
drosophila and man is just a little bit too big to have very
high hopes...
opinions, anyone?
Florian A. Siebzehnruebl
Thomas Carter
Hi Florian,
My hopes are quite high. This is not a very scary drug, just a very
short fatty acid (four carbons) with a benzene ring attatched to the
last carbon atom. It has been used for about 20 years for various
enfirmidies without serious side effects. It raises SOD levels by
about 30%, which is widely thought to increase life span. (I sure
would like to know which SOD it increases, the cytosolic SOD, or the
mitochondrial SOD?) Altho it is quite expensive now, at two to four
dollars a day, the patent expires in '04, which may bring the price
down. By then we should know enough to make a fairly informed
decision.
Thomas
mark doran
news:a7b55247.0202021727.69fab001@posting.
> My hopes are quite high. This is not a very scary drug, just a very
> short fatty acid (four carbons) with a benzene ring attatched to the
> last carbon atom. It has been used for about 20 years for various
> [infirmities?] without serious side effects.
Well, that's good to hear! I'm curious, though, about just *what* it might
be doing in people with those infirmities: what is its mechanism of action,
and how does it help? Any ideas?
Mark D.
John Barsell
and how does it help? Any ideas?
Well, as a side effect it cures cancer.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?CMD=search&DB=PubMed
Aubrey de Grey
Thomas Carter wrote:
> My hopes are quite high. This is not a very scary drug, just a very
> short fatty acid (four carbons) with a benzene ring attatched to the
> last carbon atom. It has been used for about 20 years for various
> enfirmidies without serious side effects. It raises SOD levels by
> about 30%, which is widely thought to increase life span. (I sure
> would like to know which SOD it increases, the cytosolic SOD, or the
> mitochondrial SOD?) Altho it is quite expensive now, at two to four
> dollars a day, the patent expires in '04, which may bring the price
> down. By then we should know enough to make a fairly informed
> decision.
I'm afraid I'm less excited. Though PBA may have important therapeutic
uses, the mode of action in Drosophila reported in this work (which is
in PNAS 99:838, by the way, so anyone can read it) is unlikely to have
much effect in humans. The drug elicited a 50-*fold* increase in Sod2
mRNA expression (the mitochondrial one) -- where did you get 30%? This
is basically what Epstein did recently in mice, and the mice didn't like
it at all (Raineri et al, Free Rad Biol Med 31:1018). We've known for
some time that we can increase fly or worm lifespan with transgenic or
non-enzymatic antioxidants, but for organisms that have things better
tuned (such as mammals) it seems one must focus on lowering the rate
of production of superoxide instead -- indicating that the damage that
matters is done before the superoxide becomes accessible to the enzyme
or scavenger. See innumerable papers by Barja from 1993 to 1998 or so,
my hypothesis for how this all works in J. Anti-Aging Med. 3:25 and
Muller's improvement of my model in J. Am. Aging Assoc. 23:227.
There is a more optimistic interpretation, though. A subunit of NADH
dehdrogenase (Complex 1) was inhibited (at the transcriptional level)
by 25-fold. Complex I is the main superoxide generator in normal in
vivo conditions, so lowering its activity is likely to lower all free
radical damage, irrespective of accessibility to SODs etc. Indeed, a
marked repression of Complex I has been reported in skeletal muscle
in caloric restriction (Desai et al, Arch Biochem Biophys 333:145),
and I was so impressed with this that I wrote a whole paper about how
the cell might manage it (Mitochondrion 1:129). Certainly any study
of this drug in mammals should start by looking at Complex I activity.
It's certainly fascinating that a single drug can have all these nice
effects on gene expression, though. The fact that it modifies histones
is of course suggestive in that respect, but what we are being told is
that certain genes have evolved to be particularly sensitive to histone
acetylation status -- and that, just as with the Sir2 story in yeast,
these genes include ones relevant to lifespan (at least in relatively
simple organisms).
Aubrey de Grey
Thomas Carter
Thanks, very informative as always.
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote in message news:<a3jc6m$aep$1...@pegasus.csx.cam.ac.uk>...
> Thomas Carter wrote:
>
> > My hopes are quite high. This is not a very scary drug, just a very
> > short fatty acid (four carbons) with a benzene ring attatched to the
> > last carbon atom. It has been used for about 20 years for various
> > enfirmidies without serious side effects. It raises SOD levels by
> > about 30%, which is widely thought to increase life span. (I sure
> > would like to know which SOD it increases, the cytosolic SOD, or the
> > mitochondrial SOD?) Altho it is quite expensive now, at two to four
> > dollars a day, the patent expires in '04, which may bring the price
> > down. By then we should know enough to make a fairly informed
> > decision.
>
> I'm afraid I'm less excited. Though PBA may have important therapeutic
> uses, the mode of action in Drosophila reported in this work (which is
> in PNAS 99:838, by the way, so anyone can read it) is unlikely to have
> much effect in humans. The drug elicited a 50-*fold* increase in Sod2
> mRNA expression (the mitochondrial one) -- where did you get 30%?
I goofed, sorry.
> This is basically what Epstein did recently in mice, and the mice didn't like
> it at all (Raineri et al, Free Rad Biol Med 31:1018). We've known for
> some time that we can increase fly or worm lifespan with transgenic or
> non-enzymatic antioxidants, but for organisms that have things better
> tuned (such as mammals) it seems one must focus on lowering the rate
> of production of superoxide instead -- indicating that the damage that
> matters is done before the superoxide becomes accessible to the enzyme
> or scavenger. See innumerable papers by Barja from 1993 to 1998 or so,
> my hypothesis for how this all works in J. Anti-Aging Med. 3:25 and
> Muller's improvement of my model in J. Am. Aging Assoc. 23:227.
Taken out of context, you seem to be saying that exogenous
anti-oxidants are of little or no value. I'm assuming that you are
talking about: 1. aging only or 2. MIFRA aging only
> There is a more optimistic interpretation, though. A subunit of NADH
> dehdrogenase (Complex 1) was inhibited (at the transcriptional level)
> by 25-fold. Complex I is the main superoxide generator in normal in
> vivo conditions, so lowering its activity is likely to lower all free
> radical damage, irrespective of accessibility to SODs etc. Indeed, a
> marked repression of Complex I has been reported in skeletal muscle
> in caloric restriction (Desai et al, Arch Biochem Biophys 333:145),
> and I was so impressed with this that I wrote a whole paper about how
> the cell might manage it (Mitochondrion 1:129). Certainly any study
> of this drug in mammals should start by looking at Complex I activity.
I would be comfortable with Complex I repression due to lack of
substrate as in CR. But not comfortable with it's being repressed by a
drug. The Citric Acid Cycle would slow down for lack of NAD+ and
glucose and fatty acids would back up in the plasma. Or so it seems to
me. This objection also seems pertenant to other putative CR mimics I
have read about.
> It's certainly fascinating that a single drug can have all these nice
> effects on gene expression, though. The fact that it modifies histones
> is of course suggestive in that respect, but what we are being told is
> that certain genes have evolved to be particularly sensitive to histone
> acetylation status -- and that, just as with the Sir2 story in yeast,
> these genes include ones relevant to lifespan (at least in relatively
> simple organisms).
>
> Aubrey de Grey
Please excuse this slight change of subject but this thread seems to
dying out anyway. Would anyone have comments on this very recent
article?
Thomas
Hum Mol Genet 2002 Feb 1;11(3):317-324 The relationship between
somatic mtDNA rearrangements, human heart disease and aging. Kajander
OA, Karhunen PJ, Jacobs HT. Institute of Medical Technology,
Department of Forensic Medicine, University of Tampere and Tampere
University Hospital, 33014 Finland and Institute of Biomedical and
Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. The
lifetime accumulation of low-abundance, somatic mtDNA re-arrangements
(sublimons) has been proposed as a potential contributor to aging, and
also to diseases such as cardiomyopathy or coronary heart disease.
Tissue-specific sublimons, varying in abundance by three orders of
magnitude between individuals, have recently been observed in
myocardium of control subjects. To study the relationship between
myocardial sublimon levels and various types of cardiac disease and
aging, we applied a semi-quantitative fluorescent PCR assay on
cellular DNA extracted from left ventricle in a series of 300 well
characterized male victims of sudden death up to age 70 (Helsinki
Sudden Death Study). The most prevalent classes of sublimons were
present at <0.1 to 91 copies per cell, but their abundance did not
correlate with any cardiac disease phenotype. In multiple regression
analyses age ([beta] = 0.43, P < 0.0001) and smoking ([beta] = 0.25, P
= 0.012) were the only independent factors found to correlate with
sublimon levels. Thus, sublimons are inferred to accumulate with age
in myocardium of a subset of individuals, but to levels where they do
not appear to have any phenotypic effects during a typical life span.
We propose that, instead of being a causal factor in cardiac aging,
sublimons co-exist with wild-type mtDNA in an equilibrium which is
regulated by as yet unknown mechanisms. PMID: 11823450
Thomas Carter
Hi Mark,
I didn't see your post.
See the previous thread from Jan 27.
http://groups.google.com/groups?hl=en&threadm=6da4c14.0201271129.3e323383%40posting.google.com&prev=/groups%3Fnum%3D25%26hl%3Den%26group%3Dsci.life-extension%26start%3D25%26group%3Dsci.life-extension
Thomas
Aubrey de Grey
Thomas Carter wrote:
> Taken out of context, you seem to be saying that exogenous
> anti-oxidants are of little or no value. I'm assuming that you are
> talking about: 1. aging only or 2. MIFRA aging only
Yes, basically that's what I'm saying. I'm talking about aging only,
but not MiFRA aging only.
> I would be comfortable with Complex I repression due to lack of
> substrate as in CR. But not comfortable with it's being repressed by a
> drug. The Citric Acid Cycle would slow down for lack of NAD+ and
> glucose and fatty acids would back up in the plasma. Or so it seems to
> me. This objection also seems pertenant to other putative CR mimics I
> have read about.
I'll send you a PDF. Basically the malate/aspartate shuttle may be
reversed, allowing the citric acid cycle to proceed; cytosolic NADH may
be recycled at the cell membrane. The idea that CR depletes substrate
is fragile -- the consensus is behind McCarter that specific metabolic
rate doesn't go down in CR. (In my model the oxygen not consumed at
the mitochondrion is instead consumed at the cell membrane.) Thus, my
scheme is available in a drug-induced setting as well as in CR.
> Please excuse this slight change of subject but this thread seems to
> dying out anyway. Would anyone have comments on this very recent
> article?
> Hum Mol Genet 2002 Feb 1;11(3):317-324
Very consistent with recent work from that group and Khrapko's. The
key point is that one and probably both of the rearrangements studied
in this article are poorly replicable as deletions so probably exist
mainly as duplications, which would typically have no loss of function.
Their levels in tissue homogenates, as for deletions, are non-uniform
-- they rise to very high levels in a few cells -- and that "few" is
a lot higher than the 0.1% or so for truly loss-of-function mutations.
Evolution may have failed to protect somatic mtDNA all that well from
this sort of mutation precisely because it does no phenotypic harm.
Aubrey de Grey
Thomas Carter
snip>
> > I would be comfortable with Complex I repression due to lack of
> > substrate as in CR. But not comfortable with it's being repressed by a
> > drug. The Citric Acid Cycle would slow down for lack of NAD+ and
> > glucose and fatty acids would back up in the plasma. Or so it seems to
> > me. This objection also seems pertenant to other putative CR mimics I
> > have read about.
>
> I'll send you a PDF. Basically the malate/aspartate shuttle may be
> reversed, allowing the citric acid cycle to proceed; cytosolic NADH may
> be recycled at the cell membrane. The idea that CR depletes substrate
> is fragile -- the consensus is behind McCarter that specific metabolic
> rate doesn't go down in CR. (In my model the oxygen not consumed at
> the mitochondrion is instead consumed at the cell membrane.) Thus, my
> scheme is available in a drug-induced setting as well as in CR.
Hi Aubrey,
I sure hope you're wrong about the ETC being too close to the MtDNA
for interception techniques to work. They seem to be about our best
chance for anti-aging supplementation at this time.
Except in gluconeogenesis which only occurs in the liver. I think the
malate/aspartate shuttle can only be reversed by higher mitochondrial
concentrations of NADH which would still slow down the citric acid
cycle due to allosteric inhibition of the pyruvate dehydrogenase
complex and in fact most of the other pertenant enzymes. And of course
if this happened I would still have an increase in blood sugar and
decrease in ATP production. I don't like the idea of my NADH being
oxidized by the no longer hypothetical PMOR either. Or am I completely
misunderstanding MIFRA?
Thomas
Snip>
Bill Bokunic
1000mg of Acetyl L-Carnitine, 150mg Alpha Lipoic Acid (lef brand)
100mg COQ10. Does this study suggest I might live a healthier life but
the life maximum or average life span is not changed or even
shortened? Should I be concerned about reducing the doses?
Thanks in advance for any suggestions.
Thomas Carter
Hi Bill,
In this thread we are really only talking about the effects of a drug
called PBA. It extends the lives of fruit flies and has effects on
gene expresion. Since you asked, I think there is there is almost no
chance of harm from those doses, but that you need at least half a
gram of Alpha Lipoic Acid to have a chance for significant benefit.
Thomas
Tim
You may want to read this study. It's a lone study and has never
been followed up however.
Seidman MD et al Am J Otol 2000 Mar;21(2):161-7, PMID:10733178
Tim
Aubrey de Grey
Thomas Carter wrote:
> I think the malate/aspartate shuttle can only be reversed by higher
> mitochondrial concentrations of NADH which would still slow down the
> citric acid cycle due to allosteric inhibition of the pyruvate
> dehydrogenase complex and in fact most of the other pertenant enzymes.
No, because the malate/aspartate shuttle is electrogenic. The NADH
concentration in the matrix is already higher than in the cytosol, so
the only reason electrons normally go in and not out is because they
fall down the mitochondrial proton gradient. Thus, a slightly lower
mitochondrial membrane potential will do it, even with no change in
NADH concentrations in either compartment.
> I don't like the idea of my NADH being oxidized by the no longer
> hypothetical PMOR either. Or am I completely misunderstanding MIFRA?
Not at all; this is a key point. MiFRA, since 1998, has described my
hypothesis for how totally OXPHOSless cells keep going, and my new
proposal for what happens in CR is indeed ostensibly at odds with it.
But I have a way to square them. My proposal for what's happening in
CR is that the cell is performing a relatively mild adjustment to its
normal biochemistry, starting with the malate/aspartate shuttle being
reversed and somewhat up-regulating the PMRS ("plasma membrane redox
system" -- "PMOR", plasma membrane oxidoreductase, is going out of
fashion now that we understand that the electrons get shuttled along
a chain of enzymes). I propose that this is something the system can
do cleanly, reducing oxygen to water and not making much superoxide.
The difference with totally OXPHOSless cells (mitochondrially mutant)
is that we have to worry about the redox state of the mitochondrial
quinone pool too, since it is being reduced by succinate dehydrogenase.
In CR, there is still an intact chain from quinol to oxygen (Complexes
III and IV and cytochrome c). When that is missing, we have to get
the quinol reoxidised some other way, and my proposal (since 1998) is
that the glycerophosphate shuttle is reversed. There's no literature
on that, as far as I know, but I'm fairly sure that it's a lot harder
than reversing the malate/aspartate shuttle, i.e. that the cell must
make big changes in other things (maybe including NADH concentrations).
This, I now say, is why the OXPHOSless cell stresses out its PMRS more
than it can handle, resulting in substantial superoxide production.
Aubrey de Grey
Tim
response to respiratory deficiency (Epstein CR et al, Mol Biol
Cell,Feb 2001 Vol 12(2),297-308). Whether this occurs in any other
organism or is peculiar to yeast remains to be seen though it is not
implausible. (Jazwinski, SM, Exp Gerontol 2000, Sep;35(6-7) 795-801.
Michal Jazwinski has done a lot of research in integrative modeling in
S. cerevisiae over the last several years.
Tim
Thomas Carter
Hi Aubrey,
Thx for the paper.
I will summarize what I take from the postings in this and related
threads.
PBA increases acetylation of histones thus changing gene
expression in fruit flies while increasing their life span. It may do
so in humans. The free full text is in PNAS, but is still not
available. It should be soon. Two modes of action are an increase in
MtSOD and depression of complex I of the ETC. Aubrey doesn't think
much of increasing MtSOD because the source and target are too close
together for effective intervention. He's allways right, but I'm still
not completely convinced. Apparently others (like Bruce Ames) aren't
either. The inhibition of complex I is another matter, Aubrey's paper
outlines very clearly how the inhibition or the complex, which is the
major source of ROI in the ETC, by means of CR can, by reducing
triiodothyronine (t3) a thyroid hormone, decrease the MIM potential,
which will pull in fewer electrons from cytosilic NADH and thus
reverse the Malate/Aspartate shuttle without a major increase in the
NADH concentration of the matrix, so the Krebs cycle won't be
inhibited and my blood sugar won't rise. His paper is an hypothysis,
but a simple glucose test would show if there is a problem.
Here is the abstract of Aubrey's paper. It's in "Mitochondrrion"
which is not listed in PubMed. If any one would like the full text, I
will send it to them, if Aubrey doesn't object. (It's classic De Grey:
very tightly reasoned with all bases touched, but at the end you feel
like, "Gee, could it really be true")
A proposed mechanism for the lowering of mitochondrial electron
leak by caloric restriction
Aubrey D.N.J. de Grey
a
Department of Genetics, University of Cambridge, Downing Street,
Cambridge CB2 3EH, UK
Received 23 January 2001; received in revised form 12 March 2001;
accepted 12 March 2001
Abstract
Caloric restriction (CR) of laboratory rodents, which extends their
maximum lifespan, only transiently reduces the speciĊ½c
metabolic rate of highly oxidative tissues. However, superoxide
production by mitochondria of those tissues is greatly reduced
by CR. This is probably a major contributor to the slowed aging seen
in CR, but its mechanism is unknown. Here it is proposed
that the major metabolic shift enabling reduced superoxide production
is a diversion of much of the electron flux generated by
glycolysis and the TCA cycle away from its usual destination, Complex
I, and to the plasma membrane redox system. The cell's
ATP synthesis capacity is thereby diminished, but so is its ATP
demand, due to reduced turnover of the Na+/K+ ATPase.
Direct tests of this hypothesis are proposed. q 2001 Elsevier Science
Ltd. All rights reserved.
A question for Aubrey: The recycling of ascorbic acid is
accomplished both directly by NADH and NADPH, and indrectly thru
reduction by GSH and enzymatically and nonenzymatically in the cytosol
and mitochondria with Mt concentrations as high as the millimolar
range in some cells. Could this be a significant contributor to
getting electrons out of the mitochondria and the cell?
Thomas
Aubrey de Grey
Thomas Carter wrote:
> PBA increases acetylation of histones thus changing gene expression in
> fruit flies while increasing their life span. It may do so in humans.
> The free full text is in PNAS, but is still not available. It should be
> soon. Two modes of action are an increase in MtSOD and depression of
> complex I of the ETC. Aubrey doesn't think much of increasing MtSOD
> because the source and target are too close together for effective
> intervention.
Careful: that is what I say about mammals, not about flies/worms. This
difference is very important, and is based on the very different effects
seen in mice vs flies of knocking out SOD genes:
CuZnSOD MnSOD
mice -/- normal -/+ normal
flies -/- 5-fold -/+ never
shortlived isolated
(PNAS 86:2761) (may be haplolethal)
In other words, both SODs (cytosolic and mitochondrial) matter far more
in flies than in mice. This is to be expected, since flies make far
more superoxide than mice. What it means is that in flies, there is so
much superoxide floating around that it can damage things quite a long
way from its site of production, whereas in mice, it gets mopped up a
lot faster (even with only the mitochondrial form available) and thus
has much less long-range toxicity.
> The recycling of ascorbic acid is accomplished both directly by NADH
> and NADPH, and indrectly thru reduction by GSH and enzymatically and
> nonenzymatically in the cytosol and mitochondria with Mt concentrations
> as high as the millimolar range in some cells. Could this be a
> significant contributor to getting electrons out of the mitochondria
> and the cell?
I don't think so. The problem is that virtually all ascorbate is in
the reduced form, because dehydroascorbate has to be very rapidly re-
reduced after it is formed or else it decomposes. The rate at which
you could get electrons out of the cell is thus limited by the rate at
which ascorpate is oxidised by other processes (presumably scavenging
of free radicals).
Aubrey de Grey
Dave
Aubrey de Grey wrote:
> Thomas Carter wrote:
>
>
>>PBA increases acetylation of histones thus changing gene expression in
>>fruit flies while increasing their life span. It may do so in humans.
>>The free full text is in PNAS, but is still not available. It should be
>>soon. Two modes of action are an increase in MtSOD and depression of
>>complex I of the ETC. Aubrey doesn't think much of increasing MtSOD
>>because the source and target are too close together for effective
>>intervention.
>>
>
> Careful: that is what I say about mammals, not about flies/worms. This
> difference is very important, and is based on the very different effects
> seen in mice vs flies of knocking out SOD genes:
>
> CuZnSOD MnSOD
>
> mice -/- normal -/+ normal
>
> flies -/- 5-fold -/+ never
> shortlived isolated
> (PNAS 86:2761) (may be haplolethal)
>
> In other words, both SODs (cytosolic and mitochondrial) matter far more
> in flies than in mice. This is to be expected, since flies make far
> more superoxide than mice. What it means is that in flies, there is so
> much superoxide floating around that it can damage things quite a long
> way from its site of production, whereas in mice, it gets mopped up a
> lot faster (even with only the mitochondrial form available) and thus
> has much less long-range toxicity.
Aubrey,
Excuse me for jumping in at the end of the thread, but based on what I
have read from your posts in this thread, I gather that your opinion of
drugs such as PBN and other spin traps is that they are of little value
for extending *maximal* life span in humans. Is this correct? Do you
think that they would likely be of value in increasing *average* life
span, and/or effectively increase the *quality* of life?
Thank you in advance for any feedback.
Dave
>
>>The recycling of ascorbic acid is accomplished both directly by NADH
>>and NADPH, and indrectly thru reduction by GSH and enzymatically and
>>nonenzymatically in the cytosol and mitochondria with Mt concentrations
>>as high as the millimolar range in some cells. Could this be a
>>significant contributor to getting electrons out of the mitochondria
>>and the cell?
>>
>
> I don't think so. The problem is that virtually all ascorbate is in
> the reduced form, because dehydroascorbate has to be very rapidly re-
> reduced after it is formed or else it decomposes. The rate at which
> you could get electrons out of the cell is thus limited by the rate at
> which ascorpate is oxidised by other processes (presumably scavenging
> of free radicals).
>
> Aubrey de Grey
>
--
The following is my e-mail address in ASCII numerical form:
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To e-mail me, covert back to corresponding characters.
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not yet caught on to this method. :-)
Aubrey de Grey
Dave wrote:
> Excuse me for jumping in at the end of the thread, but based on what I
> have read from your posts in this thread, I gather that your opinion of
> drugs such as PBN and other spin traps is that they are of little value
> for extending *maximal* life span in humans. Is this correct?
That's my reading of the evidence, yes.
> Do you think that they would likely be of value in increasing *average*
> life span, and/or effectively increase the *quality* of life?
Hard question. The problem with average lifespan (or indeed the average
quality of life) is that no one is average. If we consider a population
whose diet is generally deficient in lots of vitamins and minerals, their
average lifespan is relatively easy to increase by dietary or medicinal
means. An affluent population is less likely to be deficient in things,
so things that might help the other population won't help. So PBN would
quite probably help the average African, or the average black American,
simply because the average wealth of those populations is low. However,
I would also guess that extremely cheap supplements (such as a standard
multivitamin a day) would probably raise such people's health to a level
at which more sophisticated supplements would be of marginal value.
Aubrey de Grey
Thomas Carter
Thx Aubrey,
I had long surmised that this was your opinion, but had never actually
seen it stated. May now I ask you to coment on the other side of the
coin? What would be the chances of damage to a typical member of an
affluent population not deficient in things by the ingestion of
intra-mitochondrial antioxidants in general, or any in specific, or
other common interventions such as ALCAR, or any other caveat you
would care to coment on?
Thomas
Dave
Aubrey de Grey wrote:
Thank you for your response. You're correct in that it *is* a hard
question, especially considering how poorly I worded it. :-) I should
have separated my last question into two distinct questions. That is,
something like the following: 1.) Do you think that they would likely
be of value in increasing *median* life span? 2.) Might PBN or other
spin trapping radicals, anti-oxidants, etc., likely improve the
*quality* of life for the majority (or at least a large percentage) of
the population? However, I think that your answer to both of those
questions can be extrapolated easily enough from your explanation above.
Clearly, as you're no doubt aware, the vast majority (I'm tempted to say
*all*) of us here, do not fall within the sub-population that you feel
might benefit from the use of the supplements mentioned above. But what
is your opinion of Dr. P's comments in the thread started by Steven
Harris? Specifically I am referring to the following post (cut and
pasted below - with Dr P's atrocious typing and excessive use of spaces
repaired somewhat :-):
----------------------------------------------------
>From: "Steve Harris" <sbha...@ix.RETICULATEDOBJECTcom.com>
>Subject: Another Negative Antioxidant Life Span Study in Rodents
>Date: Sun, 10 Mar 2002 20:20:08 -0700
>Probably the main impact of antioxidant supplmentation in humans will
>be in atherosclerosis prevention, which doesn't apply to rodents. So
>this doesn't mean antioxidant supplementation is necessarily worthless
>in the average human. But this and many other studies put a money
>wrench into the theory that somehow antioxidants interfere with the
>basic aging process itself. There is no really good evidence that they
>do. At least, not in mammals.
Here is the key Phrase:
>"These and other observations indicate that, at present, the effects
>of dietary antioxidants are mainly demonstrated in connection with
>age-associated diseases in which oxidative stress appears to be
>intimately involved."
This reflects the distinction between the "samll" and "large" theories
of oxidative stress and aging. The "Small" theory says that activated
species are involved in identifiable pathological processes which
eventually produce things like atherosclerosis and cancer. This is
pretty well established.
Most people eventually die from one of these things. So, the role of
oxidative stress in "aging" is clear, if perhaps indirect. OTOH, the
"strong" theory says that aging per se is somehow directly related to
oxidative stress. The evidence for this is much less clear.
Dr P
----------------------------------------------------
Dave
> Aubrey de Grey
Tom Matthews
Since Aubrey provides no evidence here, it is clear that this is merely his
*opinion* and its veracity should be regarded thusly.
As is likely known by most readers on sle, my own reading of the
literature is quite opposite on the question of average lifespan and
quality of life, at least, if not extension of maximal lifespan. I also
know of many, many examples of people who have been greatly changed to a
better quality of life and almost certainly a longer lifespan by the use
of better diet and supplements even though their former diet (and even
supplements) far exceeded generally accepted minimums. While these are
anecdotal and uncontrolled, the clarity and numbers of them is such that
they are not to be ignored.
Finally, Aubrey's comment on black Americans shows that while he may be
a highly expert scientist in certain narrow areas, even his statements
about other areas, let alone his opinions, should be given nor more
credence than those of an educated layman.
--Tom Matthews
MoreLife for us all - http://morelife.org
Reality based tools for More Life in quantity & quality
Peter H. Proctor
>From: Tom Matthews <t...@morelife.org>
>Subject: Re: Drug extends fruit fly lifespan by 50%
>Date: Fri, 15 Mar 2002 02:13:15 -0500
>Since Aubrey provides no evidence here, it is clear that this is merely his
>*opinion* and its veracity should be regarded thusly.
Aubrey is a very smart fella. Like many ( most ? ) in this area,
as far as my poor undeveloped mind understands them, I take his theories on
mitochondria and aging very seriously, tho differing on a few of the details.
But this is the "Large" model for free radicals and aging. However,
at least in developed countries, most people die of something ( say,
cancer or atherosclerotic heart disease ) in which there is little or no
doubt of a free radical etiology. The problem is that it is difficult to
distinguish this from some more basic effect. So we go round and round.
Dr P
Peter H. Proctor
>From: ag...@mole.bio.cam.ac.uk (Aubrey de Grey)
>Subject: Re: Drug extends fruit fly lifespan by 50%
>Hard question. The problem with average lifespan (or indeed the average
>quality of life) is that no one is average. If we consider a population
>whose diet is generally deficient in lots of vitamins and minerals, their
>average lifespan is relatively easy to increase by dietary or medicinal
>means.
An additional issue is what is "optimal" and what does "deficient"
mena. . E.g., homocysteine appears to play a key role in both
atherosclerosis and ( probably ) alzheimer's. Supranormal consumption of
B12, folate, and B6 lower homocysteine more than normal dietary levels even
in affluent populations..
Dr P
Aubrey de Grey
Dave wrote:
>what is your opinion of Dr. P's comments in the thread started by Steven
>Harris? Specifically I am referring to the following post
>
>> This reflects the distinction between the "samll" and "large" theories
>> of oxidative stress and aging. The "Small" theory says that activated
>> species are involved in identifiable pathological processes which
>> eventually produce things like atherosclerosis and cancer. This is
>> pretty well established.
>>
>> Most people eventually die from one of these things. So, the role of
>> oxidative stress in "aging" is clear, if perhaps indirect. OTOH, the
>> "strong" theory says that aging per se is somehow directly related to
>> oxidative stress. The evidence for this is much less clear.
I agree with Peter's comments. The role of oxidative stress becomes
progressively easier to identify and prove, the later one looks in the
process of metabolism causing damage causing pathology. I don't like
to say where in that process aging ends and disease begins, largely
because it doesn't matter where -- it's just terminology.
What I tend to focus on is the tight linkage of metabolic processes to
damage accumulation, and consequently the huge difficulty of slowing
damage accumulation down, in contrast to the much more feasible (in my
view) approach of fixing it after it has been done. This applies both
early and late in the process -- and, indeed, to other types of damage
as well as to oxidative damage. If someone finds a way to slow down
oxidative or other damage enough to extend maximum (or even average
affluent) human lifespan significantly, I'll be as delighted as anyone,
but I'll also be very, very surprised.
Aubrey de Grey
Aubrey de Grey
Thomas Carter wrote:
> What would be the chances of damage to a typical member of an
> affluent population not deficient in things by the ingestion of
> intra-mitochondrial antioxidants in general, or any in specific, or
> other common interventions such as ALCAR, or any other caveat you
> would care to coment on?
Another hard question :-)
The conservative answer is that if something is rather unlikely to do
you much good, the possibility of it doing you harm (by manufacturing
error introducing toxins, by as-yet-unknown long-term side effects,
whatever) may be the predominant factor to take into account. The
alternative interpretation is that if you're nicely protected against
aging by your diet, you're also nicely protected against such accidents,
so the risk of taking supplements is less. I don't know which argument
has greater merit.
Aubrey de Grey
Tim
I would be interested in seeing the full paper. It can be sent to
ttied...@hotmail.com. Thanls in advance.
Tim