Might Carnosine Weed Out the Evil 1%?

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mik...@my-deja.com

unread,
Oct 6, 2000, 10:24:42 PM10/6/00
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All, but Aubrey especially:

Cells w/ no mtDNA are a good model for cells taken over by mt with mtDNA
(& esp mt tRNA-coding) deletions. The latter, which constitute 1% of
cells in aged humans, drive aging per Aubrey's MiFRA. The model cells die
if they don't get any pyruvate exogenously. This is (presumably) because,
with no functional ETS, excess NADH builds up & will kill the cell; extra
pyruvate takes up the exta H-, formx excretable lactate, and recycles NAD
for use.

Now, with mounting interest, I read (I've rearranged the abstract for
convenience):

Br J Cancer 1996 Apr;73(8):966-71

Inhibition of the growth of transformed and neoplastic cells by the
dipeptide
carnosine.

Holliday R, McFarland GA

PMID: 8611433, UI: 96200414

Human diploid fibroblasts growth normally in medium containing
physiological concentrations of the naturally occurring dipeptide
carnosine (beta-alanyl-L-histidine). These concentrations are cytotoxic
to transformed and neoplastic cells lines in modified Eagle medium (MEM),
whereas these cells grow vigorously in Dulbecco's modified Eagle medium
(DMEM) containing carnosine.

------>This difference is due to the presence of 1 mM sodium pyruvate in
DMEM.

Seven human cell lines and two rodent cell lines were tested and all are
strongly inhibited by carnosine in the absence of pyruvate. We have used
mixtures of normal MRC-5 fibroblasts and HeLa cells to demonstrate that
20 mM carnosine can selectively eliminate the tumour cells.

Carnosine is known to react strongly with aldehyde and keto groups of
sugars by Amadori reaction, and we propose that it depletes certain
glycolysis intermediates.

================================

Now, just how much pyruvate do our evil 1% (as modelled) need to stay
alive? And how much pyruvate is circulating in vivo?

They also note:

"oxaloacetate and alpha-ketoglutarate can substitute for pyruvate. It is
well known that tumour cells are more dependent on glycolysis than normal
cells. A reduction of glycolysis intermediates by carnosine may deplete
their energy supply, but this effect is totally reversed by pyruvate."

The evil 1% are also much more dependent on glycolysis for their enery
supply, as ETS is KOed; and their succinate dehydrogenase
activity is elevated. So depletion of alpha-ketoglutarate by carnosine
should also be much more deleterious to those cells on the Dark Side than
healthy cells. Likewise, oxaloacetate is right at the top of the TCA
cycle: deplete oxaloacetate, and there is NO more TCA activity
downstream, & hence no SDH. SDH in TCA is just 1/36 of the total ATP
generated in a healthy mt per molecule of glucose, but it is HALF of the
energy supply available to an ETS-less one, so this would be expected to
be serious -- more serious, in fact, than in cancer cells, which compared
to healthy cells are more, but unlike the evil 1% are not totally,
dependent on SDH & fermentation for energy.

Might carnosine weed out the evil 1%?

-Michael


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Before you buy.

Randall Parker

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Oct 7, 2000, 8:08:53 PM10/7/00
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Michael,

Suppose for a moment that it can. Well, are you ready to use it for that
purpose?

Stop and think, do you want to wipe out cells that are post mitotic?

The question is this: Will the death of those cells be noticeable in how
you function? Remember what Aubrey said about the Substantia Nigra
(Niigra?) which has a much higher percentage of non-OXPHOS mitochondria.

On Sat, 07 Oct 2000 02:24:42 GMT esteemed mik...@my-deja.com did'st hold
forth thusly:

Aubrey de Grey

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Oct 20, 2000, 3:00:00 AM10/20/00
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Michael Rae wrote:

> Cells w/ no mtDNA are a good model for cells taken over by mt with mtDNA
> (& esp mt tRNA-coding) deletions. The latter, which constitute 1% of
> cells in aged humans, drive aging per Aubrey's MiFRA. The model cells die
> if they don't get any pyruvate exogenously. This is (presumably) because,
> with no functional ETS, excess NADH builds up & will kill the cell; extra
> pyruvate takes up the exta H-, formx excretable lactate, and recycles NAD
> for use.

Close -- it's probably not the high NADH that matters but the low NAD+.
Also it's e- not H- that pyruvate takes up. (Well, it's really H, i.e.
e- and H+, but it's the e- that can't get out any other way.)

> Now, with mounting interest, I read (I've rearranged the abstract for
> convenience):
>
> Br J Cancer 1996 Apr;73(8):966-71
>
> Inhibition of the growth of transformed and neoplastic cells by the
> dipeptide carnosine.

Extremely interesting; well found. There's very little extracellular
pyruvate in vivo, and (I remind others - I know you know) my proposal
is that the PMOR substitutes for that absent pyruvate. So, since the
effect of carnosine is apparently at the level of TCA, not glycolysis,
that should mean that carnosine is bad for mt-mutant cells, just as you
suggest. Oddly, they suggest that carnosine depletes depletes certain
glycolysis intermediates (not TCA ones); I would say (though I haven't
read the full text yet and there may be good reasons) that TCA depletion
is much more likely: the TCA intermediates are effectively catalysts,
taking part in a cycle, whereas glycolysis is just a chain. Hence, any
depletion of glycolysis intermediates should be rescued by raising the
glucose levels in the medium, and anyway would take a lot more of the
depleter.

It's very interesting that oxaloacetate and alpha-ketoglutarate can
substitute, because I've never heard that they can replace pyruvate
in the culturing of rho-0 cells.

I will look into this more. Carnosine is rapidly got rid of though,
by the enzyme carnosinase, suggesting that any benefits of this sort
may be hard to achieve in vivo -- and also that there may be reasons
to keep carnosine down.

Randall Parker wrote:

> > Might carnosine weed out the evil 1%?

> The question is this: Will the death of those cells be noticeable in how

> you function? Remember what Aubrey said about the Substantia Nigra
> (Niigra?) which has a much higher percentage of non-OXPHOS mitochondria.

Nigra. I would prefer to get rid of them. The substantia nigra does
have a lot of such cells, but that may be largely self-accelerating:
getting rid of them as they arise (or soon after) may leave us with
more cells remaining in the long run. That said, I'd even more prefer
to restore them to OXPHOS function with nuclear transgenes.

Aubrey de Grey

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