From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Tue, 19 Feb 2002 16:22:34 -0700
Message-ID: <a4un2i$8e4$1@slb6.atl.mindspring.net>

"diana thorley" <dithorley@aol.com> wrote in message
news:3c728faf.2090312@news.CIS.DFN.DE...

> Also, on the radio and TV today there have been reports of of a study
> in the USA which proved that a combination of L-carnitine and lipoic
> acid reversed the ageing  process.

COMMENT:
They proved no such thing. For all we know, these mice may die at the same
age, but leave good-looking corpses. I once did a similar study with CoQ10,
which was very confusing.  Aging is fundamental and is not going to be
greatly changed by two little nutrients (both of which your body can already
make). If you could slow aging this easily, why doesn't your body do it?
Evolution has no reason to want you to age more rapidly when you could be
(at a small synthetic cost) age more slowly.

Whatever the metabolic cost of aging even at a significantly slower rate (as
we see in bats and birds) it must be quite large. Big repairs are being done
in flying critters, and that burns a lot of energy. More than humans have
historically been able to pay on the kind of diet we have historically
gotten, methinks. I hardly think ALC and lipoic acid are going to be The
Answer.

>The research company has patented
> the combination the formula.

Oh, well, THAT increases my confidence.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Tue, 19 Feb 2002 16:57:34 -0700
Message-ID: <a4up21$n24$1@nntp9.atl.mindspring.net>

"mark doran" <doran@dial.pipex.com> wrote in message
news:3c72e33b$0$233$cc9e4d1f@news.dial.pipex.com...

> > I once did a similar study with CoQ10,
> > which was very confusing.
>
> Ooo! Do tell! What happened?
>
> Regards,


Half the mice got CoQ10 at 0.1% of dry diet for their entire lives, after
weaning. That's a LOT. (About like 7-10 GRAMS a day for people).

 I didn't see as much of the "nursing home" appearance of old C57Bl0/CH3
hybrid mice, which results from hip arthritis (the back legs drag some) and
possibly spinal stenosis (since the mice quit grooming their hind quarters
and rears, which makes me think they can't feel them as well). The CoQ10
mice weren't as gray. They ran around and seemed to have lots more energy at
33 months (which is getting fairly old for a mouse-- it's about mean life
span in the long lived hybrids).

But they died nearly on schedule (only the mean life span increased, so the
curve was squared a bit). Three out of four of the last mice alive in the
CoQ10 group, who I expected to break my max life span record for 10%
restriction (which was about 43 months) died instead of lymphoma. A common
disease of mice.  Which in this case had merely been shifted to an older
age. They left good-looking corpses.  But for about a year there, I thought
I was going to be famous.

Repetition of this experiment is needed. Spindler et al have tried with a
lower dose of CoQ10 and got nothing, which makes me wonder if I wasn't
seeing some statistical fluke in a 35 vs 35 animal control trial.  I'm about
to run another small trial in mice from my small colony, which already will
start out old (32 months). I'll pre-stratify them by weight and appearance,
then randomize them to 1 ppt CoQ10 or not. We'll see if I get similar
effects.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Tue, 19 Feb 2002 18:34:12 -0700
Message-ID: <a4uun1$5im$1@slb1.atl.mindspring.net>

"Jim Jozwiak" <jim@josquin.composers> wrote in message
news:a4uo4f$57l$1@zook.lafn.org...
> Does anyone know what differences there are between mitochondria in humans and
> in rats?
>
> Thanks,
>
> Jim Jozwiak


I'll tell you the biggest difference: rats have a lot MORE of them per cell.
If your metabolism is going to run 5 times as fast, you have to have 5 times
the number of powerhouses.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Wed, 20 Feb 2002 22:07:29 -0700
Message-ID: <a51vjk$mea$1@nntp9.atl.mindspring.net>

"Martin Banschbach PhD" <mbansch@osu-com.okstate.edu> wrote in message
news:a50nos$9aa1@news.cis.okstate.edu...
> Steve,
>
> If you are doing this inhouse, try mercaptoethanolamine.  Mercaptoethanol
> has been done many times with very good results but mercaptoethanolamine has
> never been done (no published data that I could find).


COMMENT:

You probably missed:

J Gerontol 1990 Sep;45(5):B141-7
Dietary restriction alone and in combination with oral
ethoxyquin/2-mercaptoethylamine in mice.
Harris SB, Weindruch R, Smith GS, Mickey MR, Walford RL.

Department of Pathology, University of California, Los Angeles.

To investigate effects of dietary caloric restriction (DR) combined with
antioxidant feeding, long-lived hybrid mice were divided into four dietary
groups at weaning, and followed until natural death. Groups "C" and "R"
received control (97 kcal/wk) and restricted (56 kcal/wk) diets
respectively. Groups "C+ alpha ox" and "R+ alpha ox" received C or R diets
supplemented with an antioxidant mixture (2-mercaptoethylamine plus
ethoxyquin). R mice (mean life span 41 months) significantly outlived the
other three groups (mean life span 30-34 months). Hepatic degeneration and
increased hepatoma in the R+ alpha ox group suggested unusual hepatotoxicity
of this regimen. Antioxidants had little effect on splenic cell mitogen
response in similarly fed mice sacrificed at 12-15 months. Gompertz analysis
suggests that the beneficial effect of DR may be due to reductions in
initial vulnerability or rate-of-aging parameters, or both, and that the
relative influence of each factor may vary with animal strain and DR
protocol used.

PMID: 2394907 [PubMed - indexed for MEDLINE]


Notice the authors. It's true this study used a combination of ethoxyquin
AND 2-mercaptoethanolamine, aka cysteamine, but other people have done
cysteamine alone to death, and it doesn't work in long lived strains. Nor
did it for us. Harmon's original free radical theory of aging was kicked off
with some cysteamine studies in short lived mouse strains fed ad lib, where
it squares the curve in a few strains, but not convincingly (works in some,
not others; doesn't increase max life span).

> All of the data for
> mercaptoethanolamine is classified U.S. Army data.  If what these
> documents say (what they said when I read them in 1982) is true, you are
> going to get at least a doubling of the *maximum* life span of mice.

I don't believe it.  However, somebody may have some data where they fed
cysteamine to mice and they got a life span extension because the animals
hate the smell of the stuff and don't eat their food. Thus, this is just a
complicated form of dietary restriction. "Urg, this food smells like shit.."

The army looked at cysteamine and also its phosphate conjugate WR-1065 (WR
standing for Walter Reed) as possible radioprotectants in soldiers, since
they work modestly well in mice. That stuff is published. The army's best
radioprotectant was not this compound, but actually the thiol WR-2721, aka
ethiophos, which actually eventually made it into pharmaceutical use as
"amifostine", a compound which protects salivary glands in people undergoing
radiation for head and neck cancers where the salivaries are in the field.
Long before this, in the early 1990's, I had the idea what perhaps WR-2721
would be an anti-aging compound. I got hold of it, ran a dose-tox study, and
when I found some appropriate doses (which didn't induce weight loss) I ran
lifespan studies at those doses. Result: zip. It neither lengthened nor
shortened lifespan in my long-lived mildly restricted model. I never
published that (I may someday) because about this time I was beginning to
come to the conclusion that trying to fix aging with one or another single
chemical is about like trying to make your car immortal by changing its
sparkplugs more often.

As for 2-mercaptoethanol, it's been done by somebody else, and it increased
max life span in rodents by just a touch-- the only chemical I know of in
any study that has done this convincingly, without weight loss. Supposedly--
I'm not sure I believe that part, given its nature. This chemical, as
somebody has mentioned, has a rotten egg mercaptan smell so evil and nasty
that nobody's ever seriously suggested further exploration of it. The chief
charm of the army's WR phosphated thiols is that they didn't stink much.
2-ME might prolong your life a bit, but at the price of being a permanent
social outcast. The Frankenstein myth indeed!

BTW, a few mice in my ethoxyquin/cysteamine group died with their body
cavities full of blood. I think that was the cysteamine. I've found other
cysteine feeding studies where aortic rupture was induced by overdose on
thiols, thought to be due to mercapto-chelation of copper, followed by
copper dependent collagen synthesis defects. My guess is that cysteamine
does the same.  I wanted to put that in the paper, but Walford thought it
was too much of a stretch for our data, and nixed it. But I wouldn't eat
short chain thiols indiscriminately in huge doses, for long periods. You
might end up with your aorta going balooey.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Wed, 20 Feb 2002 11:07:48 -0700
Message-ID: <a50oui$nc5$1@nntp9.atl.mindspring.net>

"lad" <chatw@my-deja.com> wrote in message
news:1e1efc6b.0202200807.195ad3c1@posting.google.com...
> If you could slow aging this easily, why doesn't your body do it?
> > Evolution has no reason to want you to age more rapidly when you could
> > be (at a small synthetic cost) age more slowly.
>
>
> I'm no Steven J. Gould :-), but the conventional wisdom has always
> been that nature/evolution doesn't care a rat's rectum about how long
> you live. Just as long as you can crank out and successfully rear
> enough offspring.

Sure, and aging obviously causes problems with that.  If you stayed
physiologically 20 forever, you could obviously raise a lot more children
until the sabertooth or bad hunting season or placenta previa or whatever
got you.

> If we truly "lived in nature" then we'd all be moms n' dads in our
> teens (probably after a parentally arranged pairing). We'd have
> grandkids in our thirties. Then we would all check-out in our forties,
> if we're lucky.

People checked out in their 40's BECAUSE of aging.  Otherwise, those that
made through accident and famine and into their 40's would have had the
exact same individual mortality risk as at age 15.  Which would have been
high in the Paleolithic, to be sure, but still a lot lower than it actually
was, for people who made it to (what we now think of as) middle age.

> Having the wisdom and support of gramps or great-grand-mom may help
> the provision/procreation network, but it doesn't seem necessary.

No, but it's helpful.  And besides, this is "group-selection." It's a weak
force compared with individual selection, and is powerless so long as
there's much crossbreeding between groups (which there must've been for
humans, since we're all related pretty closely, as shown by our mitochondial
genes). And aging is obviously strongly bad for the reproductive success of
*individuals.*  The only reason we have it must be that the "cure" or
"postponement" of aging must involve something like need for a lot more
calories and nutrients for repair, which is/was equally bad for the
individual, in the face of externalities which made age-independent death
rates high (famines, jaguars, fights, childbirth, infections that kill even
15 year-olds, etc).  Why should you spend a lot to do maintenance on a car
(change your oil, etc) in a city where people drive crazily and you're
likely to be totaled in less than year? We see in birds and bats that nature
WILL delay aging if it's given good reason to. In other words, you cannot
suggest that we humans are designed deliberately to age as soon as we've
reproduced, because you can see from birds and bats that nature doesn't have
to design animals that way.  You're only designed to crap out after the
first reproduction *if* the odds are bad of you making it to the second set
are crumby, for *non-age-dependent* reasons.  If humans could remain
youthful (i.e., reproductive longer) by producing a little more lipoic acid
and acyl carnitine, they'd surely have evolved to do it.

Hmmm. Which brings up the interesting idea that if these things only work to
make the very elderly look more middle-aged, then nature might indeed not
have bothered. Evolution truly would have little incentive then, except
possibly through the weak grandmother-group-selection effect, for which you
only need a small percent of survivors anyway. We should remember that an
honest to god *anti-geriatric* chemical need not be an across-the-life-span
anti-aging chemical...

Which brings up yet another point, and that is that these things were tested
in mice, which don't need wise grandmothers. It may well be that we'll find
that some subset of humans (enough to ensure a few vigorous oldsters in
every tribe) already have learned the ALC+lipoic trick, and already do what
they're doing to mice. This subset might be small or large-- who knows?  If
the trick is easy, it might be large.  As in, most of us.

> (Anyway, our present arrangement sure beats having your female partner
> tearing off and eating your skull right after "your first time").

As opposed to her tearing your head off when the kids hit 4-to-6?  Which is
the way we humans do it now? <g>

> It is cultural evolution (i.e. science) that has displaced natural
> selection and lengthened our lives.

Yes.

> We figured out a few things
> regarding sanitation, antibiotics and canned food. Now, for our next
> trick, we have to get busy jiggling all those cells and genes.

Yes.


> All the same, good luck to Juvenon. Even though the ALA/ALC--(and
> sometimes CoQ10, DHEA, etc) combo formula has been sold for a while by
> different companies. NOW, if they could just come up with a perfected
> ALC that wouldn't make me so irritable!!! :-)

I think it's likely to be snake oil, or else something that only works on
the "prematurely" frail elderly-- but I applaud the spirit and the attempt!
This stuff gets people in the proper mindset to make the attack (which is
ridiculously badly funded now), and that has to be good.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Sat, 23 Feb 2002 12:15:29 -0800
Message-ID: <a58t7c$hge$1@slb7.atl.mindspring.net>

lad wrote in message <1e1efc6b.0202220645.5e4eef59@posting.google.com>...
>I think the point of it all is that, (in the strictly mechanical,
>random, evolutionary sense), nature doesn't need to make any species
>more long-lived IF it already rears enough kids to replace and
>multiply itself (careless millions of offspring in the case of
>insects, a handful in the case of careful humans).



Both strategies are successful, but neither one is more successful with
aging just "tacked on." Nature doensn't always do what's best (it doesn't
know), but it will do what ever small optimization is possible from a given
place. Aging happens only when there's a significant cost to prevent it.

>Some species (lobsters, orange roughy, rock fish) seem almost
>arbitrarily gifted with being long-lived, long-teleomered  &
>non-senescent. And, also - (in the strictly purposeful, ordered,
>creationist sense) made delicious, to show that the Creator must have
>a gourmade sense of justice! :-)

All these species have few natural preditors (or can avoid those they have
easily), and live down in nice protected places. If it was *salmon* swimming
up little foot deep streams though guantlets of bears, that didn't age, THEN
I would use the word "arbitrarily." But there is nothing arbitrary about
this. There's a REASON we don't know exactly how long lobsters and rockfish
live-- even WE can't get at them easily.

>Most of the longer lived species  have had extra eons to adapt
>compared to us primate newbies.  Instead, we got a rapidly developed
>brain that made for a cultural adaptation toward longevity . Early man
>died sooner not because of a lesser evolved "aging" effect.  He died
>because he hadn't yet invented (or learn to value) better food
>storage, crop planning, varied diet, sanitation, and predator defense
>(both the saber-toothed kind and the more voracious microbes).


But a slower aging rate (which we have) helps even here. Humans in the worst
conditions, even in prison camps, still show a doubling of mortality every
seven years-- the same as in the best conditions. That's aging. It's what
makes 30 years die when 15 year olds survive, and 40 year olds die when 30
years olds survive.

>Nature had no time, nor reason, to endown man with longer telomers or
>an enhanced ALC/ALA metabolism. Us little buggers were already killing
>everything else, eating & reproducing well and using up resources.

No. Humans struggled for millions of years without even making it out of
East Africa.


>Ultimately, longevity will be understood as an engineering problem.
>ALC/ALA is just another early, flint tool pointing to the solution.
>"Natural" and chemical tools may give away to nanotech and waveform
>solutions.  Entrophy is always inevitable, but aging's multiple causes
>will be treated just as someone maintains the many needs of a beloved
>antique car (even when it requires near total renovation or
>duplication of original

Agreed.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Sat, 23 Feb 2002 11:52:16 -0800
Message-ID: <a58rrs$3u9$1@slb7.atl.mindspring.net>

>"Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> wrote in message
>news:<a50oui$nc5$1@nntp9.atl.mindspring.net>...
>
>> "lad" <chatw@my-deja.com> wrote in message
>> news:1e1efc6b.0202200807.195ad3c1@posting.google.com...
>> > If you could slow aging this easily, why doesn't your body do it?
>> > > Evolution has no reason to want you to age more rapidly when you
>> > > could be (at a small synthetic cost) age more slowly.
>> >
>Hi,
>That is clearly the conventional wisdom, and I almost always bet on
>the favorite. In health matters I bet her to show when possible. But
>the fickle nag frequently loses. (at the track and in medical science)
>There are many possible reasons why evolution might want us dead
>early. IE, Grand, or Greatgrandmother might be a breeding ground for
>microbes that selectively take out her progeny.

That's ridiculous. If you've ever had kids you know how much more likely it
is to be the other way around. In any case, it relies on a kin selection
argument, and these are never good when they rely on having a weak kin
selection advantage (or disadvantage) overpowering a direct disadvantage to
the breeding of the individual (which aging always is). Any increased risk
you have to dying in pregancy or childbirth after 18 is due to aging. If
nature could take care of this easily, it would.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med.nutrition,sci.med,sci.life-extension
Subject: Re: Aging and ALC/lipoic acid (was: alpha lipoic acid eliminates 
	wrinkles?)
Date: Wed, 27 Feb 2002 13:05:14 -0800
Message-ID: <a5jhp3$ai2$1@slb5.atl.mindspring.net>

michaelprice wrote in message ...
>"Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> wrote in message
>news:a4un2i$8e4$1@slb6.atl.mindspring.net...
>> "diana thorley" <dithorley@aol.com> wrote in message
>> news:3c728faf.2090312@news.CIS.DFN.DE...
>>
>> > Also, on the radio and TV today there have been reports of of a study
>> > in the USA which proved that a combination of L-carnitine and lipoic
>> > acid reversed the ageing  process.
>>
>> COMMENT:
>> They proved no such thing. For all we know, these mice may die at the
>> same age, but leave good-looking corpses. I once did a similar study with
>> CoQ10, which was very confusing.  Aging is fundamental and is not going
>> to be greatly changed by two little nutrients (both of which your body can
>> already make). If you could slow aging this easily, why doesn't your body
>> do it?
>
>But the evolutionary logic that says that no endogenously metabolised
>substance (such as CoQ10, ALC and ALA) should significantly extend
>maximum life span applies equally strongly to mean life span - and we
>know that mean life spans are extendable with a range of endogenously
>metabolised substances.


Not really, for extension of mean life span by curve-squaring is often the
sort of thing that modern medicine does-- it saves people from drying of
diseases in middle age, and gets them into geriatric-land.  But evolution
doesn't care about that.  If there was some chemical which kept you from
getting a tumor at 55 and delayed it to age 75 if you had a lot more, would
your body make that stuff for you in quantity?  Likely not.


>So the evolutionary argument against the anti-aging benefit of supplying
>endogenous nutrients must be false.

Nope.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.cryonics,sci.life-extension,sci.med.dentistry,sci.med.pathology,
	sci.med.nutrition
Subject: Re: Longevity Report 91
Message-ID: <UaMk9.1707$Rt5.180911@newsread2.prod.itd.earthlink.net>
Date: Thu, 26 Sep 2002 22:50:28 GMT

Joel M. Eichen wrote in message
<8a2c2731.0209251359.58a511ed@posting.google.com>...
>"John de Rivaz" <John@deRivaz.com> wrote in message
news:<5Akk9.1785$q15.113652@newsfep2-win.server.ntli.net>...
>> I have just uploaded Longevity Report 91 to the web.
>> http://www.longevity-report.com/lr91.htm
>>
>> This is unusual in that
>>
>> 1. It contains a single article.
>>
>> 2. none of you will have read this article before.
>>
>> The Role of Enzymic Cofactors in Aging
>> or
>> How to Live to 200
>> Copyright 2002 Michael Clive Price   Updated 25/09/2002
>> Feedback to michaelprice@ntlworld.com


My feedback to Michael Price is that it just ain't that simple. Some years
ago some other researchers looked to see if mice survived longer on 1/2 RDA
vs RDA vs 2 times RDA worth of all conventional vitamins, but the other
nutrients kept controlled, and found that although there was a bit of
difference between 1/2 and 1 RDA, there was no difference in survival in 1
RDA vs 2x RDA.  That kicks the cofactor theory of aging in the butt: if
there was any effect there, you should start to be seeing it as you double
the dose from one RDA to 2.  Also, it's completely in accord with my own
experience with control groups for CR experiments, which for years I fed on
a much better vitamin regime than the simple AIN-93 levels. They got a
vitamin supplement which was specially made for me and enriched many times
RDA (though not close to toxic levels) in B vitamins, E, and Cr from yeast.
(we didn't bother with beta-carotene because mice turn it into retinol so
fast they don't get any benefti from it. Similar considerations applied to
vitamin C, which mice make on their own in doses far larger than you can
easily give them). But B's and E and Cr made absolutely no drastic
difference. The hybrid strain lived about 3 years mean, and 3.5 years max
under 10-20% restriction, and subtract 6 months from those numbers for ad
lib and add 6 months for max restriction.  This is about what rodent
researchers see with the (quite a bit lower) AIN vitamin recommendations,
which are much more in line with the old human RDAs (not even our modern
usually higher DRIs).

Thus, while you can find a lot of old unrepeated (and probably unrepeatable)
reports of life span extension with one B vitamin or another, or E, the
available evidence for "across the board" enrichment of these things
(megadose water solubles and E) absolutely does NOT suggest any kind of
synergy between them when it come to aging.

Sorry. I take Daily One and E for my arteries, and I sure wish that that
kind of thing made mice live to be 5 or 6 years old, or even any difference
that it works at all to lengthen their lives.

SBH





--
I welcome email from any being clever enough to fix my address. It's open
book.  A prize to the first spambot that passes my Turing test.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.cryonics,sci.life-extension,sci.med.dentistry,sci.med.pathology,
	sci.med.nutrition
Subject: Re: Longevity Report 91
Message-ID: <bcsl9.6211$Rt5.568217@newsread2.prod.itd.earthlink.net>
Date: Sun, 29 Sep 2002 00:55:35 GMT

michaelprice wrote in message
<97Wk9.2408$sh4.116170@newsfep2-win.server.ntli.net>...

>> Also, it's completely in accord with my own
>> experience with control groups for CR experiments,
>
>Published?



Sure. Medline 2394907 contains a control group eating the mega-vitamin
enriched diet, as does also every life span study done by Walford et al in
the 80's at UCLA (look up Weindruch, Richard and Walford, Roy).

The vitamin formula used in restriction and ad lib control studies at UCLA
was not the stingy AIN-76, but rather (in accord with Walford's prescription
to be SURE you're not malnourished) another more liberal vitamin mix from
earlier times before the AIN started trying to standardize all these lab
diets. We used to put the vitamin and mineral mixes in the diets ourselves
when we made them (I remember the B vitamin smell of the stuff) before we
switched to having Teklad do it.  I don't have the precise composition at my
fingertips but IIRC it was the ICN vitamin-mix formula for semi-synthetic
diets, and it had a whopping dose of most of the non-toxic ones, in amounts
of the mix that we used (which are in my paper, or those it references).
Enough that I never seriously considered if further megadosing of these
things would get me anywhere in rodents.

If you're really curious about the stuff you can probably google it from ICN
lab products. Hopefully the same stuff is available now that they offered in
the 80's.

If 4x RDA isn't enough to convince you, I'm sure we exceeded that with many
vitamins in this mix.

SBH

--
I welcome email from any being clever enough to fix my address. It's open
book.  A prize to the first spambot that passes my Turing test.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.cryonics,sci.life-extension,sci.med.dentistry,sci.med.pathology,
	sci.med.nutrition
Subject: Re: Longevity Report 91
Message-ID: <bgNl9.1555$ny2.165685@newsread1.prod.itd.earthlink.net>
Date: Mon, 30 Sep 2002 00:53:27 GMT

michaelprice wrote in message ...
>"Steve Harris" :
>>>> Also, it's completely in accord with my own
>>>> experience with control groups for CR experiments,
>>>
>>>Published?
>
>> Sure. Medline 2394907 contains a control group eating the
>> mega-vitamin enriched diet,
>
>Thanks for the ref, but since the *controls* received the enriched diet it
>can can't cited as a negative mega-vitamin study.  (Naturally, since you
>were testing for the effects of CR, not 'mega'-dosing.)
>
>> as does also every life span study done by Walford et al in the 80's
>> at UCLA (look up Weindruch, Richard and Walford, Roy).
>
>Interestingly this might support the notion that supra-RDA levels (at
>sub-megadose levels) extend lifespan, since I remember Walford saying
>(as a criticism of earlier experiments) that his control animals outlived
>many
>other earlier lab animals (of the same strain).



Comment:

The control group for this one counts, because the controls for IT are the
many historical controls in other trials in other labs in long lived mice
strains were run on AIN doses. To be precise, Walford's the only one I know
of who used his particular hybrid (C57B10 x C3H), and it gave him life spans
better than most labs but not all. Basically, at the high end of what was
being reported-nothing head and shoulders above anybody else who was using
C57B10s (say).  As a matter of fact I never saw any of Walford's restricted
mice live longer than 43 months, whereas the record for M. musculus
restriction life span is held by Jackson labs, and is something like 46
months. So Walford's results are good, but by no means good enough to
suspect that his vitamin supplementation of the mice had anything to do with
it. At least one other place got comparable or better results for
restriction without the ICN mix for either restricted animals or controls.

I do now have some vitamin numbers for the Walford controls. The present ICN
vitamin fortification mix 904655 (which I got off the web) is no doubt what
we used historically. It's meant to be used at 2.2% of diet, and we fed it
to controls at 3.5% of "dry" (i.e., no water added) semisynthetic diet, and
to restricted animals at 5% of diet (so it would come out the same vitamin
dose per day per animal, though not per kg diet, per kcal diet, or per kg
body wt mouse-you can have any one of these 4 in a restriction experiment,
but only 1 of 4).

Below are what you get as final diet concentration (mg/kg diet), with the
ICN mix if you use it at 3.5% of final diet, as we did for controls. Next
are how many fold over AIN recommendations this is, using as reference final
concentrations you get with the AIN-76 mix at the recommended 1% of diet. So
"3x" would be 3 times the AIN recommendation. I've rounded everything to 2
significant figures.

ICN at 3.5%, final vitamin concentrations in mg/kg diet

B1   16 mg/kg =   2.7 x AIN
B2   16                 2.7 x
niacin 68              2.3 x
B5  48                  3.0 x
B6  16                  2.3 x
folate 1.4              0.7 x
biotin 0.32            0.1 x
B12   0.022 (2.2 mcg/kg) 2.2 x

A  29  (7200 IU)  1.8 x (13,000 IU)
C  716 mg/kg   -- (no AIN rodent value)
E  350 (87 IU)  1.8x (150 IU)
D2  2.0 (800 IU)  4x (3200 IU)

(K is present in the AIN mix, but not in the ICN so we never fed it). AIN
recommendations for rodents don't include vitamin C, which we did feed.



Comments: it's interesting that the only vitamins fed less in ICN than AIN
are folate and biotin. I suppose folate had been upped in AIN due to
reproductive problems (AIN was formulated as not as a geriatric formula, but
more of a general husbandry formula supplement). Biotin was skimped on in
the old ICN no doubt due to price, and AIN fixed that.

I was surprised when I actually did the numbers that most of these ICN
numbers in our formula are really only in the 2 to 3 x AIN range, not "5x"
as I'd remembered. The difference is probably due to the fact that I'd once
compared them to human RDAs on a mg/kcal basis, which is a fairer comparison
of humans to rodents. The rodent AINs recs are liberal-- about twice the
human DRIs in terms of mg/kcal, as you can see from the fact that the diets
above are about 4,000 kcal/kg, meaning that human dietary need (depending on
body size) would be somewhere about 0.6 to 0.75 kg of this kind of diet, so
multiply the vitamin doses by that, to get the human equivalent dose if you
were living on mouse diet. That DOES come out to be more like 5x RDA or DRI,
or a bit more. You get numbers like 10 mg for B1 and B2, 30 mg for B5, and
500 mg C and 100 IU vitamin E.  These are "therapeutic multivit" type dosage
numbers, though of course far less than what you find in lots of
supplements.

Yes, you can argue that optimal health doses of these vitamins could be far
higher, but that certainly cannot be the case of SOME of them.  For example,
there's a limit of about 20 mg in how much B1 or B2 you can absorb in a
meal, so it's rather silly to take much more of them in a day than that.
Similarly, your body stores of vitamin C will probably be well saturated at
500 mg, so taking more than that and expecting to live any longer because of
it, is just not realistic.

Steve




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From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.cryonics,sci.life-extension,sci.med.dentistry,sci.med.pathology,
	sci.med.nutrition
Subject: Re: Longevity Report 91
Message-ID: <MEqm9.3909$lV3.341497@newsread1.prod.itd.earthlink.net>
Date: Tue, 01 Oct 2002 23:58:36 GMT

michaelprice wrote in message ...

>I don't know of any evidence that intramuscular injection is superior to
>oral ingestion for any vitamin (although it is for CoQ10).

Not for vitamin C, most B, vitamins, or A. However, you certainly retain a
larger % of the dose with IM B12 and IM vitamin E.  For B12 the liver
receptors saturates after you retain 10 to 20 mcg of an injected dose, but
you wouldn't absorb that much orally if you took 100 mcg or even 1000 mcg.
You do retain that much from a shot of either 100 mcg or 1000 mcg. Now, the
entire healthy loaded liver may contain 5000 mcg of B12, but it takes 20
injections or so to load it. It can't be done in a day.

Much the same kind of thing is true for solubilized forms of vitamin E,
which are given to calves with deficiencies. You can't do this nearly as
well PO as you can with a few IM doses. It takes weeks to saturate body
pools with oral vitamin E, but it can be done in one or two injections IM.



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From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: Multi-RDAs *do* extend lifespan (was Re: Longevity Report 91)
Message-ID: <zcjs9.3172$U97.325978@newsread2.prod.itd.earthlink.net>
Date: Sat, 19 Oct 2002 20:25:03 GMT

Thomas Carter wrote in message ...
>tcarter2@elp.rr.com (Thomas Carter) wrote in message
news:<a7b55247.0210161130.16d6e1d@posting.google.com>...
>
>
>>      There is also a slight indication of a U shaped curve for
>> antioxidant balance and that older animals can get out of the sweet
>> spot by extreme supplementation.
>>
>
>Hi,
>I had remembered a paper giving some indication of this, but could not
>find it until now.  It is supposed that a major mechanism of CR is a
>reduction in ROS production. If true, a combination of CR and
>antioxidant supplementation could put even an older animal out of the
>sweet spot and onto the wrong side of the redox balance. That is to
>say in more danger from antioxidants than free radicals. While I think
>this very unlikely the appended paper does give such an indication.
>And by the same reasoning implies that the redox sweet spot is at
>about the level of a 30% reduction in free radicals which is evendent
>in CR. This would also imply that there will be no more that a 30%
>increase in lifespan possible by reduction or interception of free
>radicals. In this case greater lifespan extension would have to come
>from inhanced repair mechanisms or other effects. AFAIK this is the
>only paper that bears on the coeffects of CR and antioxidant
>supplementation. Steve is one of the authors, maybe he will give some
>insights.
>Thomas
>
>J Gerontol 1990 Sep;45(5):B141-7 Dietary restriction alone and in
>combination with oral ethoxyquin/2-mercaptoethylamine in mice. Harris
>SB, Weindruch R, Smith GS, Mickey MR, Walford RL. Department of
>Pathology, University of California, Los Angeles.                  To
>investigate effects of dietary caloric restriction (DR) combined with
>antioxidant feeding, long-lived hybrid mice were divided into four
>dietary groups at weaning, and followed until natural death. Groups
>"C" and "R" received control (97 kcal/wk) and restricted (56 kcal/wk)
>diets respectively. Groups "C+ alpha ox" and "R+ alpha ox" received C
>or R diets supplemented with an antioxidant mixture
>(2-mercaptoethylamine plus ethoxyquin). R mice (mean life span 41
>months) significantly outlived the other three groups (mean life span
>30-34 months). Hepatic degeneration and increased hepatoma in the R+
>alpha ox group suggested unusual hepatotoxicity of this regimen.
>Antioxidants had little effect on splenic cell mitogen response in
>similarly fed mice sacrificed at 12-15 months. Gompertz analysis
>suggests that the beneficial effect of DR may be due to reductions in
>initial vulnerability or rate-of-aging parameters, or both, and that
>the relative influence of each factor may vary with animal strain and
>DR protocol used.   PMID: 2394907      (Both of these substances are
>well known to be beneficial antioxidants. The combination of the two
>plus CR apparantly caused liver damage. This result is probably an
>abberation of some sort, but it can't be ruled out that the result was
>due to a redox imbalance caused by the combination of CR and
>antioxidant supplementation)



COMMENT:

I agree this probably doesn't same much about antioxdative status per se.
Some antioxidants are fairly toxic, and mice under CR have little tiny
livers which really don't have the same capacity to deal with metabolism of
them. Mouse livers under chronic duress are extremely sensitive to hepatoma,
also, and there are many examples of ethical pharmaceuticals which are
"known carcinogens" in mice, except that when you look at the data, it's all
hepatoma. Mostly such things are ignored, even by the FDA.

A couple of things that aren't in print relative to the study above.
Hepatoma was the main cause of increased deaths in the antiox mice, but I
also found a couple of mice that had died in a very odd way, with body
cavities full of blood. It wasn't clear why. I thought this might be a
cysteamine effect. Aortic rupture has been seen in animals fed cysteamine
while growing, and I guessed that this was due to copper deficiency and loss
of effectively strong collagen synthesis. I thought the same thing might be
happening to my animals, but Walford didn't want to be that speculative (a
double speculation, here), so this never made it to the paper.

Later, in a study never published, I fed control and restricted mice
ethiophos (WR-2721), a pretty good sulfur-based antioxidant. It fed it at
doses about half of that required to cause weight loss, figuring that was
toxicity point.  It didn't work-- life span wasn't increased, nor decreased,
except in the CR animals. However, again I saw increased mortality only in
the restricted group with it (relative to plain restricted without it)--
another indication that restricted mice are bad at tolerating near toxic
doses of things. No sign of the aortic problem, but I didn't do all the
autopsies, and it could have been missed.

Restricted mice tolerate huge doses of chromium, folate, and CoQ10 fine in
life span studies, I found. But these all have big margins of safety even at
the doses I was feeding. CR mice I found were more sensitive to the toxicity
of 13-cis retinoic acid, and I think I did publish this. The general rule,
if I had to guess, seems to be that the substance has to be fed at doses on
the edge of toxicity anyway, for CR to uncover the increased toxicity
effect. I would guess that we are NOT particularly seeing evidence of an
"over-antioxidative" effect. The first place I'd expect that to show up
would be infectious disease resistance, and we never got the opportunity to
test this. So far as I can tell, very little work has been done in this
direction in CR.

SBH


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