CR-mimetic?
jannis
light. In a recent article LEF claims that metformin is a sucessfull
CR-mimetic that could potentialy extend the healthy human lifespan.
Their claim is based on research conducted by BioMarker
Pharmaceuticals. What to do you think of this? Also (since metformin
obviously is a proven drug for glucose- and insulin control), could it
be of benefit to younger/healthy people interested in health
maintainance and life extension? Any opinions on the cost/benefit
ratio? Fortunately BioMarker Pharmaceuticals seems to be conducting
further research on in order to establish proper dosing and eventually
find metformin substitutes(to minimize side effects I suppose) so some
of this questions my be answered in the near future. Until then
well-founded speculation and extrapolation should do.
http://www.lef.org/magazine/mag2003/2003_preprint_bio_01.html
Michael
... the Bush chickenhawks credible??
OK, OK, seriously: in reference to:
http://www.lef.org/magazine/mag2003/2003_preprint_bio_01.html
http://www.lef.org/magazine/mag2003/2003_preprint_bio_02.html
Much of the article is devoted to material w/which most here will be
familiar: the anti-aging effect of CR, the failure of other
intervetnions to match it, the promising primate studies, the
beginning of human trials. Only slightly more obscurely, they also
discuss the gene-chip studies reported by Spindler's and Weindruch's
group -- misrepresenting their most reasonable interpretation as
usual, IMO.
More importanltly, however, there are some seemingly new and, at first
glance, pretty darned bold claims being made here -- but they aren't
quite as dramatic as seems to be being presented at first clance.
Key passages & commentary:
"There is now scientific evidence that a therapy can slow the aging
process in laboratory animals. BioMarker Pharmaceuticals
(www.biomarkerinc.com), a new company funded by Life Extension, has
discovered that metformin, a drug used to treat diabetes, can mimic
many of the changes in gene expression found in calorically-restricted
mice, which live much longer, healthier lives than normally-fed mice.
The discovery that a clinically-used drug (metformin) produces genetic
effects similar to those of caloric restriction, including life span
extension, is an unprecedented breakthrough in medicine, with
astonishing implications for us all."
Now, without the teensy-tiny subordinate clause "including life span
extension", this would be a bit of a yawner. One would rather EXPECT
metformin to cause many gene expression changes similar to CR, as
among the most well-established effects of CR are on glucose & lipid
metabolism -- which metformin also affects. That tiny little phrase
adds a lot of drama, however.
At first I thought this was an independent report of LS extension by
metformin -- which would be rather exciting, as it would confirm
also-unpublished report apparently made by Roth et al at the Sixth
International Symposium on Neurobiology and Neuroendocrinology of
Aging which I attended on July 21-26, 2002:
http://groups.google.com/groups?hl=en&lr=&ie=UTF-8&safe=off&selm=3DF354D1.9020606%40morelife.org
http://groups.google.com/groups?hl=en&lr=&ie=UTF-8&safe=off&selm=3DF98F67.3080200%40morelife.org
(Sure wish I could clearly see those @$%#!! graphs!!)
Such a result would also explain a news story on the apparently
defunct juvenews.com , which I was never able to verify:
"Biomarker Pharmaceuticals Launched, 20% Increase in Mouse Lifespan
Announced with Caloric Restriction Mimetic. At the recent conference
on age-mitigating therapeutics in San Francisco (Oct. 16th) Stephen
Spindler,[...] announced that they have a new caloric restriction
mimetic compound that increases the life span of mice by approx. 20%.
If this is proven accurate in further tests it represents the first
significant age-mitigating compound that works on mammals - and may
have applications in humans. "
However, it later transpires that, contrary to what one might have
assumed from the phrasing in both the juvenews story & the LEF article
("BioMarker Pharmaceuticals ... has discovered that metformin ... can
mimic many of the changes in gene expression found in
calorically-restricted mice ... including life span extension"),
Spindler et al have NOT independently verified this result; rather,
the lifespan result alluded to above refers back to Roth et al:
"Metformin Extends Life Span
Further evidence that metformin is an anti-aging therapy is a study
conducted by scientists at the National Institute on Aging (NIA)
showing that metformin extended the life span of mice by 20%. The
results of this study were presented in November 2002 at an
NIA-sponsored meeting at the Mayan Ranch in Bandera, Texas. BioMarker
is now conducting a life span study with metformin to see if the
company can reproduce these results."
BioMarker, of course, is not the NIA. But George Roth IS with the NIA;
and a quick Google reveals:
http://www.uthscsa.edu/arec/CR/News/News.asp?NewsID=48
"SESSION 2 (10:00 -11:10 AM)
CR MIMETICS (Discussion led by Mark Lane)
Caloric Restriction Mimetics: Implications for Humans (George Roth) "
So we still have only the unpublished, unreplicated statement from
Roth's group.
By coincidence, I was already following up on this thru' another route
this last few days, after reading:
I recently read an article about CR on SAGE Crossroads:
http://www.sagecrossroads.net/news_041403.cfm
[This same news story was linked without mention of the above by Dean
a few days ago].
For the most part, it was the usual pop intro -- the effects on
rodents, the preliminary data in primates, the unwillingness of people
to cut their Caloric intake, et -- but attributed a couple of rather
dramatic statements to Roth:
"[R]esearchers have launched a pilot study for the first major
clinical trial of CR in humans. ... The research is timely, because
scientists such as George Roth, a gerontologist formerly at NIA,
predict that a "CR mimetic" -- a compound that simulates the
biochemical consequences of CR -- could enter trials or even reach
market in as little as 3 years...
Roth, who is also CEO of GeroTech Inc., is studying a
naturally-occurring compound that might alter metabolism and hormone
concentrations in ways that imitate CR. If all goes well, the mimetic
will carry few of the side effects of CR, and GeroTech will make it
available as a "nutraceutical," a natural product that would not be
subject to time-consuming regulatory approval."
That's ALSO pretty damned dramatic, of course! I contacted Dr. Roth, &
the discussion SOMEWHAT lowered my excitement level; he indicated that
the story is not quite accurate, indicating that another company --
NOT GeroTech --
has actually started clinical trials of unspecified agents, & that
there are actually several companies planning on putting out PET FOOD
CR mimetics. This, if so, is sneaky as hell: no regulatory hurdles if
it's a dietary supplement, & very little even if it's a drug ... &
what's to stop humans from using it if they think it work (tee hee!
Imagine what happens when lunatic CR-folk start eating a REALLY weird
diet ...).
Anyway, I was wondering at the time if perhaps this was BioMarker,
because of the juvenews story. But now I doubt it: I think that all
the BioMarker stuff refers back to Roth, and this is another beast
altogether.
Returning to the LEF mag piece: interestingly, there IS apparently
more overlap between CR and metformin than "the usual suspects":
"The genes that were altered in expression by both metformin and CR
are linked to drug metabolism and detoxification; energy metabolism;
protein biosynthesis and degradation; cell growth and proliferation
and the cytoskeleton. These findings suggest that metformin has more
beneficial effects than the reduction of blood glucose and insulin,
and that it may be an authentic anti-aging therapy."
PART of the problem with this is that the whole classificatioin schema
("genes linked to drug metabolism", "genes linked to detoxification",
etc makes mechanistic & even teleological assumptions which may be
arbitrary in some cases & can be used to create interpretations of the
data as a whole which don't exist from the individual genes (this is
one of the standard objections to the Weindruch/Prolla and Spindler et
al teams' interpretation of their data).
I've expressed my skepticism about this result previously; my key
objection is the simple fact that metformin is less effective than a
basic weight-loss program (7% weight reduction thru' low-calorie,
low-fat diet & moderate exercise (eg. brisk walking), for at least 150
min/week) in preventing the conversion of prediabetics to full-fleged
NIDDM (1). If a drug can't even match these basic lifestyle
interventions on the most obvious of CR effects in humans, it seems
unlikely to be an intelligent intervention in humans.
To keep my interest up, however, see their Fig 4:
http://www.lef.org/magazine/mag2003/images/2003_preprint_bio_09.jpg
... which indicates that metformin is far superior to other
insulin-sensitizers in altering gene expression in ways parallel to CR
(for whatever that's worth). Of especial interest: it works "better"
(?) than metformin plus glipizide. This keeps the result tantalizing
to me in light of the fact that Glipizide (glyburide) plus metformin
is NOT as close a parallel to the effects of CR as is metformin alone,
whereaas in humans "Simultaneous glyburide/metformin therapy is
superior to component monotherapy as an initial pharmacological
treatment for type 2 diabetes" (2). Ie, this again reinforces the
broader overlap beyond glucose-metabolic genes, AND has a certain
suggestive possibility to refute the objection about metformin vs.
lifestyle given above.
***
The other report in the LEF story: a claim that 'late-life' CR is
effective after all:
"How CR affects life span late in life
Most scientists assume that the anti-aging, life span extending
effects of CR involve the gradual prevention of age-associated
genetic and biologic changes, and that these effects lessen with
advancing age. The early studies found that, while CR could extend
life span dramatically when started early in life, it shortened life
span when started later in life. Then, Weindruch and Walford found
that CR can extend the life span of middle-aged (one-year-old) mice if
their diet is restricted gradually to allow them to adapt to reduced
caloric intake.[11]
BioMarker has found that CR can alter gene expression in male,
long-lived hybrid B6C3F1 mice very rapidly in both young and old
animals. ...
Furthermore, the company has found that CR is just as effective in
extending life span late in life as it is early in life. In the
BioMarker study, late-life CR increased the mean and maximum life span
of mice by approximately 40% (Fig. 3) and slowed the onset of
malignant tumors.[12] "
Fig 3 is:
http://www.lef.org/magazine/mag2003/images/2003_preprint_bio_08.jpg
"Fig. 3. Representation of the results of longevity studies conducted
by BioMarker. The black line shows the life span of control mice who
consumed a normal number of calories. The red line shows the life span
of mice subjected to caloric restriction starting in old age. The blue
line shows the life span of mice subjected to caloric restriction,
starting very early in life. A major finding is that CR extended the
remaining life span by the same proportion in both experimental
groups."
Now, that isn't the same thing as claiming that "late-life CR
increased the mean and maximum life span of mice by approximately
40%". Indeed, it seems unlikely (from eyeballing the graph) that
they've even clearly extended species max LS: not a 45-month-old mouse
for sure, & perhaps not even a 40-month-old (which would perhaps be
'good enough' in a small cohort). Still, it's rpretty damned exiciting
if true. For this result, the article cites:
Cao SX, Dhahbi JM, Mote PL, Spindler SR. Genomic profiling of
short-and long-term caloric restriction in the liver of aging mice.
Proc Natl Acad Sci USA, 98:10630-10635, 2001.
... but that study does not report such a result. Several previous
studies (all of them not well-designed, however) have found that CR
stops extending LS at about 17-18 mo of age (~52-55 human-equivalent
years); however, there have been methodological problems with all of
these studies. Perhaps Spindler et al finally did a PROPER late-life
study?? Still, it's hard to believe that late-life CR could yield
results fully proportional to those resulting from intervening earlier
in life.
Also: what exactly is "late-life"? In the PNAS paper above,
"late-life" actually meant 27 months, which is late-life indeed --
say, 82 human-equivalent years! I don't THINK that's quite what
they've done, based on the graph; it'd sure be nice to BioMarker's
research suggests it is possible that the ability of CR to extend life
span in old animals occurs because it may be able to reverse aging and
rejuvenate the elderly, not just slow down the aging process. If this
is so, then drugs that mimic the effects of CR should be able to
achieve both these objectives.
I can only laud their projected research plans:
"1. Further research to explore the anti-aging, lifespan extending
effects of metformin, including life span studies, studies to
determine the optimal dosage and administration of the drug, the
search for analogs of metformin that are more potent with fewer side
effects, and the combining of metformin with other drugs."
... and would like to see independent confirmation of the late-life
effect.
-Michael
1. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM,
Walker EA,
Nathan DM.
Reduction in the incidence of type 2 diabetes with lifestyle
intervention or
metformin.
N Engl J Med. 2002 Feb 7;346(6):393-403.
PMID: 11832527 [PubMed - indexed for MEDLINE]
2: Garber AJ, Larsen J, Schneider SH, Piper BA, Henry D.
Simultaneous glyburide/metformin therapy is superior to component
monotherapy
as an initial pharmacological treatment for type 2 diabetes.
Diabetes Obes Metab. 2002 May;4(3):201-8.
PMID: 12047399 [PubMed - indexed for MEDLINE]
--
The illegal invasion of Iraq has been planned for nearly a decade.
9-11, human rights, & WMD are post-hoc justifications. The real
motive: lust for global empire. http://www.sundayherald.com/27735
http://www.newamericancentury.org/RebuildingAmericasDefenses.pdf
Tom Kobzina
Would taking Metformin along with practicing CR be good, bad, or unnecessary?
Is there a test which would help to answer this question?
Steve Harris
with fasting insulins lower than reference, and yet also
good glucose control (you didn't give us your fasting
glucose, but I assume it's good)
So far as metformin goes, it would be a very dumb idea to
take it with blood glucoses anywhere near the lower end of
the range. Your brain works on glucose, and even in
starvation needs 50% of its calories as such. Do you want to
chronically starve it of its main energy source?
We don't have the data for metformin and life span
extension, even with rodents. It's a good hypothesis, but a
good hypothesis for further testing. It would be a dumb
thing to bet your life on if you don't have diabetes and
have no other reason to lower your glucose. Metformin is not
a totally benign drug. Depending on dose it has caused fatal
liver damage.
SBH
"Tom Kobzina" <tkob...@msn.com> wrote in message
news:2cc7ec87.03042...@posting.google.com...
Kingsley G. Morse Jr.
their considerable technical expertise to trying
to duplicate earlier results for vitamin B5,
chromium and charcoal, which have been found to
extend lifespan as much or more than metformin in
rodents and fruit flies.
Thanks,
Kingsley
--
If email to me bounces, make sure you deleted the D from the end of my
username in my email address.
mystique
Would you please cite studies about "vitamin B5, chromium and
charcoal, which have been found to extend lifespan"?
thanks
mystique
cha...@nas.com (Kingsley G. Morse Jr.) wrote in message news:<b86di8$a52$1...@debian1.loaner.com>...
Nelson J. Navarro
"Michael" <mik...@lycos.com> wrote in message
news:69779556.03042...@posting.google.com...
> All:
>
> ... the Bush chickenhawks credible??
That depends on the context...with regard to their apparent plan to turn the
U.S. into some kind of a fascist global empire, I would say unfortunately,
yes, they appear to be credible.
>
>
> ... which indicates that metformin is far superior to other
> insulin-sensitizers in altering gene expression in ways parallel to CR
> (for whatever that's worth). Of especial interest: it works "better"
> (?) than metformin plus glipizide. This keeps the result tantalizing
> to me in light of the fact that Glipizide (glyburide) plus metformin
> is NOT as close a parallel to the effects of CR as is metformin alone,
> whereaas in humans "Simultaneous glyburide/metformin therapy is
> superior to component monotherapy as an initial pharmacological
> treatment for type 2 diabetes" (2). Ie, this again reinforces the
> broader overlap beyond glucose-metabolic genes, AND has a certain
> suggestive possibility to refute the objection about metformin vs.
> lifestyle given above.
>
Did you see the following?
Clin Cardiol 2001 Feb;24(2):151-8 Related Articles, Links
Oral antidiabetic treatment in patients with coronary disease: time-related
increased mortality on combined glyburide/metformin therapy over a 7.7-year
follow-up.
Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A,
Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M.
Cardiac Rehabilitation Institute, the Chaim Sheba Medical Center,
Tel-Hashomer, Israel.
BACKGROUND: A sulfonylurea--usually glyburide--plus metformin constitute the
most widely used oral antihyperglycemic combination in clinical practice.
Both medications present undesirable cardiovascular effects. The issue
whether the adverse effects of each of these pharmacologic agents may be
additive and detrimental to the prognosis for coronary patients has not yet
been specifically addressed. HYPOTHESIS: This study was designed to examine
the survival in type 2 diabetics with proven coronary artery disease (CAD)
receiving a combined glyburide/metformin antihyperglycemic treatment over a
long-term follow-up period. METHODS: The study sample comprised 2,275
diabetic patients, aged 45-74 years, with proven CAD, who were screened but
not included in the bezafibrate infarction prevention study. In addition,
9,047 nondiabetic patients with CAD represented a reference group. Diabetics
were divided into four groups on the basis of their therapeutic regimen:
diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a
combination of the latter two (n = 253). RESULTS: The diabetic groups
presented similar clinical characteristics upon recruitment. Crude mortality
rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%,
p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%),
324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients
(43.9%) on combined treatment (p<0.000001). Time-related mortality was
almost equal for patients on metformin and on combined therapy over an
intermediate follow-up period of 4 years (survival rates 0.80 and 0.79,
respectively). The group on combined treatment presented the worst prognosis
over the long-term follow-up, with a time-related survival rate of 0.59
after 7 years, versus 0.68 and 0.70 for glyburide and metformin,
respectively. After adjustment to variables for prognosis, the use of the
combined treatment was associated with an increased hazard ratio (HR) for
all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96),
whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and
HR 1.26 (95% CI 0.81-1.96), respectively. Conclusions: We conclude that
after a 7.7-year follow-up, monotherapy with either glyburide or metformin
in diabetic patients with CAD yielded a similar outcome and was associated
with a modest increase in mortality. However, time-related mortality was
markedly increased when a combined glyburide/metformin treatment was used.
PMID: 11460818
I 'd like to see either a 'glitazone in combination with a PPAR alpha
agonist, e.g., fish oil; or a dual acting PPAR alpha and gamma agonist,
e.g., "ragaglitazar"; (along with high dose B vitamins, high dose vitamin D,
acetyl-l-carnitine and grape seed extract, for that matter), vs CR and
metformin.
Am J Physiol Endocrinol Metab 2003 Apr;284(4):E841-54
Dual PPARalpha /gamma activation provides enhanced improvement of insulin
sensitivity and glycemic control in ZDF rats.
Brand CL, Sturis J, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF,
Andersen B, Ye JM, Sauerberg P, Wassermann K.
Research and Development, Novo Nordisk, DK-2880 Bagsvaerd, Denmark.
Improvement of insulin sensitivity and lipid and glucose metabolism by
coactivation of both nuclear peroxisome proliferator-activated receptor
(PPAR)gamma and PPARalpha potentially provides beneficial effects over
existing PPARgamma and alpha preferential drugs, respectively, in treatment
of type 2 diabetes. We examined the effects of the dual PPARalpha/gamma
agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in
early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and
compared them with treatment with the PPARgamma preferential agonist
rosiglitazone. Despite normalization of hyperglycemia and Hb A(1c) and
reduction of plasma triglycerides by both compounds in both prevention and
early intervention studies, ragaglitazar treatment resulted in overall
reduced circulating insulin and improved insulin sensitivity to a greater
extent than after treatment with rosiglitazone. In late-intervention
therapy, ragaglitazar reduced Hb A(1c) by 2.3% compared with 1.1% by
rosiglitazone. Improvement of insulin sensitivity caused by the dual
PPARalpha/gamma agonist ragaglitazar seemed to have beneficial impact over
that of the PPARgamma-preferential activator rosiglitazone on glycemic
control in frankly diabetic ZDF rats.
PMID: 12475752
Regards,
Nelson
> --
> The illegal invasion of Iraq has been planned for nearly a decade.
> 9-11, human rights, & WMD are post-hoc justifications. The real
> motive: lust for global empire. http://www.sundayherald.com/27735
> http://www.newamericancentury.org/RebuildingAmericasDefenses.pdf
Absolutely.
Tim Tyler
: Would you please cite studies about "vitamin B5, chromium and
: charcoal, which have been found to extend lifespan"?
B5:
[1a] The Use of Drosophila Melanogaster as a Screening Agent for Longevity
Factors. I. Pantothenic Acid as a Longevity Factor in Royal Jelly. Thomas
S Gardner, Journal of Gerontology 1(3) (1948): 1-8.
[1b] The Use of Drosophila Melanogaster as a Screening Agent for Longevity
Factors. II. The Effects of Biotin, Pyridoxine, Sodium Yeast Nucleate, and
Pantothenic Acid on the Life Span of the Fruit Fly. Thomas S Gardner,
Journal of Gerontology 1(3) (1948): 9-13
Chromium:
[5a] Composition and Biological Activity of Chromium-Pyridine Carboxylate
Complexes. GW Evans and DJ Pouchnik, Journal of Inorganic Biochemistry 49,
pg 177-187 (1993). Describes the action of dietary chromium picolinate
(relative to chromium chloride and chromium nicotinate) in reducing
glycation & plasma glucose levels in rats as they aged.
[5b] Longevity effect of chromium picolinate--'rejuvenation' of
hypothalamic function? McCarty MF in Med Hypotheses 1994 Oct;43(4):253-65
"The first rodent longevity study with the insulin-sensitizing nutrient
chromium picolinate has reported a dramatic increase in both median and
maximal lifespan.." Gives additional information about the
Evans-Meyer-Pouchnik chromium picolinate experiment on rats: Cohort
maximum lifespan (last survivor) was 48 months, extending the previous
species maximum by 15%.
[5c] Chromium picolinate increases longevity. Evans GW, Meyer LK in AGE
(the Journal of the American Aging Association) Oct 1992; 15(4), 134.
[5d] Chromium Picolinate. Gary W Evans, (1996) ISBN 0895299119. Gives
additional information about the Evans-Meyer-Pouchnik chromium picolinate
experiment on rats: Mean lifespan extension of 27%
[5e] The Longevity Factor: Chromium Picolinate. RA Passwater, (1993), ISBN
0879836199.
(all from http://mcp.longevity-report.com/)
Activated charcoal seems to work in fruit flies - e.g.
http://keithlynch.net/cryonet/83/72.html - but I don't
know about mice.
--
__________
|im |yler http://timtyler.org/ t...@tt1.org
Tim
There are other constituents of royal jelly that are of at least
mild interest. The relationship of royal jelly proteins to a protein
in D. radiodurans (a bacterium highly resistant to radiation
apparently in part to superior DNA repair)may or may not prove to be
of particular interest.
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10772900&dopt=Abstract
www.pnas.org/cgi/content/full/98/9/5240
and other abstracts:
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11352630&dopt=Abstract
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12583195&dopt=Abstract
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12510789&dopt=Abstract
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12473193&dopt=Abstract
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11922114&dopt=Abstract
Regards
Tim
Tom Kobzina
of people who are insulin resistant, would be a greater concern.
Insulin drives glucose into the cells (mainly muscle cells) and out of
the blood and brain. Metformin improves the sensitivity of cells to
insulin, thereby lowering insulin and increasing brain glucose levels.
It should be fairly easy for anyone who carefully monitors himself--a
typical sci-le devotee--to tell if he has signs of hypoglycemia
(headache, excessive perspiration, irritability, and trembling).
I understand that metformin is contraindicated in people who are
hypocaloric or undernurished. Practiced diligently, CR diets are not
starvation diets nor are they nutritionally sub-par.
As far as potential liver damage from using metformin, it seems to me
that elevated ALT and AST readings would provide a sufficient warning.
"Steve Harris" <sbha...@ix.RETICULATEDOBJECTcom.com> wrote in message news:<b875no$bo1$1...@slb6.atl.mindspring.net>...
Paul Wakfer
> It seems to me that chronically high insulin levels, a characteristic
> of people who are insulin resistant, would be a greater concern.
> Insulin drives glucose into the cells (mainly muscle cells) and out of
> the blood and brain. Metformin improves the sensitivity of cells to
> insulin, thereby lowering insulin and increasing brain glucose levels.
> It should be fairly easy for anyone who carefully monitors himself--a
> typical sci-le devotee--to tell if he has signs of hypoglycemia
> (headache, excessive perspiration, irritability, and trembling).
>
> I understand that metformin is contraindicated in people who are
> hypocaloric or undernurished. Practiced diligently, CR diets are not
> starvation diets nor are they nutritionally sub-par.
>
> As far as potential liver damage from using metformin, it seems to me
> that elevated ALT and AST readings would provide a sufficient warning.
Very well stated, Tom. I totally agree.
I practice moderate CR and also take 1 gram of metformin tid.
--Paul Wakfer (was: Tom Matthews)
MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity & quality
Thomas Carter
Hi,
I have a list of things to study which includes among other
interventions all the supplements Paul takes that I don't. Maybe this
is a good time to do Metformin.
As Steve implies it would seem counter intuitive that Met would
help those who have excellent insulin/glucose control, such as most
CRONIEs should, especially those who eat frequent small, low carb
meals and take other precautions against the post prandial glucose
spike.
Michael's post about similar gene expression changes would also
tend deemphasize Met for CRONIEs.
A strong point against the study Nelson posted is that it was not
randomised, and therefore Met may have been prescribed to the more
severe cases. Never the less it does give some indication that Met may
not be that beneficial.
Are there counter points? Other good reasons to take Met?
Thomas
Paul Wakfer
The situation here involves the relative degrees of all these points.
Glucose and insulin control and the negative effects of lack of such
control is not something that is black and white. Nor is it even a one
dimensional continuum. In addition, there are some studies showing
benefits of metformin which don't appear to relate directly to
glucose/insulin control.
It is possible that if one practives very strict CR then metformin may
not be of any additional benefit. However, very strict CR can also
have negative effects.
I only practice moderate CR and consider that, particularly at my age,
all the evidence of benefits of metformin suggest that its addition
will benefit my health and longevity. I take many liver strengthening
supplements and closely monitor my liver enzymes for signs of any harm
from metformin or anything else.
BTW, *average* blood glucose is still the most important number to aim
at lowering (without incurring hypoglycemia), even more important than
lowering spikes. The non-enyzmatic glycation rate will always be
reduced by reducing the fasting blood glucose, and for that reason
lowering fasting blood glucose is probably a more effective
antiglycation measure than anything else.
> Michael's post about similar gene expression changes would also
> tend deemphasize Met for CRONIEs.
Once again this depends on the degree of CR which one is practicing.
Also don't forget, the gene expression results are not for humans. It
is not clear at this time how much CR benefits humans wrt longevity.
This is another reason why I am taking metformin (for which, granted,
it is also not clear how much it benefits human longevity).
Unfortunately, even a gram of metformin daily does not appear to be
very helpful for *my* fasting blood glucose which remains higher than
I would like to see it in spite of all my efforts to lower it.
> A strong point against the study Nelson posted is that it was not
> randomised, and therefore Met may have been prescribed to the more
> severe cases. Never the less it does give some indication that Met may
> not be that beneficial.
> Are there counter points? Other good reasons to take Met?
As I mentioned above, yes. For example, here is study showing that it
lowers cardiovascular risk factors by reducing plasma plasminogen
activator inhibitor-1 (PAI-1).
--Paul Wakfer
Thomas Carter
Thx for the reply. I will keep an open mind on Met and make a study of
it in due time.
t...@morelife.org (Paul Wakfer) wrote in message news:<4f0e9375.03050...@posting.google.com>...
>
> BTW, *average* blood glucose is still the most important number to aim
> at lowering (without incurring hypoglycemia), even more important than
> lowering spikes. The non-enyzmatic glycation rate will always be
> reduced by reducing the fasting blood glucose, and for that reason
> lowering fasting blood glucose is probably a more effective
> antiglycation measure than anything else.
>
Do you have any evidence for this? I have only one paper and it
all but states flatly that the postprandial spike is more important.
The link to the full text no longer works, but I have most of it in my
summary below.
Thomas
Abstract
Although a traditional goal of glycemic control in the treatment of
diabetes mellitus is to normalize fasting plasma glucose, emerging
data indicate that modulation of postprandial plasma glucose levels
plays an important role in overall glycemic control. This article
reviews the evidence linking postprandial glucose levels with
long-term indices of diabetes control, such as glycosylated
hemoglobin, lipid abnormalities, and the risk of microvascular and
macrovascular complications. Early in the development of type 2
diabetes, the initial burst of insulin release in response to food
intake is compromised, allowing postprandial hyperglycemia to develop.
Meal-associated hyperglycemia further contributes to increase insulin
resistance and decrease insulin production. Evidence of a strong
correlation between high postprandial glycemic levels and the
development of vascular complications underscores the significance of
treating mealtime glycemia. Emerging drugs that reduce postprandial
hyperglycemia include the D-phenylalanine derivative nateglinide,
amylin derivative pramlintide, and glucagon-like insulinotropic
peptide 94(8):804-809, 2001. © 2001 Southern Medical Association]
FULL TEXT
http://www.medscape.com/SMA/SMJ/2001/v94.n08/smj9408.01.bell/smj9408.01.bell-01.html
Introduction
The goal in the management of patients with type 2 diabetes is to
control fasting plasma glucose and glycosylated hemoglobin (HbA1c)
levels. In patients with well-controlled diabetes (HbA1c <7%, or
within 1% of normal) or glucose intolerance (fasting plasma glucose
level <126 mg/dL, and a 2-hour plasma glucose of 140 to 200 mg/dL
after 75 g of oral glucose), postprandial hyperglycemia has a greater
effect on HbA1c than fasting glucose levels. Jovanovic[1] recently
reported that the postprandial glucose level at 1 hour is the best
predictor of HbA1c in patients with well-controlled type 2 diabetes
mellitus. In addition, a French study of patients with type 2 diabetes
showed that glucose concentrations at 2 and 5 hours after a meal were
better predictors of the HbA1c than prebreakfast or prelunch
values.[2] Therefore, in patients with elevated HbA1c, the
postprandial plasma glucose levels may play a disproportionate role in
the genesis of both microvascular and macrovascular complications of
diabetes.
The recent change in plasma glucose threshold for the diagnosis of
diabetes was based on evidence such as that from the United Kingdom
Prospective Diabetes Study, which showed that 50% of patients with
type 2 diabetes already had one or more chronic complications by the
time it was diagnosed.[3] The standard for diagnosis is still a plasma
glucose level >200 mg/dL at 2 hours after a 75-g glucose load.
Postprandial levels >200 mg/dL are seen in 97% of patients with a
fasting plasma glucose value of 126 mg/dL. In addition, 52% of
patients with fasting plasma glucose <126 mg/dL still have
postprandial levels >200 mg/dL. Therefore, patients with fasting
glucose levels between 110 and 126 mg/dL should undergo a 2-hour, 75-g
glucose challenge to assess their postprandial glucose levels, since
early detection and treatment can delay or prevent the onset of
complications.[3]
Why is Glucose Control so Important?
In the fasting state, the suppression of insulin production and
stimulation of glucagon production control the concentration of blood
glucose. These processes allow the liver to mobilize glucose from its
glycogen stores and synthesize glucose from amino acids and pyruvate
(gluconeogenesis). In addition, when insulin levels are low, the
uptake of glucose by muscle is minimized, and adipocytes release free
fatty acids. This homeostatic mechanism effects a stable plasma
glucose level in the fasting state so that the brain, which has no
energy stores, has a sufficient supply of nutrients for normal
activity.
In the fed state, insulin is released in two phases. The first phase,
a short, small burst released on food intake or an increase in plasma
glucose concentration, preempts and decreases the postprandial glucose
elevation. Later, a more sustained, second-phase insulin release
directly proportional to the plasma glucose elevation occurs. In
response to this biphasic release of insulin, the liver takes up
glucose, converting it to glycogen (animal starch). The muscle and
adipose tissues also take up glucose, storing it as glycogen and
triglycerides, respectively. Furthermore, the production of free fatty
acids in adipocytes is suppressed. The loss of first-phase insulin
release has adverse metabolic and physiologic consequences, even if
the second-phase release is adequate or even excessive.
First-Phase Insulin Release
One of the earliest changes in the development of type 2 diabetes is
the loss of first-phase insulin release, which occurs with fasting
glucose levels of about 110 mg/dL. The loss can be documented by
measuring plasma insulin concentrations over the 10 minutes
immediately after an intravenous glucose load, calculated on the basis
of the patient's weight. Lack of first-phase insulin release, an
excellent predictor of both types of diabetes, is thought to be the
earliest sign of the adverse effects of hyperglycemia on
insulin-producing b-cells and insulin-sensitive tissues
(glucotoxicity).[4] When the first-phase insulin response fails,
plasma glucose levels rise sharply after a meal. Initially, this
precipitates an increased stimulation of second-phase insulin release
that, in the early stages of glucose intolerance, may lead to
postprandial hypoglycemia resulting from elevated plasma insulin
remaining after the nutrients have disappeared.[5] High insulin levels
also cause downregulation of the insulin postreceptor pathways on the
muscle and fat cells, thus increasing insulin resistance.[6]
The higher glucose level in islet cells prompts a decrease in
glucose-transporter activity, resulting in a reduction of insulin
release,[7] which is reversed by a decrease in plasma glucose level.
If there is no decrease, the prolonged hyperglyce-mia will eventually
cause an accelerated loss of insulin-producing b-cells in both type 1
and type 2 diabetes.[4] Thus, metabolic loss of first-phase insulin
release results in postprandial hyperglycemia, an increase in insulin
resistance, and a further decrease in insulin production.
Effect of Postprandial Glucose Levels on Microvascular Complications
The effects of postprandial hyperglycemia on the development of
microvascular complications of diabetes have been well documented.
There is evidence that uncontrolled glycemic peaks activate protein
kinase C, the enzyme that may link hyperglycemia to microvascular
complications.[8] Elevated glucose levels lead to increased
intracellular synthesis of diacylglycerol, which, in conjunction with
elevated intracellular calcium, activates protein kinase C.[8] The
activity of protein kinase C impairs contraction of smooth muscle
cells or pericytes, increases production of basement membrane
materials, and enhances cell proliferation and capillary permeability.
Thus, activation of protein kinase C by postprandial hyperglycemia
could be responsible for microvascular complications that may be
developing even in the early stages of diabetes.[8]
Data from the National Health and Nutrition Examination Survey showed
that patients who had 2-hour postprandial glucose levels of 194 mg/dL
had a threefold increase in the incidence of retinopathy, despite
normal fasting glucose levels.[3] Studies of Pima Indian and Egyptian
populations revealed a similar increase in the incidence of
retinopathy in subjects with normal fasting glucose levels but 2-hour
postprandial glucose values of >200 mg/dL.[3]
The development of microvascular complications in patients with type 2
diabetes has been documented in a number of clinical trials. In a
long-term study of complications in patients who had type 2 diabetes
for more than 25 years, Mohan et al[9] reported that postprandial
glucose levels were associated with diabetic nephropathy. In a recent
study of Pima Indian subjects, hyperfiltration, a precursor of
diabetic nephropathy, in subjects with impaired glucose tolerance was
found to increase with the onset of type 2 diabetes.[10] In a
population study, Beghi et al[11] showed that elevated fasting and
postprandial glucose levels, as well as prolonged disease duration,
were associated with an increased incidence of diabetic neuropathy.
Postprandial Glucose Levels and Macrovascular Complications
The glycemic threshold for the development of macrovascular
complications is lower than that for microvascular complications, so
there is more evidence for an association with postprandial glycemia.
Postprandial glucose elevations are associated with postprandial
hyperinsulinemia and higher plasma levels of triglycerides,
chylomicrons, chylomicron remnants, and free fatty acids. High
concentrations of free fatty acids have been associated with
endothelial dysfunction,[12] and high triglyceride levels have been
linked to low levels of high-density lipoprotein (HDL) cholesterol and
a preponderance of small, dense, low-density lipoprotein (LDL)
particles. Although only the relationship between fasting-state
hypertriglyceridemia and coronary artery disease (CAD) has been
established, postprandial high triglyceride levels most likely have
the same effect.[13] In addition, high postprandial glucose levels
result in protein and cellular glycosylation. Glycosylated LDL
particles are more easily oxidized and taken up by macrophages through
the scavenger receptor. This, in turn, leads to higher foam cell
production, and, ultimately, atherosclerotic plaque. In addition,
glycosylated LDL also stimulates platelet aggregation. Glycosylated
HDL is less efficient than nonglycosylated in transporting cholesterol
back to the liver for metabolism. Additionally, the formation of
advanced glycosylated end products in the collagen of the vessel wall
itself may directly stimulate or accelerate the atherosclerotic
process.[14]
Acute increases in plasma glucose also stimulate the production of
free radicals, another factor involved in the atherosclerotic
process.[15] Excessive postprandial plasma glucose levels have also
been associated with transient hypercoagulability resulting from
increased thrombin production and decreased fibrinogen breakdown.
These, in turn, result from the overproduction of plasminogen
activator inhibitor, which directly inhibits tissue plasminogen
activator activity. Control of postprandial hyperglycemia reverses
this hypercoagulable state.[16]
Endothelial dysfunction is another consequence of postprandial
hyperglycemia. Activation of protein kinase C in the endothelium
increases adhesion molecules[17] that facilitate leukocyte uptake into
the blood vessel wall; increases production of the vasodilators nitric
oxide and prostaglandin; increases expression of the vasoconstrictor
endothelin; and induces platelet aggregation.[8]
The Honolulu Heart Study found that the risk of CAD correlated with
plasma glucose levels measured 1 hour after a 50-g oral glucose load.
The incidence of CAD was twice as high in patients with postprandial
plasma glucose levels between 157 and 189 mg/dL as in those with
levels <144 mg/dL,[18] and the incidence of sudden death was doubled
with postprandial plasma glucose levels >151 mg/dL.[19] The Whitehall
Study of British male civil servants showed that plasma glucose levels
>96 mg/dL 2 hours after a meal were associated with a twofold increase
in mortality from CAD.[20] Another British study, the Islington
Diabetes Survey, reported that the incidence of major CAD (defined as
major electrocardiographic changes or myocardial infarction) was 17%
in subjects with a 2-hour postprandial glucose level between 120 and
180 mg/dL, compared with 9% in subjects with levels <120 mg/dL.[21]
The Bedford Survey showed that protection from CAD was lost in
patients with elevated postprandial glucose.[22] By studying the
progression of CAD in young men with previous myocardial infarction,
Bavenholm et al[23] found that fasting and postprandial plasma glucose
levels were independently related to disease progression. The Oslo
Study indicated that the nonfasting plasma glucose level was a
predictor of fatal stroke in diabetic patients, with the risk
increasing by 13% for each 18-mg/dL elevation in postprandial
glucose.[24] The Diabetes Intervention Study also showed that
postprandial, not fasting, hyperglycemia was an independent risk
factor for myocardial infarction and cardiac death.[25]
The Hoorn Study documented an increased risk of peripheral vascular
disease in elderly patients with diabetes and in subjects with
impaired glucose tolerance.[26] Ankle to brachial pressure indices
<0.9 were found in 7% of nondiabetic subjects, 9.5% of subjects with
impaired glucose tolerance, 15.1% of patients with newly diagnosed
diabetes, and 20.9% of patients with established type 2 diabetes.
After logistical regression analysis and correction for other
cardiovascular risk factors, the 2-hour postprandial plasma glucose
value remained an independent risk factor for peripheral vascular
disease, whereas plasma insulin did not.[26]
Overexposure to insulin in response to postprandial hyperglycemia has
been shown to be a risk factor for cardiovascular events. The Paris
Prospective Study found that postprandial hyperinsulinemia was a
better predictor for fatal CAD than either hyperglycemia or
diabetes.[27] Similarly, the Helsinki Policemen Study revealed an
independent association between fatal and nonfatal CAD events and 1-
and 2-hour postprandial insulin levels that was stronger than that
with fasting plasma insulin levels.[28] Finally, a recent report
suggested an association between postprandial levels and intellectual
function in elderly Alzheimer's patients who were not ApoE4
positive.[29]
Another factor associated with postprandial hyperglycemia is
postprandial hyperlipidemia. Elevated triglyceride levels after a meal
predict the development of CAD and are associated with carotid artery
atherosclerosis in nonobese white subjects.[30] Therefore, a reduction
of postprandial glucose levels, which also reduces plasma insulin and
lipids after a meal, could reduce the incidence of CAD
Methods of Controlling Postprandial Hyperglycemia
Postprandial glycemic control is important in avoiding microvascular
and macrovascular complications, lowering insulin resistance,
restoring normal insulin secretion, and avoiding complications in the
offspring of women with diabetes. It is recommended that the treatment
of diabetes include methods that lower both fasting and postprandial
glucose levels. (He lists no methods other than drugs!!)
Paul Wakfer
> Hi Paul,
> Thx for the reply. I will keep an open mind on Met and make a study of
> it in due time.
>
> t...@morelife.org (Paul Wakfer) wrote in message news:<4f0e9375.03050...@posting.google.com>...
> >
> > BTW, *average* blood glucose is still the most important number to aim
> > at lowering (without incurring hypoglycemia), even more important than
> > lowering spikes. The non-enyzmatic glycation rate will always be
> > reduced by reducing the fasting blood glucose, and for that reason
> > lowering fasting blood glucose is probably a more effective
> > antiglycation measure than anything else.
> >
> Do you have any evidence for this?
The "evidence" is logical, based on the mechanism by which glucose
causes glycation. It is a dynamical process involving the chance of a
glucose molecule approaching an amine tail of a protein chain in the
right orientation and close enough to react. The rate of any such
reactions will change monotonically with the concentrations of the
reacting components (that is part of the meaning of "non-enzymatic").
> I have only one paper and it
> all but states flatly that the postprandial spike is more important.
I think perhaps you have misinterpreted this. The evidence is very
sparse, but there are hints that the glycation rate increases faster
than linearly with glucose concentration. This would mean that a
fluctuating glucose concentration curve with a larger amplitude would
be more glycating than one with a smaller amplitude given that both
have the same average or area under the curve (AUC). However, reducing
the AUC (by reducing the base level about which it flutuates) is going
to simultaneously reduce the glycation rate for *all* portions of the
curve. It may also be true that even if you do not reduce the AUC then
it is important to reduce the spikes. If this is true, then in the
case of some wildly spikey situations, I suppose it may even be
possible to reduce the total glycation by reducing the spikes even if
the AUC rises a little, but I think that would be very rare and is a
really quite insignificant phenomenon.
Don't forget that reducing postprandial spikes will generally also
reduce the effective average level of glucose concentration (which is
equivalent to the AUC). I think what the paper is really saying is
that reducing the spikes may be the most effective method by which to
reduce the AUC as well as reducing any multiplied glycation rate which
high concentrations cause. Don't forget that it is much easier to
drastically reduce spikes than it is to reduce the fasting basal level
(ie the lower end of the amplitude swings) without inducing
hypoglycemia.
The particular value of metformin for this process is that it reduces
both the base level about which ones glucose flutuates and also the
upward excursions from this base level (the heighth of the spikes
above it).
It is also important to note that the paper that you quoted refers
only to the insulin resistant or diabetic condition where phase one
insulin release is greatly reduced leading to high levels of
postprandial glucose concentration of relatively long duration (not
really spikes). For this situation in particular, it would clearly be
most helpful to lower the level of these long duration swings in
glucose level if for no other reason than because it would lower the
average level enormously. However, a healthy, already insulin
sensitive person, who is attempting to optimize, likely has narrow
spikes rather than ones of long duration. So for this person, reducing
the height of the spikes will have less effect on the average than for
an insulin resistant or diabetic person. Thus, for a healthy insulin
sensitive person, I think that reducing the average is the most
important aim, so long as one also reduces the heighth of the spikes
by at least as much in the process.
Bruce Bowen
> with fasting insulins lower than reference, and yet also
> good glucose control (you didn't give us your fasting
> glucose, but I assume it's good)
>
> So far as metformin goes, it would be a very dumb idea to
> take it with blood glucoses anywhere near the lower end of
> the range. Your brain works on glucose, and even in
> starvation needs 50% of its calories as such. Do you want to
> chronically starve it of its main energy source?
>
> We don't have the data for metformin and life span
> extension, even with rodents. It's a good hypothesis, but a
> good hypothesis for further testing. It would be a dumb
> thing to bet your life on if you don't have diabetes and
> have no other reason to lower your glucose.
What about your typical, non-diabetic, slightly overweight, 40ish+
male, with 230 total Cholesterol and intrinsically low HDL? Not your
anorexic head case.
The Life Extension Foundation has a whole spread on
Metformin/Glucophage on their current/May web page, mentioning all
sorts of wonderful effects and new data on it's CR Mimetic effects.
> Metformin is not
> a totally benign drug. Depending on dose it has caused fatal
> liver damage.
>
This is true of
Vitamin A
Niacin
Cognac, Jack Daniels, etc.
Statins
...
etc.
-Bruce
Steve Harris
"Bruce Bowen" <bru...@my-deja.com> wrote in message
news:b824a8a0.03050...@posting.google.com...
> The Life Extension Foundation has a whole spread on
> Metformin/Glucophage on their current/May web page,
mentioning all
> sorts of wonderful effects and new data on it's CR Mimetic
effects.
The only CR mimetic effect I'm interested in is prolonged
life.
>
> > Metformin is not
> > a totally benign drug. Depending on dose it has caused
fatal
> > liver damage.
> >
>
> This is true of
>
> Vitamin A
> Niacin
> Cognac, Jack Daniels, etc.
> Statins
> ...
> etc.
Yes, but those dogs all bark before they bite. Metformin's
an especially scary drug in this regard, causing liver
necrosis in those susceptible without a lot of warning
first, and at doses which are (or were thought to be) more
or less therapeutic. We gradually learned not to use it in
people with congestive heart failure, and stay on the low
end of what we used to consider the therapeutic range. The
funny deaths delayed its acceptance in the US by at least 15
years. Don't think of metformin like Jack Daniels or
statins, think of it like digitalis and coumadin. The idea
of skinny nondiabetic calorie restricted laypeople willy
nilly using it as part of a life extension program in the
absence of good data for the pro side, and probably without
good lab support in many cases, scares me. Not a good idea.
SBH
Steve Harris
who are
> hypocaloric or undernurished. Practiced diligently, CR
diets are not
> starvation diets nor are they nutritionally sub-par.
Which is not to say that they provide all the protection
against liver toxicity from hepatotoxic challenges, as a
normal diet. We don't KNOW what it is about malnutrition
that makes the liver especially vulnerable. For all I know
it could be the low energy itself, and have nothing to do
with protein or vitamins. Merely assuming otherwise is dumb,
when it's your life on the line. Does the liver process
lactate as well, in undernutrition, as it does if it has
abundant energy and glucose? My guess is that it doesn't.
So why take a drug which will stress it more? The LDH on
your liver enzyme panel tells you exactly NOTHING about how
well your liver's lactate processing system is working. Nor
really the AST and ALT-- they're simply markers of acute
liver cell damage and leakage.
> As far as potential liver damage from using metformin, it
seems to me
> that elevated ALT and AST readings would provide a
sufficient warning.
For some things. They won't tell you that you're close to
main type of metformin toxicity, which is lactic acidosis.
Metformin itself isn't liver-metabolized (though lactate
is), so the main thing that triggers metformin buildup is
reduced renal clearance. That can happen on a day you get
dehydrated, take an NSAID, exercise especially hard, get
infected-- who knows? The other end of the coin is how much
stress you're putting on your lactate production and
clearance systems, which involve your skeletal muscles and
your liver and your cardiac and even pulmonary function. As
for your renal function, it even falls with aging, and how
close you are to the edge of starting to develop lactic
acidois when you're on metformin is something for which
there's no medical test. You get your creatinine levels
checked regularly, you stay on the lower dose range of the
drug, cross your fingers, and hope. Kind of dumb if you're
not treating diabetes.
But hey, don't listen to me. Do whatever the hell you like.
SBH
Tim Tyler
: "Tom Kobzina" <tkob...@msn.com> wrote in message
:> I understand that metformin is contraindicated in people
:> who are hypocaloric or undernurished. Practiced diligently, CR
:> diets are not starvation diets nor are they nutritionally sub-par.
: Which is not to say that they provide all the protection
: against liver toxicity from hepatotoxic challenges, as a
: normal diet. We don't KNOW what it is about malnutrition
: that makes the liver especially vulnerable. For all I know
: it could be the low energy itself, and have nothing to do
: with protein or vitamins. [...]
I imagine the liver gets a bit of a rest while on CR.
Does that make it lazy - and unable to respond to challenges?
If so, you might think that CR'd organisms would be more liable
to being poisoned. I don't think there's much evidence for
that - while there is definite evidence that CR protects
against a range of toxins.
CR is also likely to protect against those "hepatotoxic challenges"
that come from ingested toxins - by reducing their overall volume -
and of course it protects against age-related decline in liver function.
In Spindler's study of the changes with age of gene expression in the
liver he found that of the 46 liver genes whose expression changed
systematically with age, only 3 failed to respond positively to calorie
restriction.
- http://www.findarticles.com/cf_0/m0DED/2_22/79023126/print.jhtml
Steve Harris
"Tim Tyler" <t...@tt1.org> wrote in message
news:HEGK7...@bath.ac.uk...
> I imagine the liver gets a bit of a rest while on CR.
You can imagine all you like. I don't believe it. I've seen
evidence for extra liver toxicity of 13 cis retinoic acid,
ethoxyquin, and (still unpublished) toxicity from WR-2721 in
CR mice. Now, admitadly that's using iso-dosing per animal,
so smaller CR animals are getting the same amount of toxin
as larger slightly restricted or non-restricted ones. Still,
if CR helped the liver deal with toxins on an absolute
basis, you should see a CR animal able to deal with a larger
absolute dose of a toxin, not just a larger dose/kg.
> Does that make it lazy - and unable to respond to
challenges?
>
> If so, you might think that CR'd organisms would be more
liable
> to being poisoned. I don't think there's much evidence
for
> that - while there is definite evidence that CR protects
> against a range of toxins.
Okay, what studies? Mine is below. I saw the livers, and
they didn't look good.
> CR is also likely to protect against those "hepatotoxic
challenges"
> that come from ingested toxins - by reducing their overall
volume -
> and of course it protects against age-related decline in
liver function.
I know of no evidence that CR protects against age-related
decline in liver function. It might, or it might not-- it
would be a very difficult thing to test, since the decline
mentioned is subtle and hard to test for.
As for CR protecting against toxins in food by cutting down
food and thus total toxin dose, that may be true, but it
doesn't apply to the sort of supplementation issues we're
discussing here.
> In Spindler's study of the changes with age of gene
expression in the
> liver he found that of the 46 liver genes whose expression
changed
> systematically with age, only 3 failed to respond
positively to calorie
> restriction.
But such studies are hard to interpret to say the least. Old
mice get fat. Are these gene changes due to aging or
obesity? I have little doubt that CR protects against
whatever gene expression changes are caused by obesity. But
so what?
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]
Thomas Carter
> : "Tom Kobzina" <tkob...@msn.com> wrote in message
>
> :> I understand that metformin is contraindicated in people
> :> who are hypocaloric or undernurished. Practiced diligently, CR
> :> diets are not starvation diets nor are they nutritionally sub-par.
>
> : Which is not to say that they provide all the protection
> : against liver toxicity from hepatotoxic challenges, as a
> : normal diet. We don't KNOW what it is about malnutrition
> : that makes the liver especially vulnerable. For all I know
> : it could be the low energy itself, and have nothing to do
> : with protein or vitamins. [...]
>
> I imagine the liver gets a bit of a rest while on CR.
Hi Tim,
Don't think so. The liver weight is reduced 35--40% in CR rodents.
> Does that make it lazy - and unable to respond to challenges?
The liver has been called a thousands organs in one sack. I would
imagine only the cells involved in metabolism are reduced while the
detoxification cells are relatively unaffected.
Thomas
Tim Tyler
: "Tim Tyler" <t...@tt1.org> wrote in message
:> I imagine the liver gets a bit of a rest while on CR.
: You can imagine all you like. I don't believe it.
I figure, less food -> less work for the liver.
: I've seen evidence for extra liver toxicity of 13 cis retinoic
: acid, ethoxyquin, and (still unpublished) toxicity from WR-2721 in
: CR mice. Now, admitadly that's using iso-dosing per animal,
: so smaller CR animals are getting the same amount of toxin
: as larger slightly restricted or non-restricted ones. Still,
: if CR helped the liver deal with toxins on an absolute
: basis, you should see a CR animal able to deal with a larger
: absolute dose of a toxin, not just a larger dose/kg.
I expect the results will depend somewhat on the toxin.
It would be pretty miraculuos if CR protected against
every possible poisoning route.
However, it does seem to help against a number:
Kainic acid and 3-nitropropionic acid:
``In the rats whose diet was restricted, the kainic acid caused much
less damage to hippocampal nerve cells than in those whose diet was
not restricted. Also, the kainic acid caused severe learning and
memory deficits in the control group, but little or no learning
and memory deficits in the dietary-restricted rats.
The results were even more obvious in the model of Parkinson's
disease and Huntington's disease. The toxin caused severe motor
problems in the normally fed rats, but had essentially no effect
on the rats that had been on the reduced calorie diet.
"The beneficial effects of the dietary restriction were striking,"
Mattson said. "The importance of these studies is that they
demonstrate that food restriction can reduce the vulnerability of
nerve cells in the brain to insults relevant to several different
human age-related disorders."''
- http://www.mc.uky.edu/mcpr/news/1999/January/mattson.htm
Thioacetamide:
``Previously we reported that moderate calorie restriction or diet
restriction (DR, calories reduced by 35% for 21 days) in male
Sprague-Dawley rats protects from a lethal dose of thioacetamide
(TA). DR rats had 70% survival compared with 10% in rats fed ad libitum
(AL) because of timely and adequate compensatory liver cell division
and tissue repair in the DR rats.'' - PMID: 12377994
Azoxymethane (a carcinogen) in: PMID: 2393850
...and PMID: 8631954 and PMID: 10444432 suggest CR may protect against
ammonia toxicity.
:> CR is also likely to protect against those "hepatotoxic
:> challenges" that come from ingested toxins - by reducing
:> their overall volume - and of course it protects against
:> age-related decline in liver function.
: I know of no evidence that CR protects against age-related
: decline in liver function. It might, or it might not-- it
: would be a very difficult thing to test, since the decline
: mentioned is subtle and hard to test for.
: As for CR protecting against toxins in food by cutting down
: food and thus total toxin dose, that may be true, but it
: doesn't apply to the sort of supplementation issues we're
: discussing here.
:> In Spindler's study of the changes with age of gene
:> expression in the liver he found that of the 46 liver
:> genes whose expression changed systematically with age,
:> only 3 failed to respond positively to calorie restriction.
: But such studies are hard to interpret to say the least. Old
: mice get fat. Are these gene changes due to aging or
: obesity? I have little doubt that CR protects against
: whatever gene expression changes are caused by obesity. But
: so what?
Avoiding objections such as that one is the reason why the
controls in studies are typically fed rationed diets that are
somewhat restricted - in order to dissociate the effects of
obesity avoidance from those of further calorie restriction.
The full text of Spindler's study is at:
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11535822
: 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. [...]
: PMID: 2394907 [PubMed - indexed for MEDLINE]
Thanks. I /think/ this is the first "negative" CR/toxin study I've
seen.
From your description, it sounds like the mice are being poisoned.
I can't clearly see whether that effect was significant - and as
you point out they are probably getting more toxin per gram of
body mass than the controls. I would guess the compounds
in question are toxic in a manner where CR doesn't offer much
protection.
Tim Tyler
: Tim Tyler <t...@tt1.org> wrote in message news:<HEGK7...@bath.ac.uk>...
:> I imagine the liver gets a bit of a rest while on CR.
: Don't think so. The liver weight is reduced 35--40% in CR rodents.
Surely a sign that it has less work to do! ;-)
David Wright
Steve Harris <sbha...@ix.RETICULATEDOBJECTcom.com> wrote:
>
>"Tim Tyler" <t...@tt1.org> wrote in message
>news:HEGK7...@bath.ac.uk...
>> I imagine the liver gets a bit of a rest while on CR.
>
>
>You can imagine all you like. I don't believe it. I've seen
>evidence for extra liver toxicity of 13 cis retinoic acid,
I should hope so. As I recall, 13-cis retinoic acid is better known
as Accutane and surely can do interesting things to your liver; I had
to get a monthly blood test while I was taking the stuff.
-- David Wright :: alphabeta at prodigy.net
These are my opinions only, but they're almost always correct.
"If I have not seen as far as others, it is because giants
were standing on my shoulders." (Hal Abelson, MIT)
Steve Harris
"David Wright" <wri...@clam.prodigy.net> wrote in message
news:1M_ta.965$pP7.81...@newssvr15.news.prodigy.com...
> In article <b99881$hts$1...@slb6.atl.mindspring.net>,
> Steve Harris <sbha...@ix.RETICULATEDOBJECTcom.com> wrote:
> >
> >"Tim Tyler" <t...@tt1.org> wrote in message
> >news:HEGK7...@bath.ac.uk...
> >> I imagine the liver gets a bit of a rest while on CR.
> >
> >
> >You can imagine all you like. I don't believe it. I've
seen
> >evidence for extra liver toxicity of 13 cis retinoic
acid,
>
> I should hope so. As I recall, 13-cis retinoic acid is
better known
> as Accutane and surely can do interesting things to your
liver; I had
> to get a monthly blood test while I was taking the stuff.
>
Yes, yes, it's well known that 13-CRA is liver toxic. What I
saw was EXTRA toxicity in the calorie restricted animals.
They died early at doses/animal that normal animals didn't
get any life shortening from.
13 CRA tox is probably much like vitamin A toxicity--a
matter of how much your liver can hold. More than that kills
you rapidly. CR animals have smaller livers, and that it's
it.
SBH
galya
> better known
> > as Accutane and surely can do interesting things to your
> liver; I had
> > to get a monthly blood test while I was taking the stuff.
> >
>
>
>
> Yes, yes, it's well known that 13-CRA is liver toxic. What I
> saw was EXTRA toxicity in the calorie restricted animals.
> They died early at doses/animal that normal animals didn't
> get any life shortening from.
>
> 13 CRA tox is probably much like vitamin A toxicity--a
> matter of how much your liver can hold. More than that kills
> you rapidly. CR animals have smaller livers, and that it's
> it.
>
L-carnitine may ameliorate Isotretinoin (Accutane) liver toxicity.
galya
J Eur Acad Dermatol Venereol 1999 Nov;13(3):205-9
L-carnitine supplementation in patients with cystic acne on
isotretinoin therapy.
Georgala S, Schulpis KH, Georgala C, Michas T Dermatological Clinic of
Athens University, A. Syngros, Hospital, Kesariani, Greece.
BACKGROUND: Patients with cystic acne (CA) on Isotretinoin (Iso)
therapy might present muscular symptoms as side effect of the drug.
Myalgia, weakness, hypotension are also some of the main
characteristics of carnitine (car) deficiency. METHODS: Two hundred
and thirty (N = 230) patients with CA were treated with Isotretinoin
(0.5 mg/kg per 24 h). All the patients were requested to visit our
out-patient department at the onset of muscular symptoms. Laboratory
tests including car (total, free, acylcarnitine) were determined in
blood and urine before treatment, at the onset of muscular symptoms
and after the end of a 45 day study. Fifty percent of the patients
with muscular involvement received L-carnitine (100 mg/kg per 24 h per
os) (group C) and 50% placebo (group P). RESULTS: Their laboratory
tests showed the well known increases of their liver enzymes and
lipids, whereas car blood levels were remarkably decreased at the
onset of their muscular symptoms and or at the end of the study. Their
supplementation with L-car, in patients of group C (N = 20) without
Iso discontinuation or reduction, resulted in the disappearance of
their muscular symptoms within 5-6 days and normalization not only of
the increased levels of their liver enzymes but also those of car, at
the 45 day of their therapy. Additionally, the patients who received
placebo (group P, N = 20) continued complaining for mualgias. The rest
of the patients (group A, N = 190) did not experience any muscular
symptoms, their laboratory tests showed elevation of liver enzymes and
lipids and a decrease in car levels in the blood whereas a remarkable
increase of car excretion was determined in their urine. CONCLUSIONS:
Iso therapy decreases car blood levels in patients with CA. L-car
supplementation might treat liver and muscular side effects of the
drug. These hopeful preliminary results need further investigation.
Publication Types: Clinical trial
PMID: 10642057, UI20105043
David Wright
Vitamin A toxicity? Surely you can't be serious! Why, I
saw someone on misc.health.alternative assure me that there
was no such thing as vitamin A toxicity.
Now, if you'll excuse me, I must go have my dinner -- a
heaping plateful of polar bear liver...