PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.
timo...@my-deja.com
fasting. This may be similar to Acipimox.
Nat Med. 2003 Mar;9(3):352-5. Epub 2003 Feb 3. Links
PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-
lipolytic effect.Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A,
Pfeffer K, Offermanns S.
Institute of Pharmacology, University of Heidelberg, Heidelberg,
Germany.
Nicotinic acid (niacin), a vitamin of the B complex, has been used for
almost 50 years as a lipid-lowering drug. The pharmacological effect
of nicotinic acid requires doses that are much higher than those
provided by a normal diet. Its primary action is to decrease lipolysis
in adipose tissue by inhibiting hormone-sensitive triglyceride lipase.
This anti-lipolytic effect of nicotinic acid involves the inhibition
of cyclic adenosine monophosphate (cAMP) accumulation in adipose
tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase.
A G-protein-coupled receptor for nicotinic acid has been proposed in
adipocytes. Here, we show that the orphan G-protein-coupled receptor,
'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-
G, human HM74), is highly expressed in adipose tissue and is a
nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74
results in a G(i)-mediated decrease in cAMP levels. In mice lacking
PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA)
and triglyceride plasma levels was abrogated, indicating that PUMA-G
mediates the anti-lipolytic and lipid-lowering effects of nicotinic
acid in vivo. The identification of the nicotinic acid receptor may be
useful in the development of new drugs to treat dyslipidemia.
PMID: 12563315 [PubMed - indexed for MEDLINE]
Related LinksGPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced
flushing. [J Clin Invest. 2005]Niacin mediates lipolysis in adipose
tissue through its G-protein coupled receptor HM74A. [Biochem Biophys
Res Commun. 2005](D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis
via the nicotinic acid receptor PUMA-G. [J Biol Chem. 2005]Niacin
induces PPARgamma expression and transcriptional activation in
macrophages via HM74 and HM74a-mediated induction of prostaglandin
synthesis pathways. [Biochem Pharmacol. 2006]G protein-coupled
receptor for nicotinic acid in mouse macrophages. [Biochem Pharmacol.
2002]See all Related Articles...
timo...@my-deja.com
Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):387-90. Links
Effects of acipimox on the lipolysis rate in subcutaneous adipose
tissue of obese subjects.Flechtner-Mors M, Jenkinson CP, Alt A, Adler
G, Ditschuneit HH.
Department of Internal Medicine, University of Ulm, Germany.
mario...@medizin.uni-ulm.de
BACKGROUND: Acipimox is a hypolipidaemic agent reducing serum
concentrations of triglycerides and non-esterified fatty acids.
Acipimox may reduce triglyceride synthesis by decreasing non-
esterified fatty acid availability from adipocytes, but this effect
has yet to be demonstrated in vivo. Lipolysis after acipimox treatment
was examined in subcutaneous adipose tissue of severely obese subjects
with associated metabolic disorders. METHODS: The microdialysis
technique was performed in abdominal subcutaneous adipose tissue of
eight hyperinsulinaemic subjects. After oral treatment with acipimox,
glycerol concentration was determined as an index of lipolysis rate.
Blood flow was assessed by the ethanol escape technique. The rates of
release of glycerol from human adipose tissue maximally stimulated by
norepinephrine were also investigated in the presence of acipimox.
Eight weight- and age-matched subjects served as a control group.
RESULTS: Under acipimox treatment, basal glycerol release decreased in
subcutaneous adipose tissue, whereas no effect was observed on blood
flow. In stimulated adipose tissue acipimox showed no effect.
CONCLUSION: In the present study basal glycerol outflow from adipose
tissue was inhibited by acipimox. The anti-lipolytic action of the
agent may diminish elevated plasma concentrations of free fatty acids
in subjects with severe obesity. Copyright 2001 John Wiley & Sons,
Ltd.
PMID: 11747144 [PubMed - indexed for MEDLINE]
Related LinksMetformin inhibits catecholamine-stimulated lipolysis in
obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose
tissue: an in situ microdialysis study. [Diabet Med. 1999]Effects of
acipimox, a nicotinic acid derivative, on lipolysis in human adipose
tissue and on cholesterol synthesis in human jejunal mucosa. [Clin Sci
(Lond). 1985]In vivo alpha(1)-adrenergic lipolytic activity in
subcutaneous adipose tissue of obese subjects. [J Pharmacol Exp Ther.
2002]Microdialysis assessment of local adipose tissue lipolysis during
beta-adrenergic stimulation in upper-body-obese subjects with type II
diabetes. [Clin Sci (Lond). 1999]Studies of phosphodiesterase effects
on adipose tissue metabolism in obese subjects by the microdialysis
technique. [J Physiol Pharmacol. 2005]See all Related Articles...
Paul Antonik Wakfer
> Nicotinic acid prevents the surge of free fatty acidws induced by
> fasting. This may be similar to Acipimox.
There is no need for the qualifier "may". It is entirely similar to
the effects of acipimox (also called Olbetam) since acipimox is a much
more potent nicotinic acid analog. I currently take 250 mg of acipimox
twice daily during my 19-20 hour fast between my once daily meals, in
order to augment the autophagic processes taking place during the
fasting period. See my chemical, drug and supplement intake regimen
at: http://morelife.org/personal/health/his-regimen.html and my review
page for acipimox at: http://morelife.org/prescripdrugs/acipimox.html
--Paul Wakfer
MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project - http://selfsip.org
Self-sovereignty, rational pursuit of optimal lifetime happiness,
individual responsibility, social preferencing & social contracting
jc101
> On Oct 18, 4:34 pm, timoth...@my-deja.com wrote:
>
> > Nicotinic acid prevents the surge of free fatty acidws induced by
> > fasting. This may be similar to Acipimox.
>
> There is no need for the qualifier "may". It is entirely similar to
> the effects of acipimox (also called Olbetam) since acipimox is a much
> more potent nicotinic acid analog. I currently take 250 mg of acipimox
> twice daily during my 19-20 hour fast between my once daily meals, in
> order to augment the autophagic processes taking place during the
> fasting period. See my chemical, drug and supplement intake regimen
> page for acipimox at:http://morelife.org/prescripdrugs/acipimox.html
>From this link above :
"Groups of 3-month-old male Sprague-Dawley rats were (a) given
standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted
1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like
FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by
the gastric tube. ... It is concluded that life-long weekly-repeated
transient inhibition of insulin secretion by antilipolytic drugs may
have an anti-aging effect, additive to the anti-aging effect of a
milder caloric restriction. Speculation is that transiently lower
plasma insulin levels might stimulate the anti-aging cell-repair
mechanism autophagy, which has longer lasting effects on cell
housekeeping." Also from the full paper: "Rats on a caloric restricted
regimen spend most of the day in a state of fasting and higher
autophagic proteolysis. The administration of antilipolytic drugs
suppresses the release of FFA by the adipose tissue and stimulates
autophagy. We have observed that Acipimox does not affect autophagy
and biomarkers of aging if given to rats fed ad libitum (unpublished).
"
One should look at the rat data carefully before concluding that daily
or twice daily administration of acipimox effects increased autophagy
rates. Rats have maybe 1/25 the lifespan of humans. A one day fast for
them is equivalent to more than 3 weeks in humans. There is no
evidence that tiny amounts of acipimox between meals increases
autophagy in humans. It doesn't in rats fed ad libitum. I suspect one
really has to starve to build this autophagy rate. Otherwise all you
would get is increased blood glucose, since FFA levels are lowered and
the body needs its fuel.
The following from an earlier correspondence: "....the sudden,
dramatic increase in plasma glucagon/insulin ratio may stimulate
autophagy and lysomal proteolysis..."
but does the autophagy continue after this increase falls off? in that
case
of prolonging autophagy over time, would a longer lower period be
better? We
don't know and that was my point.
You need enough to start the FFA change, and may need it for a
substantial
period of time to get any longer term autophagic changes made, since
human
and rats are on different metabolic time frames. A rat week is 1/150
of
their lifespan, but 1/4000 of human lifespan. So maybe humans need
acipimox
4 times a day for a couple of weeks with fasting all those 2 weeks to
equal
what the rats had because of their lifespan differences. 2 weeks of
fasting
with 4 x acipimox each day - done twice a year would put it on a
similar
lifespan derived timetable for humans. That's more towards traditional
ritual religious and famine induced practices. That might be radical
enough
to change autophagy in humans. You would have to plan on just chilling
in
Malibu and listening to the waves for those 2 weeks, cause you sure
couldn't
get any work or thought done in that time.
Hard to say, but I still think this is mostly for the elderly who
would
benefit from this more. Maybe there will be more data by the time we
get to
65 or 70, when lysosomes are getting all stopped up. I suspect it will
prove
out to need long periods of fasting/acipimox to do anything in humans.
You
really have to shake up the routine of the body for it to make big
changes.
Remember, this is to simulate starved conditions. Autophagy is to
deliver
food sources to replace what isn't there from diet, just waste hanging
around each cell. In the same way that periodic (or chronic) low level
radiation upregulates the immune system of the body for cancer and
infection
prevention, periodic starvation has a longer term effect, apparently,
to
make the body more efficient in its metabolism and recycling for a
certain
longer timeframe. We just don't know what the period is for the
starvation
yet, ..."
I wouldn't conclude from the rat 1 day fasting with acipimox data that
any increased autophagy is available in humans from a one day fast
with (small amount of) acipimox..
JLC
Olafur Pall Olafsson
On Oct 19, 12:28 pm, jc101 <uniqueprodu...@comcast.net> wrote:
> On Oct 18, 7:28 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > On Oct 18, 4:34 pm, timoth...@my-deja.com wrote:
>
> > > Nicotinic acid prevents the surge of free fatty acidws induced by
> > > fasting. This may be similar to Acipimox.
>
> > There is no need for the qualifier "may". It is entirely similar to
> > the effects of acipimox (also called Olbetam) since acipimox is a much
> > more potent nicotinic acid analog. I currently take 250 mg of acipimox
> > twice daily during my 19-20 hour fast between my once daily meals, in
> > order to augment the autophagic processes taking place during the
> > fasting period. See my chemical, drug and supplement intake regimen
> > at:http://morelife.org/personal/health/his-regimen.htmlandmy review
> > page for acipimox at:http://morelife.org/prescripdrugs/acipimox.html
> >From this link above :
>
> "Groups of 3-month-old male Sprague-Dawley rats were (a) given
> standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted
> 1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like
> FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by
> the gastric tube. ... It is concluded that life-long weekly-repeated
> transient inhibition of insulin secretion by antilipolytic drugs may
> have an anti-aging effect, additive to the anti-aging effect of a
> milder caloric restriction. Speculation is that transiently lower
> plasma insulin levels might stimulate the anti-aging cell-repair
> mechanism autophagy, which has longer lasting effects on cell
> housekeeping." Also from the full paper: "Rats on a caloric restricted
> regimen spend most of the day in a state of fasting and higher
> autophagic proteolysis. The administration of antilipolytic drugs
> suppresses the release of FFA by the adipose tissue and stimulates
> autophagy. We have observed that Acipimox does not affect autophagy
> and biomarkers of aging if given to rats fed ad libitum (unpublished).
> "
>
> One should look at the rat data carefully before concluding that daily
> or twice daily administration of acipimox effects increased autophagy
> rates. Rats have maybe 1/25 the lifespan of humans. A one day fast for
> them is equivalent to more than 3 weeks in humans.
I disagree that a one day fast for rats is equivalent to more than 3
weeks in humans. First of all the relative difference between 3 weeks
and a day is far more than the relative difference in metabolic rate
between rats and humans. Secondly while rats have a faster metabolism
than humans many of the changes that happen in rats during a single
day fast also occur in humans during a single day fast. These include
lower insulin and glucose levels, higher glucagon levels and increased
lipolysis and proteolysis.
> There is no
> evidence that tiny amounts of acipimox between meals increases
> autophagy in humans.
Tiny by what standards? While the doses of acipimox used by humans may
be small relative to that used in studies on rats, if they are still
sufficient to cause lowering of plasma FFAs then I don't think they
are tiny at all. Also while there may be no *direct* evidence that
acipimox between meals increases autophagy in humans there is strong
evidence indicating that it does so. Acipimox acutely lowers FFAs in
humans and if you take it when in a fasted state your body has to turn
to something else for fuel if FFAs are not available. The only other
fuel source is glucose and in a fasting state the body has to turn to
itself for glucose. This glucose comes from a combination of the
glucose stored in the body as glycogen and from breakdown of the
body's own amino acids by gluconeogenesis. It is through this last
that autophagy is increased. Also the human body's stores of glycogen
are very small and most of it is confined to muscle and is thus not
accessible to other tissues. The rest is stored in the liver and is
easily depleted with short term fasting.
> It doesn't in rats fed ad libitum. I suspect one
> really has to starve to build this autophagy rate. Otherwise all you
> would get is increased blood glucose, since FFA levels are lowered and
> the body needs its fuel.
But if you get increased blood glucose where do you suppose it comes
from? In a fasting state the body gets glucose either from glycogen or
from gluconeogenesis. Once liver glycogen is depleted the body has to
turn to gluconeogenesis for glucose. This is only possible with the
breakdown of the bodies own amino acids, and since the human body does
not store free amino acids to supply these amino acids the body has to
turn to autophagy. Consequently once liver glycogen is mostly empty
autophagy will be activated, if it were not humans would quickly die
once their liver glycogen is depleted because the brain cannot survive
without glucose and it takes a while for the body to switch to ketosis
and start burning ketones, longer than it takes to empty the livers
glycogen stores. Therefore limiting FFAs available as fuel for the
body by taking acipimox in a fasting state should consequently
accelerate the depletion of liver glycogen stores and increase
autophagy.
> The following from an earlier correspondence: "....the sudden,
> dramatic increase in plasma glucagon/insulin ratio may stimulate
> autophagy and lysomal proteolysis..."
> but does the autophagy continue after this increase falls off?
I don't think whether it continues or falls off is of prime importance
here, as long as autophagy does increase for at least a short while it
should be beneficial for life-extension.
> in that case
> of prolonging autophagy over time, would a longer lower period be
> better? We
> don't know and that was my point.
I don't know, but whichever the case any increase in autophagy will
likely be beneficial for life-extension.
> You need enough to start the FFA change, and may need it for a
> substantial
> period of time to get any longer term autophagic changes made, since
> human
> and rats are on different metabolic time frames. A rat week is 1/150
> of
> their lifespan, but 1/4000 of human lifespan.
I think your're making a big mistake by comparing the differences in
the lifespan between rats and humans. Do you really think a human cell
will need weeks to start digesting itself by means of autophagy once
deprived of nutrients? I think metabolic rate is the important factor
here. Metabolism is the sum of the anabolic and catabolic processes
occurring in a cell. Autophagy is a catabolic process. While the
difference in lifespan between rats and humans is quite large, on a
cellular level rats and humans are not that different. Their metabolic
rate only differs by a factor of about 3,4. Given their difference in
metabolic rate I think a single day of fasting for a rat is closer to
a few days for a humans in terms of activation of autophagy.
> So maybe humans need
> acipimox
> 4 times a day for a couple of weeks with fasting all those 2 weeks to
> equal
> what the rats had because of their lifespan differences. 2 weeks of
> fasting
> with 4 x acipimox each day - done twice a year would put it on a
> similar
> lifespan derived timetable for humans. That's more towards traditional
> ritual religious and famine induced practices. That might be radical
> enough
> to change autophagy in humans. You would have to plan on just chilling
> in
> Malibu and listening to the waves for those 2 weeks, cause you sure
> couldn't
> get any work or thought done in that time.
I don't think you need nearly that long of a time to activate and
benefit from increased autophagy. Just a single day of fasting will
result in a significant breakdown of muscle tissue in humans. See this
quote from the full text of PMID: 16815497 as an example:
"As starvation progresses the amount of total muscle proteolysis
decreases [1]. In humans the first day of starvation results in
degradation of 75 g of muscle protein, but later in starvation only 20
g of muscle protein is degraded per day [1]. One cause of this protein-
sparing effect is activation of lipolysis (see below), which provides
free fatty acids (FFAs) as an alternative fuel for muscle, liver,
kidney, and heart."
> Hard to say, but I still think this is mostly for the elderly who
> would
> benefit from this more.
Yes but I think this applies to most life-extension treatments as
well. In any case early prevention is the key.
> Maybe there will be more data by the time we
> get to
> 65 or 70, when lysosomes are getting all stopped up. I suspect it will
> prove
> out to need long periods of fasting/acipimox to do anything in humans.
This I disagree with. I think fasting for short periods of time (like
10-16 hours) will be beneficial for life-extension particularly if
combined with other methods such as acipimox and exercise, although
the benefits may not end up being quite as large as if one would fast
for a whole day regularly.
> You
> really have to shake up the routine of the body for it to make big
> changes.
>
> Remember, this is to simulate starved conditions. Autophagy is to
> deliver
> food sources to replace what isn't there from diet, just waste hanging
> around each cell. In the same way that periodic (or chronic) low level
> radiation upregulates the immune system of the body for cancer and
> infection
> prevention, periodic starvation has a longer term effect, apparently,
> to
> make the body more efficient in its metabolism and recycling for a
> certain
> longer timeframe. We just don't know what the period is for the
> starvation
> yet, ..."
But we do know that the glucagon/insulin ratio is raised, glucose is
lowered and lipolysis and proteolysis are increased within the first
few hours of starvation and I do not see any reason why autophagy
would not also begin to increase somewhat also, as I've explained
above.
> I wouldn't conclude from the rat 1 day fasting with acipimox data that
> any increased autophagy is available in humans from a one day fast
> with (small amount of) acipimox..
I disagree. A loss of 75 g of muscle protein during the first day of
starvation as reported in the quote I refered to above basically
proves that autophagy will be strongly activated during a single day
fast. I expect this loss would've been even greater if acipimox
would've been consumed during the day of fasting since in that case
the amount of FFAs available for fuel would be limited further placing
a higher demand for energy from other sources, such as the body's
muscles.
> JLC
David
exercise in particular), by inhibiting the release of fatty acids from
adipose tissue, don't we end up promoting body fat gain? One would
think that long-term niacin or acipimox use could be detrimental by
increasing body fat and all of the body-fat-associated comorbidities.
Paul Antonik Wakfer
> On Oct 18, 7:28 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > On Oct 18, 4:34 pm, timoth...@my-deja.com wrote:
>
> > > Nicotinic acid prevents the surge of free fatty acidws induced by
> > > fasting. This may be similar to Acipimox.
>
> > There is no need for the qualifier "may". It is entirely similar to
> > the effects of acipimox (also called Olbetam) since acipimox is a much
> > more potent nicotinic acid analog. I currently take 250 mg of acipimox
> > twice daily during my 19-20 hour fast between my once daily meals, in
> > order to augment the autophagic processes taking place during the
> > fasting period. See my chemical, drug and supplement intake regimen
I find it strange to see this coming from you, since you were the
person who first alerted me to the potential benefits of acipimox. And
in correspondence to someone else (copied to me) on 10/06/2006 you
wrote (note that I have quoted you so that there is no question of
wrongly interpreting your words):
"I tried Bergamini's acipimox/day of fasting yesterday and it is not
that
difficult, lowered lipids and glucose were tolerable for the day,
although
I felt a little bit 'spacey', no niacin-type flushing occurred. Will
move
up to 2 tablets in the morning spaced out by about 3-4 hours and
report back
to you within 2 weeks.
"Rapamycin mTOR inhibition has been proposed for enhancing autophagy,
but
not demonstrated, and may not proceed without lowering of amino acid
levels.
But I think that the acipimox/day of fast will be preferable to
substantial
calorie restriction and more easily achieved. It should be useful to
preserve cells in the elderly that are challenged by defective
mitochondria
and accumulating waste . Coupled with enough resveratrol and fairly
low
insulin / moderate IGF-1 throughout the week, could be an interesting
signalling recipe to keep cells clean."
Perhaps you have changed your mind since then?
> The following from an earlier correspondence: "....the sudden,
> dramatic increase in plasma glucagon/insulin ratio may stimulate
> autophagy and lysomal proteolysis..."
What correspondence is this from? It does not occur in any
correspondence between us, as is implied by your phrase "earlier
correspondence". I think that it is important to state the source and
author of a quote when making it.
Furthermore, it is impossible to tell which of the following remarks
were made by you, currently in this post, and which were made in an
"earlier correspondence" (and by whom). This is particularly the case
since your next lines end with a quote mark, that has no corresponding
opening quote mark.
> JLC
Finally, I wish to thank and commend Olafur for his excellent and
accurate rebuttal of many of the remarks and conclusions of JLC.
jc101
Hey now !
Acipimox/fasting is great stuff. A tiny dose really lowers FFA. Just
realize that no one has shown any increase in autophagy on a one day
human fast with acipimox, that is Bergamini's discrepancy in
extrapolating rat data to his PISA human plan. The rat data has to be
understood for what it is, these animals go through a couple of weeks
worth of (human) heartbeats in the 24 hrs they were fasted. Whether it
is ~4 days by metabolic rate or ~21 day by life span equivalent, all I
am saying is thinking that one day of acipimox/fasting will turn on
autophagy is a matter of faith. There is no data to show this, and
sure it breaks down more muscle to make glucose, and increases plasma
glucose because there is less FFA, but these are not useful endpoints.
Does it clean out lysosomes? We don't know. I would say ad libitum
food to normal BMI, and a long fast of maybe a week with acipimox
(several times a year) mimics this data better, and is preferable to
CR.
The good news is that mTOR can be lowered several ways, including ARBs
like Micardis, and rapamycin, as well as resveratrol working
'upstream', so there are CR mimetic meds now with testable results,
and these will deliver the autophagy increase without the well known
problems of CR. Then when you add in removal of the stored iron in
hemosiderin and paracrystalline iron (by regular blood donation) that
has built up over a lifetime causing oxidative stress (and lipofuscin
production), one can end up with some darn clean cells.
JLC
Olafur Pall Olafsson
> Fasting gurus aside, and all other things being equal (diet and
> exercise in particular), by inhibiting the release of fatty acids from
> adipose tissue, don't we end up promoting body fat gain?
Yes, since you'll burn less fat during the fasting the end result will
be promotion of fat gain.
> One would
> think that long-term niacin or acipimox use could be detrimental by
> increasing body fat and all of the body-fat-associated comorbidities.
Well as I always say, nothing is all good or bad. For a fat person
trying to lose fat obviously acipimox may do more harm than good. For
such a person losing the fat is far more important in terms of health
than focusing on autophagy. But for lean people with already very low
bodyfat levels I think this shouldn't cause any problems, and I think
the benefits of increased autophagy will far outweight the potential
harm of a slight gain in fat. In any case if such people start gaining
fat then they are simply eating too much. In such people lipolysis is
generally already very low because the body becomes highly resistant
to losing any more fat once you get very lean so I don't think
acipimox will effect fat loss as much in a lean person as it will in a
fat person. Also the leaner you are the less fat you have to burn and
generally the easier it will be for you to activate autophagy during
fasting because without fat to burn your body will have to turn to
protein instead. This is just one of the many benefits of having low
levels of bodyfat.
Olafur Pall Olafsson
I did reply to this yesterday but for some reason my post didn't
appear on the group. Here is my reply again.
On Oct 20, 2:03 am, David <david.spro...@gmail.com> wrote:
> Fasting gurus aside, and all other things being equal (diet and
> exercise in particular), by inhibiting the release of fatty acids from
> adipose tissue, don't we end up promoting body fat gain?
Yes, since you'll burn less fat during the fasting the end result will
be promotion of fat gain.
> One would
> think that long-term niacin or acipimox use could be detrimental by
> increasing body fat and all of the body-fat-associated comorbidities.
Well as I always say, nothing is all good or bad. For a fat person
Paul Antonik Wakfer
I have no idea just what you are trying to communicate with the above.
In addition, if you really wish to be understood and persuasive,
particularly on this group, then you should communicate inline and
respond to all the points which are addressed to you. By not
responding inline, whether intentionally or accidently, you have
evaded addressing my request for clarification of the source of the
quote that you previously made and for clarification of just which
parts of your text were quote and which were your current comments.
> Acipimox/fasting is great stuff. A tiny dose really lowers FFA. Just
> realize that no one has shown any increase in autophagy on a one day
> human fast with acipimox, that is Bergamini's discrepancy in
> extrapolating rat data to his PISA human plan.
No. There are sound and positive human experiments relating to all the
assumptions of his conclusion. There is only no final experiment on
humans of the direct result. This is not different than for many other
supplements taken for various purposes. In fact, you yourself have in
the past told me (very proudly) that you are generally one of the
early takers of many things because you require much less direct
evidence. However, your reasoning appears to be only true for yourself
and you criticize others for doing the same.
> The rat data has to be
> understood for what it is, these animals go through a couple of weeks
> worth of (human) heartbeats in the 24 hrs they were fasted. Whether it
> is ~4 days by metabolic rate or ~21 day by life span equivalent,
I did not say anything to which the above relates. If you wish to
respond to Olafur's message, then you should do so directly and again
inline.
> all I
> am saying is thinking that one day of acipimox/fasting will turn on
> autophagy is a matter of faith.
No. Fasting (plus CR, which I have always done) most certainly *will*
turn on autophagy and there is excellent evidence that acipimox will
promote additional autophagy. How much promotion is a matter of
reasonable debate. However, any increase is better than no increase.
As has been stated many times on this group and elsewhere. If one does
nothing the result will be that one declines normally in function with
age and dies at about the same age as everyone else. Since no measures
have yet been *proven* (using the gold standard double blind placebo
controlled trials methods) to extend human lifespan, the only
reasonable approach is to use measures that have less but still good
evidence in their favor, particularly those that also have evidence
that they will not have negative effects. From my research on them, I
consider acipimox supplementation and a one day fast to both be such
safe measures. Yes, a 2 day fast would likely even be better, but I
don't think that I have the stomach capacity for a eating 2 days worth
of even a calorie reduced diet and also think that I would be too
hungry to work effectively on the second day. Still at some point, I
may try eating every second day.
Finally, this is a sci group and "faith" has nothing to do with what
occurs here for the vast majority of posters, most particularly not
for me.
> There is no data to show this, and
> sure it breaks down more muscle to make glucose, and increases plasma
> glucose because there is less FFA, but these are not useful endpoints.
I did not say anything to which the above relates. If you wish to
respond to Olafur's message, then you should do so directly and again
inline.
> Does it clean out lysosomes? We don't know.
Please do not use the collective "we". It is impossible for you to
know what others do or do not know.
> I would say ad libitum
> food to normal BMI, and a long fast of maybe a week with acipimox
> (several times a year) mimics this data better, and is preferable to
> CR.
"Preferable" is a totally subjective evaluation. With all of the
various potential and actual positive and negatives relating to these
2 approaches, you cannot possibly decide for anyone but yourself which
of them is overall "preferable". In any case, I am constantly doing
all 3: moderate CR, fasting and acipimox. This combination appears to
work best for me (by my own total evaluation relating to all negatives
and positives - which is something that neither you nor anyone else
can fully know) and I am giving my reasons for that evaluation as best
that I can. All the information that I use to make my evaluations is
available in great detail and continually updated on my website,
morelife.org, (along with all the life extension measures that I take)
and both open for criticism/comment and further explanation on my
morelife Yahoo group. (I would very much like to see many others,
especially those who post here, do something similar.)
> The good news is that mTOR can be lowered several ways, including ARBs
> like Micardis, and rapamycin, as well as resveratrol working
> 'upstream', so there are CR mimetic meds now with testable results,
> and these will deliver the autophagy increase without the well known
> problems of CR.
Most of any such problems are purely in the minds of the intrepid or
are with respect to extreme amounts of CR. There are no problems at
all with the moderate form of CR which I have done for 17 years now.
My physiological parameters clearly show that I am on a reasonable
degree of CR (BMI of 19.2 for one thing) and my website clearly shows
how this can be accomplished without discomfort or daily loss of
mental/physical abilities. Besides none of the so called CR mimetics
exhibit the total benefits of CR. However, yes, rapamycin looks to be
an excellent life extension drug for many reasons. I have been avidly
studying it recently and will very likely soon start taking it at the
rate of 1/2 mg daily (my current dosage estimate).
> Then when you add in removal of the stored iron in
> hemosiderin and paracrystalline iron (by regular blood donation) that
> has built up over a lifetime causing oxidative stress (and lipofuscin
> production), one can end up with some darn clean cells.
I used to agree with this and for some years regularly donated blood
for this purpose, to help others and to contribute so that blood was
available if I ever needed a transfusion. I do not do this any more
for several reasons:
1) my hemoglobin and ferritin levels were already sufficiently low.
2) Iron is a major necessary mineral required by the body to function
well
3) Iron seems to become depleted in the body with age
4) Donating blood also removes perfectly good white bloods cells which
then need to be regenerated and some of which are part of the body's
immunity that has been acquired from past infections. For many
reasons, I don't think that it is a good idea to continually deplete
these white blood cells.
Paul Antonik Wakfer
In addition, the use of rapamycin (or other TOR inhibiting methods, of
which CR and low bodyfat are only two) will both decrease lipid
storage and increase lipolysis. This is one reason why I think that
acipimox and rapamycin (or other TOR inhibiting methods) should work
well together.
Olafur Pall Olafsson
> On Oct 20, 12:41 pm, jc101 <uniqueprodu...@comcast.net> wrote:
>
>
>
> > On Oct 19, 11:59 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > > On Oct 19, 8:28 am, jc101 <uniqueprodu...@comcast.net> wrote:
>
> > > > On Oct 18, 7:28 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > > > > On Oct 18, 4:34 pm, timoth...@my-deja.com wrote:
>
> > The rat data has to be
> > understood for what it is, these animals go through a couple of weeks
> > worth of (human) heartbeats in the 24 hrs they were fasted. Whether it
> > is ~4 days by metabolic rate or ~21 day by life span equivalent,
>
> I did not say anything to which the above relates. If you wish to
> respond to Olafur's message, then you should do so directly and again
> inline.
Thanks Paul, I take under what you said above. The act of not
responding inline is particularly annoying as it makes it impossible
to see what exactly the person is addressing and thus makes it much
harder to keep up a meaningful logical discussion. Discussions tend to
turn into a mess if not done inline. Also I basically agree fully with
what you said in your reply to Jay and do no think it needs to be
restated. For these reasons I will refrain from responding to Jays
comments, unless or until he addresses me directly and does so inline.
jc101
> On Oct 18, 7:28 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > On Oct 18, 4:34 pm, timoth...@my-deja.com wrote:
>
> > > Nicotinic acid prevents the surge of free fatty acidws induced by
> > > fasting. This may be similar to Acipimox.
>
> > There is no need for the qualifier "may". It is entirely similar to
> > the effects of acipimox (also called Olbetam) since acipimox is a much
> > more potent nicotinic acid analog. I currently take 250 mg of acipimox
> > twice daily during my 19-20 hour fast between my once daily meals, in
> > order to augment the autophagic processes taking place during the
> > fasting period. See my chemical, drug and supplement intake regimen
Looks like I left out a reference for "....the sudden, dramatic
increase in plasma glucagon/insulin ratio may stimulate autophagy and
lysomal proteolysis..." This is from the Donati and Bergamini 2004
Experimental Gerontology paper 15236765.
Suggest the reader without library access go to
http://morelife.org/prescripdrugs/acipimox.html ""The administration
of an anti-lipolytic agent to fasting rats causes a sudden decline of
free fatty acids and glucose and an increase in the glucagon/insulin
ratio leading to an intensification of autophagic proteolysis, as
shown by an increase in liver autophagic compartment and a release of
valine in plasma (Pollera et al., 1990; Bergamini and Kovacs, 1990;
Bergamini et al., 1993)"
Unfortunately these papers don't discuss whether this works for rats
eating their entire day's food supply at just one meal, then acipimox
later on during the same 24 hr period. Wonder if that just increases
their blood glucose levels with no change in autophagy? "We have
observed that acipimox does not affect autophagy and biomarkers of
aging if given to rats fed ad libitum (unpublished). " from the
reference link listed above.
JLC
Paul Antonik Wakfer
On Oct 20, 2:31 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
> On Oct 20, 12:41 pm, jc101 <uniqueprodu...@comcast.net> wrote:
[big snip]
> > The good news is that mTOR can be lowered several ways, including ARBs
> > like Micardis, and rapamycin, as well as resveratrol working
> > 'upstream', so there are CR mimetic meds now with testable results,
> > and these will deliver the autophagy increase without the well known
> > problems of CR.
>
> Most of any such problems are purely in the minds of the intrepid or
> are with respect to extreme amounts of CR.
The word "intrepid" above should have been "trepid", by which in this
case I mean those who are overly cautious, timorous and afraid because
they do not either have enough confidence in their own knowledge and
ability to handle a little stress or in their ability to find
solutions to minimize such stress and make it easily acceptable.
I can see no positive reason why moderate CR should not be acceptable
to any human. Therefore, I can give no credibility at all to anyone
who calls hirself a life extensionist yet who dismisses CR out of hand
as being impossible or impractical to do.
[snipped rest]
--Paul Wakfer
MoreLife for the rational -http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project -http://selfsip.org