Hey, guys, pardon the scientific gibberish, but I thought some of the
Instinctos here would resonate with the mention of Maillard's molecules
in the posting below. (For those who don't know, Maillard was a
scientist who discovered that cooked foods produced carcinogenic
compounds, which came to be named after him.)
From: "Brian C. Rowley" <[log in to unmask]>
To: [log in to unmask]
Subject: Questions about acetyl l-carnitine
Date: Sat, 4 Jan 1997 13:28:25 -0800
***Reply from Manuel Portero***
From: [log in to unmask]
>Hello all
>I'm a PhD student on ageing-related diseases. I've been reading the
>excellent report on acetyl l-carnitine (ALC) about its use in diseases
>(diabetic neuropathy and Alzheimer's disease somehow might have any
>common relation in basis of a nonenzymatic reaction called the Maillard
reaction (Yan, S.D., Chen, X., Fu, J,. Chen, M., Zhu, H., Roher, A., Slattery,
T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern,
D., Schmidt,A.M. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's
>disease. Nature, 382, 685-691, 1996; Smith, M.A., Taneda, s., Richey,
P.L.,Miyata, S., Yan, S.D., Stern, D., Sayre, L.M., Monnier, V.M., Perry, G.
>Advanced Maillard reaction end products are associated with Alzheimer
>disease pathology. Proc Natl Acad Sci USA, 91, 5710-5714,
1994.;Brownlee, M. Glycation and diabetic complications. Diabetes 43, 836-841, 1994.;
for a review try www.geocities.com/CapeCanaveral/8824))
>I've some questions about acetyl-carnitine.
>First, if this compound works by increasing the mitochondrial fatty acid
>influx and this increases oxidative activity, what are the effects on
free radical production. One should expect, if there is no direct or indirect
>antioxidant activity from acetyl-carnitine, that this increase on
oxidative activity might increase oxidative stress. Have been any trials with
>combinations of n-acetyl carnitine with antioxidants?
***Reply from Brian Rowley*******************************
***Acetyl l-carnitine itself is a powerful antioxidant. I don't
know of any trials where it has been combined with other antioxidants. You
make a very intelligent point; it's true that increased mitochondrial activity
(and therefore mitochondrial free radical generation...) would be expected to
increase oxidative damage. Acetyl l-carnitine supplementation in rats
completely restores the synthesis of energy-generating (and presumably
free-radical generating) mitochondrial enzymes in old rats to the levels
of young rats (ref #1). Also, a 35% decline in mitochondrial fatty acid
oxidation seen with aging in rat heart was immediately reversed by the
addition of acetyl l-carnitine (ref #2).
ref#1: Gadaleta MN, et al. Mitochondrial DNA transcription and
translation in aged rat. Effect of acetyl-l-carnitine. Annals of the New
York Academy of Sciences. 717:150-60, 1994 Jun 30.
ref #2: Paradies G, et al. Carnitine-acylcarnitine translocase
activity in cardiac mitochondria from aged rats: the effect of
acetyl-L-carnitine. Mechanisms of Ageing & Development 84(2):103-12, 1995
Oct 13.
However, in spite of such increase in mitochondrial oxidative
activity, acetyl l-carnitine apparently has a protective against free
radical damage. According to one study, free radical damage to muscle
(caused by superoxide-producing granulocytes stimulated by
ischemia-reperfusion injury) can be substantially prevented by acetyl
l-carnitine supplementation. Five patients undergoing aortic
reconstructive surgery were given 2560 mg of acetyl-carnitine intravenously over a
half-hour period prior to surgery. During the surgery, their skeletal
muscles were necessarily damaged when blood flow was cut off for a time
and then reintroduced. However, although granulocytes swarmed to the damaged
muscle, acetyl l-carnitine blocked formation of damaging superoxide.
Viewed microscopically, the muscles of the acetyl l-carnitine-treated patients
had much less damage than the muscles of the untreated patients, and damages
to the muscle mitochondria were less (ref #3).
Free radical damage to brain proteins, which happens when
bloodflow to the brain is cut off temporary, was also prevented with acetyl
l-carnitine administration in dogs. Protecting the brain from free
radicals is one of many proposed explanations as to why acetyl l-carnitine
improves the symptoms of Alzheimer's patients (ref #4).
It is also true that acetyl l-carnitine restores proliferation of
peripheral blood lymphocytes from old humans. Acetyl l-carnitine also
protects those same lymphocytes from oxidative stress (ref #5).
So what we are faced with is the following: acetyl l-carnitine
increases mitochondrial oxidation but protects muscle and brain proteins
from free radical damage, and even mitochondria themselves from free
radical damage (ref #3). Lastly it has a rejuvenating effect on senescent
lymphocytes, restores their proliferative ability, yet makes them more
resistant to oxidative stress rather than causing such stress. The
clinical and experimental results for Alzheimer's disease, diabetic neuropathy and
regeneration of damaged neurons (including increase in brain cell
surviva in culture) are all positive so far; I haven't found a negative study.
You see why scientists are excited!
ref #3: Adembri C, et al. Ischemia-reperfusion of human skeletal
muscle during aortoiliac surgery: effects of acetylcarnitine. Histology &
Histopathology 9(4):683-90, 1994 Oct.
ref #4: Liu Y. Rosenthal RE. Starke-Reed P. Fiskum G.
Inhibition of postcardiac arrest brain protein oxidation by acetyl-L-carnitine. Free
Radical Biology & Medicine. 15(6):667-70, 1993 Dec.
ref #5: Franceschi C. Cossarizza A. Troiano L. Salati R.
Monti D. Immunological parameters in aging: studies on natural immunomodulatory
and immunoprotective substances. International Journal of Clinical
Pharmacology Research. 10(1-2):53-7, 1990.
*********************************
>From: [log in to unmask]
>Second, what are the absorption-plasmatic distribution pathways of this
>molecule; are there any specific transporters in special cells , such as
>intestinal epithelia, neuron, or adipocyte.
***Acetyl l-carnitine is very rapidly absorbed and appears in the
bloodstream shortly after consumption. It is not bound to albumin or
other blood proteins, so it is also quickly eliminated (in about 24 hours). Two
or more 500 mg doses are consumed over the course of the day, as a rule.
Acetyl l-carnitine penetrates the blood-brain barrier easily and goes into the
brain (and inner mitochondrion). Renal tubular reabsorption saturates, so
several small doses are better than one big dose***
> What is a reasonable human dose? ***500-2000 mg***
>> and what's the concentration in food?
***Substantially less***
>Thanks for your attention, and best wishes for the new year
>Manuel Portero
****Original post from Brian Rowley********************
>From: "Brian C. Rowley" <[log in to unmask]>
>Subject: acetyl l-carnitine
> Acetyl l-carnitine (a compound produced by the body and found in
milk and meats) is currently generating much excitement. For example,
several large scale double-blind, placebo controlled, randomized,
multi-centre trials conducted in Italy suggest that acetyl l-carnitine
improves the cognitive function of Alzheimer's patients. This makes
sense, as acetyl l-carnitine is known to: (1) protect CNS neurons
>in culture, delaying cell death (2) increase the number of nerve growth
factor (NGF) receptors on neurons, (3) protect severed or crushed neurons
from degenerating and (4) have other neurotrophic effects (e.g., it
causes favourable changes in the structure of neuromuscular junctions). It would
therefore make sense if acetyl l-carnitine was a viable Alzheimer's
treatment. I should also add that acetyl l-carnitine is currently
undergoing phase III clinical trials in the U.S. for diabetic neuropathy, a disease
apparently treatable with acetyl l-carnitine, according to a number of
preliminary studies. Therefore as far as nerves are concerned, acetyl
l-carnitine is known to be a promising compound.
> It is also true, however, that a main physiological function of
acetyl l-carnitine is to facilitate entry of fats into the mitochondria,
something it does better than l-carnitine itself. Application of 1
micromole acetyl l-carnitine to mitochondria increases oxidative activity by 260%
(Siliprandi, N, et al. Stimulation of oxidation of mitochondrial fatty
acids and of acetate by acetylcarnitine. Biochemical Journal 96:777-780, 1965).
Furthermore, the amount of acetylcarnitine in our bodies declines with
age, as does mitochondrial activity. As a result, it is not too much of a leap
to suggest that decline in acetylcarnitine levels might partly explain (1)
why most of us are less energetic than children and have slower metabolism
and (2) why most of us get progressively fatter as we age. It might be that a
reduction in acetyl l-carnitine with age causes mitochondria to burn fat
less efficiently with age, which results in lower metabolism and greater
body fat.
> If that's true, one might expect long term supplementation with
acetylcarnitine to prevent age-associated fat gain. The following study
suggests that this is true (note that 4 months for a rat is like 12 years
for a human; also note that bigger adipocytes (fat cells) = more fat, as
fat cell number is constant)
>
>Unique Identifier
> 96057151 Authors> Baldassarri P. Calvani M.
Institution Research Institute on Aging, Sigma-Tau S.p.A., Pomezia, Italy.
>Title The aging process of skin and the increase in size of subcutaneous
> adipocytes. Source International Journal of Tissue Reactions.
16(5-6):229-41, 1994.
>Abstract
> The aging of skin has been associated with an increase in size of the
> adipocytes located within the subcutaneous tissue. This topic is the
subject of our study conducted on rats clinically treated with
L-acetyl-carnitine
> (LAC) at 4, 8, 16, and 21 months of age and on a control group. Normal
rats showed a significant increase in adipocyte diameter between four and
eight months, and between sixteen and twenty-one months of age. Rats treated
with L-acetyl-carnitine did not show significant changes up to the age of
sixteen months, but did so between sixteen and twenty-one months of age.
> Four-month-old rats, both those under treatment and controls, did not
show a significant change in adipocyte diameter. On the other hand, rats
receiving L-acetyl-carnitine showed significantly smaller adipocyte diameters
than those of the control group. Our results demonstrate that the long-term
> administration of L-acetyl-carnitine blocks the progressive increase
in size of the subcutaneous adipocytes present in the rat's aging skin. We
> hypothesize that L-acetyl-carnitine reequilibrates the catabolic
deficit of fats in the skin of the elderly.
>Here's a key data table from the paper:
> Control Acetyl l-carnitine
>Age Fat cell diameter Fat cell diameter (micrometers)
>4 months 36.99 37.66
>8 months 40.49 34.76
>16 months 42.97 36.76
>21 months 55.79 42.97
> All standard errors (expressed as standard deviation, for some
reason!) were very tight (high significance), and the technician who
measured the fat cell diameters didn't know whether he was measuring
tissuefrom control, or acetylcarnitine-treated rats (blinded). Good news for
rats?
> Brian Rowley
>
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