Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice.
timo...@my-deja.com
Improved mitochondrial function and increased life span after chronic
melatonin treatment in senescent prone mice.Rodríguez MI, Escames G,
López LC, López A, García JA, Ortiz F, Sánchez V, Romeu M, Acuña-
Castroviejo D.
Instituto de Biotecnología, Departamento de Fisiología, Universidad de
Granada, Facultad de Medicina, Avda. de Madrid 11, E-18012, Granada,
Spain.
We investigated whether chronic melatonin administration influences
mitochondrial oxidative stress and life span in mice. Diaphragmatic
mitochondria from female senescent prone (SAMP8) and senescent
resistant (SAMR1) mice at 5 and 10 months of age were studied.
Mitochondrial oxidative stress was determined by measuring the levels
of lipid peroxidation, glutathione and glutathione disulfide, and
glutathione peroxidase and reductase activities. Mitochondrial
function was assessed by measuring the activity of the respiratory
chain complexes and the ATP content. The results suggest that the age-
dependent mitochondrial oxidative damage in the diaphragm of SAMP8
mice was accompanied by a reduction in the electron transport chain
complex activities and in ATP levels. Furthermore, melatonin
administration between 1 and 10 months of age normalized the redox and
the bioenergetic status of the mitochondria and increased the ATP
levels. Melatonin also increased both half-life and longevity, mainly
in SAMP8 group. These results suggest an age-related increase in
mitochondria vulnerability to oxidation in SAM mice at 10 months of
age that was counteracted by melatonin therapy. The effects of
melatonin on mitochondrial physiology probably underline the ability
of the indoleamine to increase maximal life span in these animals.
PMID: 18485648 [PubMed - as supplied by publisher]
Paul Antonik Wakfer
This paper shows important benefits from melatonin supplementation on
the antioxidative parameters with aging (Lipid peroxidation decreased,
GPx and GRd increased, GSH:GSSG and total glutathione increased over
controls) and on the lifespan even for the SAMR1 mice. The dosage used
was 10 mg/kg which is not far above that attainable by and relative to
a human.
The survival curve for the SAMR1 mice shows a nice squaring effect
even though the longest lived animal of the melatonin group only lived
to 26 months, just one month more than the longest lived animal from
the unsupplemented group.
--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
Paul Antonik Wakfer
> Reality based tools for more life in quantity and quality
> Self-sovereignty, rational pursuit of optimal lifetime happiness,
> individual responsibility, social preferencing & social contracting
After writing the above I remembered about "crypto-CR" and so wrote
the following to the corresponding author of the paper.
"I was interested to see the nice squaring of the survival curve and
slight maximum lifespan increase for the melatonin supplemented SAMR1
mice. However, your paper mentions no weight measurements being
taken.
If the weights of the supplemented and vehicle mice are not measured
during their lifespan (or their actual food intake) then it is not
possible to infer the that increase in average and maximal lifespan
was
not due simply to a slight calorie restriction effect. The lower
calorie
intake in the supplemented group being a direct result of the
supplementation (this effect is generally referred to as crypto-CR).
So my question is: "did you rule out possible cryto-CR?"
fr....@free.fr
10 mg/kg for a rat gives 3mg/kg for a human ; that means, for a 60 kg
person, a daily dosage of 180 mg
I'm currently taking 3mg each day and 180 mg seems quite high, not
regarding safety, but regarding the attention level during the day.
I remember I read a study involving women during six months with a
daily dosage of 75 mg (!!) which consequences contraception
but I don't think I could take that without feeling lethargic all day
Paul Antonik Wakfer
The experimental animals were mice, not rats. So the human equivalent
dosage is about half what you calculated.
> I'm currently taking 3mg each day and 180 mg seems quite high, not
> regarding safety, but regarding the attention level during the day.
> I remember I read a study involving women during six months with a
> daily dosage of 75 mg (!!) which consequences contraception
> but I don't think I could take that without feeling lethargic all day
I think that whether or not one feels lethargic will depend both on
the timing of taking the melatonin and whether or not one raises the
dosage slowly to gradually accommodate oneself to it. Presumably the
mice taking 10mg/kg on a continuous basis during their waking period
did not sleep all day long as a result.
Before I thought about the crypto-CR possibility, I had planned to
slowly raise my daily dosage from a current of 10 mg just before
sleep, to a goal of 20 mg just before sleep and another 10 mg both
with my morning pills and my one meal pills. However, I have decided
not to do so until I hear back from the paper author about the
possibility of crypto-CR being the cause of the benefits seen for the
normal (SAMR1) mice.
Paul Antonik Wakfer
I just received the following reply:
--------------------------
Dear Paul:
Thanks very much for your observation. In fact, weight increase, and
feed
and water intake were controlled. Both controls and melatonin-treated
animals developed at similar extent and thus, the increased longevity
and
survival in the latter were related to the treatment itself.
Sincerely,
Darío Acuña-Castroviejo
Professor of Neuroendocrinology
----------------------------
Based on the reply, I have decided to proceed with my original thought
to attempt to greatly increase my melatonin dosage (to 40 mg daily,
for a start) by ramping up slowly from my present 10 mg daily. I will
continue to take most of it before sleep and will increase slowly only
as I find that it does not cause any sleepiness during my waking/
working hours. Any evidence based cautionary or negative thoughts on
this from others would be appreciated.
Thomas Carter
> On May 24, 2:03 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
>
>
>
>
> > On May 23, 10:13 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
>
> > > On May 23, 4:04 pm, timoth...@my-deja.com wrote:
>
> > > > �Exp Gerontol. 2008 Apr 6. [Epub ahead of print] Links
> > > > Improved mitochondrial function and increased life span after chronic
> > > > L�pez LC, L�pez A, Garc�a JA, Ortiz F, S�nchez V, Romeu M, Acu�a-
> > > > Castroviejo D.
> > > > Instituto de Biotecnolog�a, Departamento de Fisiolog�a, Universidad de
> Professor of Neuroendocrinology
> ----------------------------
>
> Based on the reply, I have decided to proceed with my original thought
> to attempt to greatly increase my melatonin dosage (to 40 mg daily,
> for a start) by ramping up slowly from my present 10 mg daily. I will
> continue to take most of it before sleep and will increase slowly only
> as I find that it does not cause any sleepiness during my waking/
> working hours. Any evidence based cautionary or negative thoughts on
> this from others would be appreciated.
>
> --Paul Wakfer
>
> 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,
>
> - Show quoted text -
Hi Paul,
When I went to 30 mg melatonin I found that morning grogginess and
vidid dreams went away after a couple of months. Bright light therapy
is effective in conjunction with melatonin. It takes only a few
minutes to catabolize plasma melatonin. It has also been reported to
be beneficial in some cases of bipolar disorder. In the bathrom is a
good place to eliminate plasma melatonin I would imagine. I have three
pertinent PMID numbers, but not the search. I guess I didn't save it.
BTW the long string of beneficial Italian/Checkoslovakian (all done by
teams with interlocking authorship.) cancer/melatonin clinical trials
is now being tested by American and Canadian teams. The first report
is in. There was actually an shortening of survival in glioma patients
compared with historical results. The Italian study reported a
benefit.
Thomas
9340660 18076544 18070004
Int J Radiat Oncol Biol Phys. 2007 Apr 5; [Epub ahead of print]
Links
Randomized phase II trial of high-dose melatonin and radiation therapy
for rpa class 2 patients with brain metastases (RTOG 0119).Berk L,
Berkey B, Rich T, Hrushesky W, Blask D, Gallagher M, Kudrimoti M,
McGarry RC, Suh J, Mehta M.
Department of Radiation Oncology, H. Lee Moffitt Cancer Center,
University of South Florida, Tampa, FL.
PURPOSE: To determine if high-dose melatonin for
Radiation Therapy Oncology Group (RTOG) recursive partitioning
analysis (RPA) Class 2 patients with brain metastases improved
survival over historical controls, and to determine if the time of day
melatonin was given affected its toxicity or efficacy. RTOG 0119 was a
phase II randomized trial for this group of patients. METHODS AND
MATERIALS: RTOG RPA Class 2 patients with brain metastases were
randomized to 20 mg of melatonin, given either in the morning (8-9 am)
or in the evening (8-9 pm). All patients received radiation therapy
(30 Gy in 10 fractions) in the afternoon. Melatonin was continued
until neurologic deterioration or death. The primary endpoint was
overall survival time. Neurologic deterioration, as reflected by the
Mini-Mental Status Examination, was also measured. RESULTS: Neither of
the randomized groups had survival distributions that differed
significantly from the historic controls of patients treated with
whole-brain radiotherapy. The median survivals of the morning and
evening melatonin treatments were 3.4 and 2.8 months, while the RTOG
historical control survival was 4.1 months. CONCLUSIONS: High-dose
melatonin did not show any beneficial effect in this group of
patients.PMID: 17418968
fr....@free.fr
Hi Paul
Is it possible to get a copy of the full text (particularly the
survival curve)?
François Rose
fr....@free.fr
>
> - Show quoted text -
Thanks Paul
As I wrote above, I'm currently taking 3 mg melatonin each day and I'm
planning to increase it slowly.
I tried 4.5 mg for a while but I felt too groggy so I quit.
Thomas's advice seems quite interesting, especially regarding bright
light therapy
François Rose