X-Message-Number: 26247
Date: Wed, 25 May 2005 19:41:35 -0700 (PDT)
From: Doug Skrecky <>
Subject: antiaging effect of acipimox and once-weekly fasting

[Acipimox may aid, and glutamine may hinder the anti-aging effect
of once-weekly fasting.]

Exp Gerontol. 2004 Jul;39(7):1061-7
Anti-aging effects of anti-lipolytic drugs.
Genetic disruption of insulin and insulin-like signaling pathways
may extend lifespan. Hyperinsulinemia and insulin resistance may
accelerate aging. The hypothesis was tested that a once-a-week
life-long inhibition of insulin secretion by the administration of
anti-lipolytic drugs might have anti-aging effects. 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. The AL, FW and EOD groups received saline
intragastrically. Treatment with ACIPIMOX transiently decreased
plasma free fatty acids, glucose and insulin and increased valine
plasma levels, and had no long-term effect on food consumption and
body weight. By age 6, 12 and 24 months subgroups were taken and the
age-related changes in liver dolichol and autophagic
proteolysis--which are correlated with life-expectancy--were
measured. Liver dolichol levels increased and autophagic proteolysis
decreased in mature and older AL rats; EOD and FWA fully
counteracted these changes; FW rats had significant but smaller
beneficial effects. 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.

Proc Natl Acad Sci U S A. 2003 May 13;100(10):6216-20.
Epub 2003 Apr 30.
Intermittent fasting dissociates beneficial effects of dietary
restriction on glucose metabolism and neuronal resistance to injury
from calorie intake.
Dietary restriction has been shown to have several health benefits
including increased insulin sensitivity, stress resistance, reduced
morbidity, and increased life span. The mechanism remains unknown,
but the need for a long-term reduction in caloric intake to achieve
these benefits has been assumed. We report that when C57BL6 mice are
maintained on an intermittent fasting (alternate-day fasting)
dietary-restriction regimen their overall food intake is not
decreased and their body weight is maintained. Nevertheless,
intermittent fasting resulted in beneficial effects that met or
exceeded those of caloric restriction including reduced serum
glucose and insulin levels and increased resistance of neurons in
the brain to excitotoxic stress. Intermittent fasting therefore has
beneficial effects on glucose regulation and neuronal resistance to
injury in these mice that are independent of caloric intake.

Exp Gerontol. 2003 May;38(5):519-27
Ageing-related changes in the in vivo function of rat liver
macroautophagy and proteolysis.
Autophagy is a universal, highly regulated mechanism responsible
for the degradation of long-lived proteins, cytomembranes and
organelles during fasting and may be the cell repair mechanism that
mediates the anti-ageing effects of calorie restriction (Bergamini
and Gori, 1995). The function of autophagy was studied in vivo on
male Sprague Dawley rats fed ad libitum or 40% food restricted.
Autophagy was induced in overnight fasted rats by the injection of
an anti-lipolytic agent and was investigated by electron microscopy.
Changes in regulatory plasma nutrients and hormones were assessed
and rate of proteolysis was calculated from the release of
14C(6)-valine from pre-labelled resident proteins. Results in rats
fed ad libitum showed that autophagic-proteolytic response to
antilypolitic agents was paramount in one month-old rats; was high
but delayed in 2 month-old rats, decreased remarkably in 6
month-old rats and almost negligible at older age. Parallel
ageing-related changes were observed in the effects of treatment
lowering glucose and insulin plasma levels. Calorie restriction
prevented all changes. In view of the known suppressive effects of
insulin, it may be concluded that the age-changes of autophagy are
secondary to the ageing-related alteration in glucose metabolism and
hormone levels, whose appearance is delayed by calorie restriction.
Data may support the hypothesis that ad libitum feeding accelerates
the rate of ageing by raising insulin plasma levels and suppressing
autophagy and membrane maintenance, and that calorie restriction may
break this vicious circle.


Exp Mol Pathol. 1987 Feb;46(1):114-22.
Increased degradation in rat liver induced by antilipolytic agents:
a model for studying autophagy and protein degradation in liver?
A dramatic increase in the plasma glucagon/insulin ratio can be
induced by treating fasted rats with antilipolytic drugs (e.g.,
with 3,5-dimethylpyrazole, 12 mg/kg body wt). These hormone changes
are the physiologically appropriate response to a rapid decrease in
free fatty acids and glucose plasma levels. Under this experimental
condition, many vacuolated lysosomes can be observed at the electron
microscopic level as early as 30 min and autophagic vacuoles are
detectable in the liver cells 1 hr after the administration of the
drug. By 1 hr and 45 min, vacuoles often contain recognizable
peroxisomes. At the biochemical level, liver proteolysis in vitro is
increased significantly. Very interestingly, changes in peroxisomal
(but not mitochondrial or reticulum or cytosolic) enzyme activities are
detected that are preventable by the administration of glutamine (i.e.,
of an inhibitor of proteolysis in vivo) but not by an isocaloric amount
of glycine or alanine. It is concluded that the administration of
antilipolytic agents to fasted animals may provide a convenient (i.e.,
an inexpensive, highly reproducible and timable) physiologic model to
study hormone-induced autophagy in liver cells.

J Nutr Biochem. 2005 Mar;16(3):129-37.
Beneficial effects of intermittent fasting and caloric restriction on
the cardiovascular and cerebrovascular systems.
Intermittent fasting (IF; reduced meal frequency) and caloric
restriction (CR) extend lifespan and increase resistance to
age-related diseases in rodents and monkeys and improve the health
of overweight humans. Both IF and CR enhance cardiovascular and brain
functions and improve several risk factors for coronary artery disease
and stroke including a reduction in blood pressure and increased
insulin sensitivity. Cardiovascular stress adaptation is improved and
heart rate variability is increased in rodents maintained on an IF or
a CR diet. Moreover, rodents maintained on an IF regimen exhibit
increased resistance of heart and brain cells to ischemic injury in
experimental models of myocardial infarction and stroke. The beneficial
effects of IF and CR result from at least two mechanisms--reduced
oxidative damage and increased cellular stress resistance. Recent
findings suggest that some of the beneficial effects of IF on both the
cardiovascular system and the brain are mediated by brain-derived
neurotrophic factor signaling in the brain. Interestingly, cellular
and molecular effects of IF and CR on the cardiovascular system and
the brain are similar to those of regular physical exercise,
suggesting shared mechanisms. A better understanding of the cellular
and molecular mechanisms by which IF and CR affect the blood vessels
and heart and brain cells will likely lead to novel preventative and
therapeutic strategies for extending health span.


Biochim Biophys Acta. 1985 Mar 29;839(1):96-104
Effects of antilipolytic agents on rat liver peroxisomes and peroxisomal
oxidative activities.
The mechanisms involved in the inhibitory effects of antilipolytic
agents on rat liver peroxisomal fatty acid oxidative activity have been
explored. Treatment of fasting rats with antilipolytic drugs (either
3,5-dimethylpyrazole (12 mg/kg body weight) or Acipimox (25 mg/kg body
weight] resulted in a decrease in free fatty acid and glucose plasma
levels within 5-10 and in a significant increase in the plasma glucagon
to insulin ratio within 15. Changes in the fatty acid oxidative activity
appeared with a 2.5-3 h delay and were then very rapid (a 30-40% decrease
in the activity occurred in additional 2 h). Many peroxisomal enzyme
activities (including non-beta-oxidative activities such as uricase and
D-amino acid oxidase) exhibited similar changes with the same delay.
Simultaneously with the enzyme changes, at the electron microscope level
many autophagic vacuoles were detected in the liver cells, often
containing peroxisomal structures. Glutamine, an inhibitor of proteolysis
in vivo, prevented the decrease in enzyme activities. It was concluded
that the decrease in peroxisomal enzyme activities may be the consequence
of enhanced peroxisome degradation due to the stimulation of autophagic
processes in liver cells.

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