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PERIODICAL
FASTING AND CALORIC RESTRICTION FOR LIFE EXTENSION,
DISEASE TREATMENT AND CREATIVITY.
(clinical and experimental data)
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FASTING AND CALORIC RESTRICTION PRODUCE VARIOUS BIOLOGICAL
EFFECTS |
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2005
Department of Biochemistry, School
of Medicine, Maltepe University, Istanbul, Turkey.
BACKGROUND: During Ramadan,
Muslims fast during the daylight hours for a month.
The duration of restricted food and beverage intake
is approximately 12 h/day which makes Ramadan a unique
model of intermittent fasting. Many physiological
and psychological changes are observed during Ramadan
that are probably due to the changes in eating and
sleeping patterns. METHODS: Serum total cholesterol,
triglycerides, high-density lipoprotein (HDL), low-density
lipoprotein (LDL), prothrombin time, activated partial
thromboplastin time (aPTT), plasma fibrinogen, D-dimer
and homocysteine levels were measured in 24 healthy
fasting volunteers (12 females, 12 males) aged 21-35
years. Venous blood samples were taken 1 week before
Ramadan, on the 21st day of Ramadan and 20 days after
Ramadan. RESULTS: No significant changes were observed
on serum total cholesterol, triglycerides and LDL
levels. HDL levels were significantly elevated during
Ramadan (p < 0.001) and 20 days after Ramadan (p
< 0.05). Prothrombin time, aPTT, fibrinogen and
D-dimer levels were in the physiologic limits in all
samples but D-dimer levels were significantly low
at the end of Ramadan in comparison to pre- and post-fasting
levels (p < 0.001). Homocysteine levels, being
still in reference ranges, were low during Ramadan
(p < 0.05) and reached the pre-fasting levels after
Ramadan. CONCLUSION: Our results demonstrate that
intermittent fasting led to some beneficial changes
in serum HDL and plasma homocysteine levels, and the
coagulation status. These changes may be due to omitting
at least one meal when the body was particularly metabolically
active and possibly had a low blood viscosity level
at the same time. We conclude that intermittent fasting
may have beneficial effects on hemostatic risk markers
for cardiovascular diseases. Copyright (c) 2005 S.
Karger AG, Basel.
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Department of Physiology, University
of Texas Health Science Center at San Antonio, San
Antonio, TX, USA.
As has been experimentally determined,
oxidative modification to biological systems can be
extensive, although the identification and stochiometric
relation of the reactive species that cause these
alterations have not been fully elucidated. In this
review, arguments are presented to support the notion
that the combined effects of membrane lipid peroxidation
and its by-products, reactive aldehydes are likely
responsible for membrane-associated functional declines
during aging. As evidence for a systemic response
to overall oxidative stress, the molecular inflammation
hypothesis of aging is discussed by considering that
the activation of inflammatory genes act as a bridge
linking normal aging to pathological processes.
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Department of Biology, Massachusetts
Institute of Technology, Cambridge, Massachusetts
02139, USA.
Calorie restriction (CR) is
the only experimental manipulation that is known to
extend the lifespan of a number of organisms including
yeast, worms, flies, rodents and perhaps non-human
primates. In addition, CR has been shown to reduce
the incidence of age-related disorders (for example,
diabetes, cancer and cardiovascular disorders) in
mammals. The mechanisms through which this occurs
have been unclear. CR induces metabolic changes, improves
insulin sensitivity and alters neuroendocrine function
in animals. In this review, we summarize recent findings
that are beginning to clarify the mechanisms by which
CR results in longevity and robust health, which might
open new avenues of therapy for diseases of ageing.
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1Natural Products Research Institute,
College of Pharmacy, Seoul National University, Seoul,
Korea.
OBJECTIVE:: To investigate how
and to what extent platycodin saponin (PS) from Platycodi
Radix exerts a favorable influence on obesity and
hyperlipidemia. DESIGN:: Sprague-Dawley rats were
fed with a high fat (HF) diet for 4 weeks and then
the animals were treated with 35 or 70 mg/kg of PS
for another 4 weeks. Changes in body weight and daily
calorie intake were measured regularly during the
experimental period and the degree of linear correlation
for the above two variables was further analyzed.
The in vitro lipase inhibition of each PS compound
and the in vivo fecal lipid excretion were examined
in hope of revealing their relationship. The concentrations
of hepatic triglyceride and cholesterol in serum.
RESULTS:: The body weight reduction (13+/-4% vs HF
control, P<0.05) by PS administration was highly
correlated to the food intake restriction (Pearson's
linear coefficient r=0.752, P<0.005). The in vitro
inhibition of lipase by each isolated compound and
mixture of PS were virtually identical. Consequently,
the fecal TG excretion was increased by 2.1-3.2 folds
depending on the dose of PS. The serum TG and LDL-cholesterol
concentrations were decreased without noticeable changes
in HDL-cholesterol levels. Concomitantly, the contents
of the hepatic TG, cholesterol, and the liver surface
fat pads were decreased in ubiquity, but no noticeable
biochemical abnormalities or histological tissue damages
were observed. CONCLUSIONS:: The administration of
PS produced profound effects on the control of obesity
and lipid metabolism, which resulted in LDL-cholesterol
reduction. PS also caused a remarkable reduction in
calorie intake, which was highly correlated to the
body weight loss. These results suggest that PS has
a greater role in antiobesity, hypolipidemia, and
liver protection than previously thought. Hence, PS
could be a potential therapeutic alternative in the
treatment of obesity and hyperlipidemia.International
Journal of Obesity advance online publication, 19
April 2005; doi:10.1038/sj.ijo.0802948.
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2004
Hman Performance Laboratory,
Department of Kinesiology, University of Connecticut,
Storrs, CT 06269-1110, USA.
In recent years, restriction
of carbohydrate intake for weight loss has become
widespread. Our research group began studying physiological
responses to very-low-carbohydrate ketogenic diets
(VLCKDs) in the late 1990s because we felt there was
a significant void in the literature and limited understanding
of metabolic responses to VLCKDs. This launched us
into a line of research examining the physiological
effects of VLCKDs. In this paper, we briefly overview
nine studies we have published on isoenergetic and
hypoenergetic VLCKDs in men and women. These studies
have focused on blood lipid responses to VLCKDs, but
we have also addressed changes in body weight, body
composition, and hormones. Compared with low-fat diets,
short-term VLCKDs consistently result in improvements
in fat loss, fasting and postprandial triacylglycerols,
high-density lipoprotein-cholesterol, the distribution
of low-density lipoprotein-cholesterol subclasses,
and insulin resistance. These are the key metabolic
abnormalities of metabolic syndrome, a problem of
epidemic proportions in the United States. There is
substantial variability in total cholesterol and low-density
lipoprotein-cholesterol responses to VLCKD. The factors
responsible for this variability are not known, and
studies designed to identify methods to predict blood
lipid responses to VLCKD and other dietary approaches
represent critical areas for nutrition researchers.
Further research is warranted to validate the physiological
effects of VLCKD over longer periods of time, including
studies that modify the quality of macronutrients
(i.e., the type of fat and protein) and the interaction
with other interventions (e.g., exercise, dietary
supplements, drugs).
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2003
Emory University School of Medicine,
Department of Pharmacology, Rollins Research Center,
Atlanta, GA 30322, USA.
PURPOSE: The ketogenic diet
(KD) is an effective treatment for intractable epilepsy.
However, little is known about its underlying mechanisms.
METHODS: In this study, in vivo extracellular field
responses to angular bundle stimulation were recorded
in the dentate gyrus of Sprague-Dawley rats fed one
of three diets: ketogenic calorie-restricted (KCR),
normal calorie-restricted (NCR), or normal ad libitum
(NAL). Input/output curves and paired-pulse relations
were used to assess network excitability. A maximal
dentate activation (MDA) protocol was used to measure
electrographic seizure threshold and duration. RESULTS:
Animals fed calorie-restricted (CR) diets exhibited
greater paired-pulse inhibition, an elevated MDA threshold,
and an absence of spreading depression-like events
compared with ad libitum-fed controls. In the MDA
model of epileptogenesis, the rate of increase in
electrographic seizure duration after repeated stimuli
was markedly reduced in KCR-fed animals compared with
NCR- and NAL-fed controls. CONCLUSIONS: These data
suggest that CR, by itself, can be anticonvulsant,
and treatment with a KCR diet may be both anticonvulsant
and antiepileptogenic.
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Department of Biology, Georgetown
University, Box 571229, Washington, DC 20057-1229,
USA.
The purpose of this study was
to evaluate the contributions of ketonemia, caloric
restriction, and carbohydrates to seizure protection
in rats fed selected diets. Male Sprague-Dawley rats
were fed experimental diets of two basic types, one
high in carbohydrates and restricted to 90, 65, or
50% of the normal daily caloric requirement and the
other a normal rodent chow diet restricted to 90 or
65% of the daily caloric requirement. After consuming
their respective diets for 20 days, animals were subjected
to tail-vein infusion of pentylenetetrazole (PTZ)
to determine seizure threshold, taken as the dose
required to evoke the first clonic reaction. Seizure
thresholds were compared to those of rats fed control
diets of either normal rodent chow fed ad libitum
or a standard high-fat (ketogenic) diet calorie-restricted
to 90% of daily caloric requirement, all animals age-
and weight-matched at the time of diet onset. All
diets were balanced for vitamins and minerals and
contained at least 10% protein (by weight). Seizure
threshold and ketonemia were elevated in both experimental
diets in approximate proportion to the degree of calorie
restriction. Animals fed the most severely restricted
high-carbohydrate diet (50%) had seizure thresholds
equal to those fed the ketogenic diet but had significantly
lower ketonemia.
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2001
Unit on Metabolic Control, LMMB/NIAAA,
Rockville, Maryland, USA.
Ketosis, meaning elevation of
D-beta-hydroxybutyrate (R-3hydroxybutyrate) and acetoacetate,
has been central to starving man's survival by providing
nonglucose substrate to his evolutionarily hypertrophied
brain, sparing muscle from destruction for glucose
synthesis. Surprisingly, D-beta-hydroxybutyrate (abbreviated
"betaOHB") may also provide a more efficient source
of energy for brain per unit oxygen, supported by
the same phenomenon noted in the isolated working
perfused rat heart and in sperm. It has also been
shown to decrease cell death in two human neuronal
cultures, one a model of Alzheimer's and the other
of Parkinson's disease. These observations raise the
possibility that a number of neurologic disorders,
genetic and acquired, might benefit by ketosis. Other
beneficial effects from betaOHB include an increased
energy of ATP hydrolysis (deltaG') and its linked
ionic gradients. This may be significant in drug-resistant
epilepsy and in injury and anoxic states. The ability
of betaOHB to oxidize co-enzyme Q and reduce NADP+
may also be important in decreasing free radical damage.
Clinical maneuvers for increasing blood levels of
betaOHB to 2-5 mmol may require synthetic esters or
polymers of betaOHB taken orally, probably 100 to
150 g or more daily. This necessitates advances in
food-science technology to provide at least enough
orally acceptable synthetic material for animal and
possibly subsequent clinical testing. The other major
need is to bring the technology for the analysis of
multiple metabolic "phenotypes" up to the level of
sophistication of the instrumentation used, for example,
in gene science or in structural biology. This technical
strategy will be critical to the characterization
of polygenic disorders by enhancing the knowledge
gained from gene analysis and from the subsequent
steps and modifications of the protein products themselves.
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1999
Department of Pediatrics, Division
of Endocrinology, The University of North Carolina
at Chapel Hill, Chapel Hill, NC 27599-7220, USA.
Voluntary fasting is practiced
by many humans in an attempt to lose body weight.
Conflicting results have been published on the effects
of food deprivation on serum lipids. To study the
effect of acute starvation on serum lipids, 10 nonobese
(93-124% of ideal body weight), healthy adults (6
men, 4 women, 21-38 y old) fasted (no energy) for
7 d. Fasting increased total serum cholesterol from
4.90 +/- 0.23 to 6.73 +/- 0.41 mmol/L (37.3 +/- 5.0%;
P < 0.0001) and LDL cholesterol from 2.95 +/- 0.21
to 4.90 +/- 0.36 mmol/L (66.1 +/- 6. 6%; P < 0.0001).
Serum apolipoprotein B (apo B) increased from 0.84
+/- 0.06 to 1.37 +/- 0.11 g/L (65.0 +/- 9.2%; P <
0.0001). The increases in serum cholesterol, LDL and
apo B were associated with weight loss. Fasting did
not affect serum concentrations of triacylglycerol
and HDL cholesterol. Serum concentrations of insulin-like
growth factor-I (IGF-I) decreased from 246 +/- 29
(prefast) to 87 +/- 10 microg/L after 1 wk of fasting
(P < 0.0001). We conclude that, in nonobese subjects,
fasting is accompanied by increases in serum cholesterol,
LDL and apo B concentrations, whereas IGF-I levels
are decreased.
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1995
Indiana University School of
Medicine, Department of Biochemistry and Molecular
Biology, Fort Wayne, USA.
Serum cholesterol and triglycerides
were determined in 36 lean, healthy adults (mean body
mass index = 24.3 +/- 0.4 kg m-2) during a period
of fasting of 7-21 days. Fasting for 1 week resulted
in significant elevation of serum cholesterol (mean
increase 25%, range 0-68) and triglycerides (mean
increase 24%). No correlation was observed between
pre-fast cholesterol level and fasting-induced hypercholesterolaemia.
Continued fasting for up to 21 days resulted in lowering
of both cholesterol and triglycerides to pre-fast
levels. One week of hypocaloric re-feeding resulted
in significantly lower than pre-fast cholesterol (mean
decrease 13%) and significantly higher than prefast
triglycerides (mean increase 86%). The net change
in serum cholesterol observed as a result of fasting
and re-feeding correlated with prefast cholesterol
(r = -0.6901, p = 0.0001). No significant change in
the ratio of unesterified cholesterol to total cholesterol
was observed during fasting. Fasting for 3 weeks followed
by 1 week of hypocaloric re-feeding, however, resulted
in a significant (p = 0.05) increase in this ratio
from 0.27 +/- 0.0057 to 0.34 +/- 0.01. Fasting for
1 or 2 weeks followed by re-feeding also resulted
in a similar increase in the ratio of unesterified
cholesterol to total cholesterol. Cholesterol in the
HDL fraction remained within normal range throughout
the fasting and re-feeding period, with no significant
changes between time points.
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1994
Department of Medicine, Stanford
University School of Medicine 94305.
Hormone-sensitive lipase (HSL)
is the rate-limiting enzyme in lipolysis. The activity
of HSL is thought to be primarily regulated by phosphorylation-dephosphorylation
reactions. Although FFA levels are elevated during
fasting, it has been difficult to demonstrate an increase
in HSL activity with fasting. The current studies
were undertaken to explore directly the regulation
of HSL _expression in adipose tissue in the rat during
fasting. Rats were fasted for periods up to 5 days
and HSL activity, HSL immunoreactive protein, and
HSL mRNA levels were measured both in intact epididymal
adipose tissue and in isolated adipose cells. Fasting
caused a progressive decline in total body weight
and the weight of epididymal fat pads, whereas adipose
cell size decreased approximately 50% after 2 days
of fasting. Serum FFA levels approximately doubled
within 1 day of fasting and remained elevated thereafter.
Basal lipolysis, measured as glycerol release, did
not increase until 2 days of fasting. HSL activity
remained relatively unchanged until 3 days of fasting
when it was increased twofold after 3-5 days of fasting.
Likewise, HSL immunoreactive protein and HSL mRNA
levels increased twofold after 3-5 days of fasting.
Thus HSL activity appears to be regulated by pretranslational
mechanisms during prolonged fasting. However, increases
in FFA flux during short-term fasting appear to involve
either post-translational control of HSL or the regulation
of other enzymes.
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Children's Hospital, Helsinki
University Central Hospital, Finland.
Fifty-eight voluntary and healthy
subjects (mean age 42.3 +/- 11.2 years) participated
in 7-day supervised fasting trial during which only
fruit and berry juices, tea and water were consumed.
Venous blood was drawn before and after 1-week fasting
and 3 months after the termination of the trial. The
subjects' body weight and blood pressure values were
also recorded. The results showed a statistically
significant decrease in blood thrombocyte counts after
1-week fasting (p < 0.05), while a significant increase
was observed in serum beta-hydroxybutyrate and alanine
aminotransferase activities (p < 0.001). All other
blood values, including glucose and creatinine, remained
stable throughout the trial.
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1990
Department of Medicine, University of Washington School
of Medicine, Seattle
Calorie restriction is widely
used as a primary therapy for obese pregnant women
with gestational diabetes. To better understand the
metabolic consequences of marked calorie restriction,
we performed a randomized prospective trial under
metabolic ward conditions. Obese gestationally diabetic
women were randomized to control (n = 5) and calorie-restricted
(n = 7) groups. All patients consumed an approximately
2400-kcal/day diet during the 1st wk of the study,
and at the end of the 1st wk, metabolic features of
the two groups were statistically indistinguishable.
During the 2nd wk, the control group continued to
consume approximately 2400 kcal/day, whereas the calorie-restricted
group consumed approximately 1200 kcal/day. Twenty-four-hour
mean glucose levels remained unchanged in the control
group (6.7 +/- 0.8 mM wk 1 vs. 6.8 +/- 0.8 mM wk 2),
although they dropped dramatically in the calorie-restricted
group (6.7 +/- 1.0 mM wk 1 vs. 5.4 +/- 0.5 mM wk 2,
P less than 0.01). Fasting plasma insulin also declined
in the calorie-restricted group (265 +/- 165 pM wk
1 vs. 145 +/- 130 pM wk 2), resulting in a significant
change between groups (P less than 0.02). Surprisingly,
fasting plasma glucose and glucose tolerance measured
by the 3-h oral glucose tolerance test did not change
within or between groups. Fasting levels of beta-hydroxybutyrate
rose in the calorie-restricted group (290 +/- 240
microM wk 1 vs. 780 +/- 30 microM wk 2) but not in
the control group (P less than 0.01). Finally, urine
ketones increased significantly (P less than 0.02)
in the calorie-restricted group, whereas they remained
absent in the control group.(ABSTRACT TRUNCATED AT
250 WORDS).
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University of Pennsylvania
School of Medicine, Philadelphia.
Resting energy expenditure (REE),
weight, and body composition were measured up to seven
times in 13 obese women during a 24-wk study. Patients
were randomly assigned to a very-low-calorie diet
(VLCD, 500 kcal/d) or a balanced-deficit diet (BDD,
1200 kcal/d). After 8 wk of supplemented fasting,
REE of the VLCD patients decreased by 17% whereas
that of the BDD patients was virtually unchanged.
REE of the VLCD patients increased during 12 subsequent
weeks of realimentation such that differences in REE
between the two groups were not statistically significant
at week 24 (VLCD = -11%, BDD = -2%). Reductions in
weight and fat-free mass (FFM) were 12.1% and 3.6%
for the VLCD patients and 10.6% and 4.1% for the BDD
patients, respectively. There were no significant
differences between the groups in pre- to posttreatment
changes in REE normalized to FFM. Results suggest
that REE recovers partially after consumption of a
VLCD. They also provide evidence of a possible metabolic
advantage of weight loss by a more moderate restriction.
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1986
This work was performed to assess
age effects on fasting-induced hyperketonemia and
to determine if measurement of cerebral glucose utilization
by positron emission tomography after 6 to 8 hr of
fasting is associated with hyperketonemia that could
influence cerebral glucose metabolism. Acetoacetate
and 3-hydroxybutyrate were assayed in venous blood
from healthy men of various ages, subjected to an
18-hr fast. At 18 hr of fasting but not at 14 hr or
earlier, 3-hydroxybutyrate concentrations were correlated
significantly with age; concentrations of acetoacetate
and 3-hydroxybutyrate were significantly higher than
at earlier times in the fast, p less than or equal
to .05, with elevations of 82% and 214% over baseline,
respectively. Acetoacetate and 3-hydroxybutyrate concentrations
were higher on the day when cerebral glucose utilization
was determined than after a comparable fast at another
time. The observed level of hyperketonemia, however,
would not substantially influence cerebral glucose
metabolism. The findings indicate that aging is associated
with increased susceptibility to fasting-induced hyperketonemia.
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