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PERIODICAL
FASTING AND CALORIC RESTRICTION FOR LIFE EXTENSION,
DISEASE TREATMENT AND CREATIVITY.
(clinical and experimental data)
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| 3.2
FASTING AND CALORIC RESTRICTION PREVENT AND CURE DISEASES
(Evidence) |
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Brain disorders
such as Alzheimer's and Parkinson's diseases could be
prevented by simply eating less, a British neuroscientist
has claimed. Dr Mark Mattson, leading a scientific team
in the US, found that rats fed on a low calorie diet
are less affected by brain-destroying chemicals than
those eating normally. It's well known that high food
intake increases the risk of heart disease, diabetes
and cancer, but Mattson said the findings are "the first
to suggest that reduced calorie intake also may help
shield the brain". In the study, reported in Annals
of Neurology, one group of rats was fed 30% less food
than the control group, and both were then treated with
two different brain toxins. One toxin simulates brain
damage found in people with Alzheimer's disease and
those who've suffered a stroke. The other mimics the
brain damage caused by Huntington's and Parkinson's
diseases. In both cases, the rats on the low-cal diet
suffered much less brain damage, with fewer memory and
motor skill deficits compared with that suffered by
rats on a normal diet. Dr Arthur Everitt, founder of
the Australian Association of Gerentology, said the
findings are consistent with previous studies showing
the health benefits of caloric restriction. "It's crazy
for people to allow themselves to become overweight,"
he said.
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2005
Department of Animal Physiology-II,
Faculty of Biological Sciences, Complutense University,
Madrid, 28040, Spain.
Previous studies in mammalian
models indicate that the rate of mitochondrial reactive
oxygen species ROS production and the ensuing modification
of mitochondrial DNA (mtDNA) link oxidative stress
to aging rate. However, there is scarce information
concerning this in relation to caloric restriction
(CR) in the brain, an organ of maximum relevance for
ageing. Furthermore, it has never been studied if
CR started late in life can improve those oxidative
stress-related parameters. In this investigation,
rats were subjected during 1 year to 40% CR starting
at 24 months of age. This protocol of CR significantly
decreased the rate of mitochondrial H(2)O(2) production
(by 24%) and oxidative damage to mtDNA (by 23%) in
the brain below the level of both old and young ad
libitum-fed animals. In agreement with the progressive
character of aging, the rate of H(2)O(2) production
of brain mitochondria stayed constant with age. Oxidative
damage to nuclear DNA increased with age and this
increase was fully reversed by CR to the level of
the young controls. The decrease in ROS production
induced by CR was localized at Complex I and occurred
without changes in oxygen consumption. Instead, the
efficiency of brain mitochondria to avoid electron
leak to oxygen at Complex I was increased by CR. The
mechanism involved in that increase in efficiency
was related to the degree of electronic reduction
of the Complex I generator. The results agree with
the idea that CR decreases aging rate in part by lowering
the rate of free radical generation of mitochondria
in the brain.
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2003
Neuropsychopharmacological Research
Unit of the Hungarian Academy of Sciences, P.O.B.
370, H-1445, Budapest, Hungary.
The recent discovery of the
enhancer regulation in the mammalian brain brought
a different perspective to the brain-organized realization
of goal-oriented behavior, which is the quintessence
of plastic behavioral descriptions such as drive or
motivation. According to this new approach, 'drive'
means that special endogenous enhancer substances
enhance the impulse-propagation-mediated release of
transmitters in a proper population of enhancer-sensitive
neurons, and keep these neurons in the state of enhanced
excitability until the goal is reached. However, to
reach any goal needs the participation of the catecholaminergic
machinery, the engine of the brain. We developed a
method to detect the specific enhancer effect of synthetic
enhancer substances [(-)-deprenyl, (-)-PPAP, (-)-BPAP]
by measuring the release of transmitters from freshly
isolated selected discrete brain areas (striatum,
substantia nigra, tuberculum olfactorium, locus coeruleus,
raphe) by the aid of HPLC with electrochemical detection.
To test the validity of the working hypothesis that
in any form of goal-seeking behavior the catecholaminergic
and serotonergic neurons work on a higher activity
level, we compared the amount of norepinephrine, dopamine,
and serotonin released from selected discrete brain
areas isolated from the brain of sated and food-deprived
rats. Rats were deprived of food for 48 and 72 hours,
respectively, and the state of excitability of their
catecholaminergic and serotonergic neurons in comparison
to that of sated rats was measured. We tested the
orienting-searching reflex activity of the rats in
a special open field, isolated thereafter selected
discrete brain areas and measured the release of norepinephrine,
dopamine, and serotonin from the proper tissue samples
into the organ bath. The orienting-searching reflex
activity of the rats increased proportionally to the
time elapsed from the last feed and the amount of
dopamine released from the striatum, substantia nigra
and tuberculum olfactorium, that of norepinephrine
released from the locus coeruleus and that of serotonin
released from the raphe increased significantly in
the hungry rats proportionally to the time of fasting.
For example: the amount of dopamine released from
the substantia nigra of sated rats (4.62 +/- 0.20
nmoles/g wet weight) increased to 5.95 +/- 0.37 (P
< 0.05) and 10.67 +/- 0.44 (P < 0.01) in rats deprived
of food for 48 and 72 hours, respectively.
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Laboratory of Neurosciences, National
Institute on Aging, Gerontology Research Center, Baltimore,
Maryland 21224, USA.
Although all cells in the body
require energy to survive and function properly, excessive
calorie intake over long time periods can compromise
cell function and promote disorders such as cardiovascular
disease, type-2 diabetes and cancers. Accordingly, dietary
restriction (DR; either caloric restriction or intermittent
fasting, with maintained vitamin and mineral intake)
can extend lifespan and can increase disease resistance.
Recent studies have shown that DR can have profound
effects on brain function and vulnerability to injury
and disease. DR can protect neurons against degeneration
in animal models of Alzheimer's, Parkinson's and Huntington's
diseases and stroke. Moreover, DR can stimulate the
production of new neurons from stem cells (neurogenesis)
and can enhance synaptic plasticity, which may increase
the ability of the brain to resist aging and restore
function following injury. Interestingly, increasing
the time interval between meals can have beneficial
effects on the brain and overall health of mice that
are independent of cumulative calorie intake. The beneficial
effects of DR, particularly those of intermittent fasting,
appear to be the result of a cellular stress response
that stimulates the production of proteins that enhance
neuronal plasticity and resistance to oxidative and
metabolic insults; they include neurotrophic factors
such as brain-derived neurotrophic factor (BDNF), protein
chaperones such as heat-shock proteins, and mitochondrial
uncoupling proteins. Some beneficial effects of DR can
be achieved by administering hormones that suppress
appetite (leptin and ciliary neurotrophic factor) or
by supplementing the diet with 2-deoxy-d-glucose, which
may act as a calorie restriction mimetic. The profound
influences of the quantity and timing of food intake
on neuronal function and vulnerability to disease have
revealed novel molecular and cellular mechanisms whereby
diet affects the nervous system, and are leading to
novel preventative and therapeutic approaches for neurodegenerative
disorders.
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2001
Laboratory of Neurosciences,
Gerontology Research Center, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland
21224, USA.
In a long-term longitudinal
study of aging in rhesus monkeys, a primary objective
has been to determine the effects of aging and caloric
restriction (CR) on behavioral and neural parameters.
Through the use of automated devices, locomotor activity
can be monitored in the home cages of the monkeys.
Studies completed thus far indicate a clear age-related
decline in activity consistent with such observations
in many other species, including humans. However,
no consistent effects of CR on activity have been
observed. Selected groups of monkeys have also been
involved in brain imaging studies, using magnetic
resonance imaging (MRI) and positron emission tomography
(PET). MRI studies completed thus far reveal a clear
age-related decline in the volumes of the basal ganglia,
the putamen, and the caudate nucleus, with no change
in total brain volume. PET analysis has revealed an
age-related decline in the binding potential of dopamine
D2 receptors in the same brain regions. These results
are consistent with findings in humans. Although additional
longitudinal analysis is needed to confirm the present
results, it would appear that locomotor activity,
volume of the basal ganglia, as well as dopamine D2
receptor binding potential provide reliable, noninvasive
biomarkers of aging in rhesus monkeys.
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Biology Department, Boston College,
Chestnut Hill, Massachusetts 02167, USA.
Caloric restriction (CR) involves
underfeeding and has long been recognized as a dietary
therapy that improves health and increases longevity.
In contrast to severe fasting or starvation, CR reduces
total food intake without causing nutritional deficiencies.
Although fasting has been recognized as an effective
antiseizure therapy since the time of the ancient
Greeks, the mechanism by which fasting inhibits seizures
remains obscure. The influence of CR on seizure susceptibility
was investigated at both juvenile (30 days) and adult
(70 days) ages in the EL mouse, a genetic model of
multifactorial idiopathic epilepsy. METHODS: The juvenile
EL mice were separated into two groups and fed standard
lab chow either ad libitum (control, n=18) or with
a 15% CR diet (treated, n=17). The adult EL mice were
separated into three groups; control (n=15), 15% CR
(n=6), and 30% CR (n=3). Body weights, seizure susceptibility,
and the levels of blood glucose and ketones (beta-hydroxybutyrate)
were measured over a 10-week treatment period. Simple
linear regression and multiple logistic regression
were used to analyze the relations among seizures,
glucose, and ketones. RESULTS: CR delayed the onset
and reduced the incidence of seizures at both juvenile
and adult ages and was devoid of adverse side effects.
Furthermore, mild CR (15%) had a greater antiepileptogenic
effect than the well-established high-fat ketogenic
diet in the juvenile mice. The CR-induced changes
in blood glucose levels were predictive of both blood
ketone levels and seizure susceptibility. CONCLUSIONS:
We propose that CR may reduce seizure susceptibility
in EL mice by reducing brain glycolytic energy. Our
preclinical findings suggest that CR may be an effective
antiseizure dietary therapy for human seizure disorders.
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2000
Laboratory of Neurosciences,
National Institute on Aging Gerontology Research Center,
5600 Nathan Shock Drive, 21224-6825, Baltimore, MD,
USA.
Mattson MP (2000) indicate that
Calorie restriction enhance anti-aging processes in
brain. In particular he is writing: "Our recent studies
have shown that dietary restriction (reduced calorie
intake) can increase the resistance of neurons in
the brain to dysfunction and death in experimental
models of Alzheimer's disease, Parkinson's disease,
Huntington's disease and stroke. The mechanism underlying
the beneficial effects of dietary restriction involves
stimulation of the _expression of 'stress proteins'
and neurotrophic factors. Interestingly, dietary restriction
also increases numbers of newly-generated neural cells
in the adult brain suggesting that this dietary manipulation
can increase the brain's capacity for plasticity and
self-repair. Work in other laboratories suggests that
physical and intellectual activity can similarly increase
neurotrophic factor production and neurogenesis. Collectively,
the available data suggest the that dietary restriction,
and physical and mental activity, may reduce both
the incidence and severity of neurodegenerative disorders
in humans".
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Faculty of Food Science and Biotechnology,
Pukyong National University; 599-1 Daeyeon-Dong, Nam-Gu,
Pusan 608-737, Korea.
This study was to evaluate the
effect of dietary restriction (DR) on lifespan and oxidative
stress of dementia mouse model SAMP8 with impaired learning
and memory. SAMP8 female mice were fed either ad libitum
(AL) or fed 60% of food intake of AL. Results showed
that basal metabolic rates (BMR) were significantly
lower (15 to 22%) in DR with increased median and maximum
lifespans, suggesting feed and gross efficiencies were
significantly lower in DR than in AL. Grading score
of senescence resulted in a marked improvement about
2-fold by DR compared with AL. The amounts of lipofuscin
at 12 months were significantly lowered 16% in DR than
that of AL. Median and maximal lifespans significantly
increased (28.5% and 16.4%, respectively) by DR, and
also lowered superoxide radical about 15~45% in DR compared
with AL at 4, 8 and 12 months of age. On the other hand,
superoxide dismutase (SOD) activities were higher (about
15~30%) in DR than those in AL group of SAMP8 except
for 4 months of age. Our results suggest that 40% calorie
restricted SAMP8 can effectively suppress dementia-related
abnormalities during aging.
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Laboratory of Neurosciences,
Gerontology Research Center, National Institute on
Aging, Baltimore, MD 21224, USA.
The adult brain contains neural
stem cells that are capable of proliferating, differentiating
into neurons or glia, and then either surviving or
dying. This process of neural-cell production (neurogenesis)
in the dentate gyrus of the hippocampus is responsive
to brain injury, and both mental and physical activity.
We now report that neurogenesis in the dentate gyrus
can also be modified by diet. Previous studies have
shown that dietary restriction (DR) can suppress age-related
deficits in learning and memory, and can increase
resistance of neurons to degeneration in experimental
models of neurodegenerative disorders. We found that
maintenance of adult rats on a DR regimen results
in a significant increase in the numbers of newly
produced neural cells in the dentate gyrus of the
hippocampus, as determined by stereologic analysis
of cells labeled with the DNA precursor analog bromodeoxyuridine.
The increase in neurogenesis in rats maintained on
DR appears to result from decreased death of newly
produced cells, rather than from increased cell proliferation.
We further show that the __expression of brain-derived
neurotrophic factor, a trophic factor recently associated
with neurogenesis, is increased in hippocampal cells
of rats maintained on DR. Our data are the first evidence
that diet can affect the process of neurogenesis,
as well as the first evidence that diet can affect
neurotrophic factor production. These findings provide
insight into the mechanisms whereby diet impacts on
brain plasticity, aging and neurodegenerative disorders.
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1999
Pediatric Epilepsy Center, The
Johns Hopkins Medical Institutions, Baltimore, MD,
USA.
OBJECTIVES: To evaluate the
change in atonic or myoclonic seizures associated
with the Lennox-Gastaut syndrome during the initiation
of the ketogenic diet, and to describe the development
of a blinded crossover study of the efficacy of the
ketogenic diet. DESIGN: A before-after trial. SETTING:
The Johns Hopkins Hospital, Baltimore, Md. PATIENTS:
Change in clinical seizure frequency was examined
in 17 consecutively treated patients with atonic or
myoclonic seizures. In a few patients, a 24-hour ambulatory
electroencephalogram was obtained before and after
diet initiation. We demonstrated the ability to manipulate
the ketosis induced by fasting with the addition of
glucose (dextrose) in 1 patient. INTERVENTIONS: Children
fasted for 36 hours, and the diet was gradually introduced
over 3 days. Parents were instructed to keep a baseline
seizure frequency calendar for the month before the
initiation of the diet. These calendars continued
to be maintained as the diet was initiated. MAIN OUTCOME
MEASURE: Seizure decrease from baseline. RESULTS:
The atonic or myoclonic seizures decreased in these
children by more than 50% immediately. Using a 24-hour
ambulatory electroencephalogram, we documented that
the seizures reported by a parent represent only a
fraction of the electroclinical events; the technique
could be used to measure the profound decrease in
electrically documented seizures. Ketosis was eliminated
with glucose, 60 g/d. CONCLUSIONS: It is feasible
to evaluate the ketogenic diet's efficacy in atonic
or myoclonic seizures in a blinded, crossover study.
The diet can be manipulated on a short-term basis
in a blinded manner, and ketosis can be achieved or
eliminated.
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1989
School of Behavioural Sciences,
Macquarie University, Sydney, NSW, Australia.
Two groups of aged rats, a dietary
restricted group fed approximately 10 g per day from
6 weeks of age and a group fed ad lib throughout their
life span, were compared with a young adult group
on an 8-arm radial maze and a flavor memory task.
The young adult displayed efficient performance on
the radial-arm maze within the 15 day test period.
In contrast, both aged groups exhibited significantly
poorer performance in the maze in comparison with
the young adult group neither aged group differed
from chance at the end of the 15 days. The flavor
memory task required the animals to consume a novel
flavor. Their loss of neophobia, as indexed by their
subsequent consumption, was then taken as an indication
of the extent to which they remembered the novel flavor
and its effects. The young adult group lost their
neophobia more rapidly than either of the aged groups,
which did not appear to differ from each other. Taken
together, this pattern of results indicates that dietary
restriction does not protect animals from the memory
loss observed in aged animals.
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1987
Female C3B10RF1 mice maintained
on either a control (approximately 95 kcal/week) or
restricted (approximately 55 kcal/week) diet since
weaning were tested in a behavioral battery at 11
to 15 or 31 to 35 months of age (middle-aged vs. aged).
Age-related declines observed among control groups
in tests of motor coordination (rotorod) and learning
(complex maze) were prevented by the restriction regime.
In addition, diet restriction increased locomotor
activity in a runwheel cage among mice of both ages
but did not affect exploratory activity in a novel
arena.
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2004
Program in Nutritional Metabolism,
Massachusetts General Hospital, Harvard Medical School,
55 Fruit Street, LON 207, Boston, Massachusetts 02114,
USA.
Leptin is a nutritionally regulated
hormone that may modulate neuroendocrine function
during caloric deficit. We hypothesized that administration
of low-dose leptin would prevent changes in neuroendocrine
function resulting from short-term caloric restriction.
We administered physiologic doses of r-metHuLeptin
[(0.05 mg/kg sc daily or identical placebo in divided
doses (0800, 1400, 2000, and 0200 h)] to 17 healthy,
normal-weight, reproductive-aged women during a 4-d
fast. Leptin levels were lower in the placebo-treated
group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0
ng/ml, P < 0.001, placebo vs. leptin-treated at
end of study). Fat mass decreased more in the leptin
than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2
+/- 0.1 kg, P = 0.03). Both overnight LH area (38.9
+/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05)
and LH peak width increased (15.8 +/- 7.1 vs. -2.3
+/- 6.7 min, P = 0.06) and LH pulsatility decreased
(-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03)
more in the leptin vs. placebo group. LH pulse regularity
was higher in the leptin-treated group (P = 0.02).
Twenty-four-hour mean TSH decreased more in the placebo
than the leptin-treated group, respectively (-1.06
+/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03).
No differences in 24-h mean GH, cortisol, IGF binding
protein-1, and IGF-I were observed between the groups.
Hunger was inversely related to leptin levels in the
subjects randomized to leptin (r = -0.76, P = 0.03)
but not placebo (r = -0.18, P = 0.70) at the end of
the study. Diminished hunger was seen among subjects
achieving the highest leptin levels. Our data provide
new evidence of the important role of physiologic
leptin regulation in the neuroendocrine response to
acute caloric deprivation.
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2003
Department of Internal Medicine
V and Integrative Medicine, Kliniken Essen Mitte,
Am Deimelsberg 34 a, 45276 Essen, Germany.
It is commonly reported that
short term fasting leads to mood enhancement and emotional
harmonisation. We investigated psychosocial well-being
and the neuroendocrine response, assessed by nightly
urinary excretion of cortisol and catecholamines,
in 28 inpatients with chronic pain syndromes during
and after a one-week modified fast. Twenty-two of
the patients (51.4 +/- 2.7 years, BMI 26.8 +/- 1.0
kg/m2) participated in a 7-day fast with daily intake
of 300 kcal/day, six control patients (47.5 +/- 4.0
years; BMI 22.9 +/- 1.1 kg/m2) received a vegetarian-based
diet. With fasting significant increases of the urinary
concentration of noradrenaline (17.8 +/- 3.0-27.8
+/- 3.8 microg/ml), adrenaline (1.5 +/- 0.2-3.4 +/-
0.7 microg/ml) and cortisol (26.1 +/- 3.7-40.7 +/-
6.1 microg/ml) were observed, whereas controls showed
no significant endocrine changes. The neuroendocrine
response to fasting was pronounced in younger subjects
(age <50 years) and in the presence of a BMI >25 kg/m2,
moreover the increase in cortisol excretion was significantly
higher in subjects with lower baseline cortisol levels.
Mood and well-being increased non-significantly in
both groups. Fasting was well tolerated, and regarded
as beneficial by most fasting patients. Our results
show that short-term fasting leads to neuroendocrine
activation and may suggest that the extent of this
response is dependent on the individual metabolic
and endocrine state at baseline.
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Boston College Biology Department,
Chestnut Hill, Massachusetts, USA.
Brain cells are metabolically
flexible because they can derive energy from both glucose
and ketone bodies (acetoacetate and beta-hydroxybutyrate).
Metabolic control theory applies principles of bioenergetics
and genome flexibility to the management of complex
phenotypic traits. Epilepsy is a complex brain disorder
involving excessive, synchronous, abnormal electrical
firing patterns of neurons. We propose that many epilepsies
with varied etiologies may ultimately involve disruptions
of brain energy homeostasis and are potentially manageable
through principles of metabolic control theory. This
control involves moderate shifts in the availability
of brain energy metabolites (glucose and ketone bodies)
that alter energy metabolism through glycolysis and
the tricarboxylic acid cycle, respectively. These shifts
produce adjustments in gene-linked metabolic networks
that manage or control the seizure disorder despite
the continued presence of the inherited or acquired
factors responsible for the epilepsy. This hypothesis
is supported by information on the management of seizures
with diets including fasting, the ketogenic diet and
caloric restriction. A better understanding of the compensatory
genetic and neurochemical networks of brain energy metabolism
may produce novel antiepileptic therapies that are more
effective and biologically friendly than those currently
available.
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