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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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