neurodegenerative disorders
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.
Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems.
J Nutr Biochem. 2005 Mar;16(3):129-37.
Mattson MP, Wan R.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224.
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.
Redefining neuroprotective gene therapeutic strategies: Lessons learned from caloric restriction and NAD(+) metabolism.
J Alzheimers Dis. 2004 Dec;6(6 Suppl):S43-6.
Henricksen LA, Federoff HJ.
Center for Aging and Developmental Biology, Aab Institute for Biomedical Sciences, Universityof Rochester Schoolof Medicineand Dentistry, Rochester, MN.
Herein a case is made for the development of novel cytoprotective approaches based upon molecular mechanisms thought to underlie the caloric restriction phenomenon. This analysis leads to the prediction that molecular genetic perturbations affecting the metabolism of nuclear NAD(+) and metabolites will be neuroprotective.
An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats.
Life Sci 2003 May 9;72(25):2923-30
Miklya I, Knoll B, Knoll
J. 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.
Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms.
J Neurochem. 2003 Feb;84(3):417-31.
Mattson MP, Duan W, Guo Z.
Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland 21224.
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.
Will caloric restriction and folate protect against AD and PD?
Neurology. 2003 Feb 25;60(4):690-5.
Mattson MP.
Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, MD 21224.
Recent epidemiologic studies of different sample populations have suggested that the risk of AD and PD may be increased in individuals with high-calorie diets and in those with increased homocysteine levels. Dietary restriction and supplementation with folic acid can reduce neuronal damage and improve behavioral outcome in mouse models of AD and PD. Animal studies have shown that the beneficial effects of dietary restriction result, in part, from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and can prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although further studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to neurodegenerative disorders.
Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies.
J Neurochem. 2003 Aug;86(3):529-37
Greene AE, Todorova MT, Seyfried TN.
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.
The short-term effects of fasting on the neuroendocrine system in patients with chronic pain syndromes.
Clinical studies Nutr Neurosci. 2003 Feb;6(1):11-8
Michalsen A, Schneider S, Rodenbeck A, Ludtke R, Huether G, Dobos GJ.
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.
Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms.
J Neurochem. 2003 Feb;84(3):417-31
Mattson MP, Duan W, Guo Z.
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.
Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose.
Epilepsia 2001 Nov;42(11):1371-8
Greene AE, Todorova MT, McGowan R, Seyfried TN.
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.
Aging and caloric restriction in nonhuman primates: behavioral and in vivo brain imaging studies.
Ann N Y Acad Sci 2001 Apr;928:316-26
Ingram DK, Chefer S, Matochik J, Moscrip TD, Weed J, Roth GS, London ED, Lane MA.
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.
Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms.
Mech Ageing Dev. 2001 May 31;122(7):757-78.
Mattson MP, Duan W, Lee J, Guo Z.
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825.
Dietary restriction (reduced calorie intake with nutritional maintenance) can extend lifespan and may increase the resistance of the nervous system to age-related diseases including neurodegenerative disorders. An environment enriched in intellectual and physical activities can also allay many of the adverse effects of aging on the brain. The mechanisms underlying the beneficial effects of dietary restriction and environmental enrichment on the brain involve stimulation of the expression of neurotrophic factors and 'stress proteins'. The neurotrophic factors and stress proteins induced by dietary restriction may protect neurons by suppressing oxyradical production, stabilizing cellular calcium homeostasis and inhibiting a form of programmed cell death called apoptosis. Interestingly, dietary restriction and environmental enrichment also increase numbers of newly-generated neural cells in the adult brain suggesting that these behavioral modifications can increase the brain's capacity for plasticity and self-repair. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is leading to novel therapeutic agents that mimick their beneficial effects.
Existing data suggest that Alzheimer's disease is preventable.
Ann N Y Acad Sci. 2000;924:153-9.
Mattson MP.
Laboratory of Neurosciences, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224.
The ultimate goal of Alzheimer's disease (AD) research is to prevent the onset of the neurodegenerative process and thereby allow successful aging without cognitive decline. Herein I argue that a simple and effective preventative approach for AD may be in hand. AD is a disorder associated with the aging process and is, accordingly, characterized by cellular and molecular changes that occur in age-related diseases in other organ systems. Such changes include increased levels of oxidative stress, perturbed energy metabolism, and accumulation of insoluble (oxidatively modified) proteins (prominent among which are amyloid beta-peptide and tau). The risk of several other prominent age-related disorders, including cardiovascular disease, cancer, and diabetes, is known to be influenced by the level of food intake--high food intake increases risk, and low food intake reduces risk. An overwhelming body of data from studies of rodents and monkeys has documented the profound beneficial effects of dietary restriction (DR) in extending life span and reducing the incidence of age-related diseases. Reduced levels of cellular oxidative stress and enhancement of energy homeostasis contribute to the beneficial effects of DR. Recent findings suggest that DR may enhance resistance of neurons in the brain to metabolic, excitotoxic, and oxidative insults relevant to the pathogenesis of AD and other neurodegenerative disorders. While further studies will be required to establish the extent to which DR will reduce the incidence of AD, it would seem prudent (based on existing data) to recommend DR as widely applicable preventative approach for age-related disorders including neurodegenerative disorders.
Neuroprotective signaling and the aging brain: take away my food and let me run
Brain Res 2000 Dec 15;886(1-2):47-53
Mattson MP.
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".
Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy.
Exp Gerontol. 2000 Jul;35(4):489-502.
Mattson MP.
Laboratory of Neurosciences - 4F01, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 23224.
The molecular, biochemical and cellular events that result in synaptic dysfunction and neuronal degeneration in the brain in Alzheimer's disease (AD) are becoming known. Age-related increases in cellular oxidative stress, and impairment of energy metabolism, result in disruption of neuronal calcium homeostasis and increased vulnerability of neurons to excitotoxicity and apoptosis. Inherited forms of AD that result from mutations in the beta-amyloid precursor protein (APP) and presenilins accelerate the neurodegenerative cascade by increasing production and deposition of neurotoxic forms of amyloid beta-peptide and by perturbing calcium homeostasis. Dietary restriction (DR; reduced calorie intake with maintained nutrition) extends life span of rodents and (probably) humans. DR increases resistance of neurons to dysfunction and degeneration, and improves behavioral outcome, in experimental models of AD and other age-related neurodegenerative disorders by a mechanism involving a mild stress response. Telomerase, a specialized reverse transcriptase, has been proposed to possess anti-aging properties. The catalytic subunit of telomerase (TERT) is expressed in neurons throughout the brain during development, but is absent from neurons in the adult brain. TERT exhibits neuroprotective properties in experimental models of neurodegenerative disorders suggesting that manipulations that induce telomerase in neurons may protect against age-related neurodegeneration. Finally, the exciting and exploding field of stem cell research suggests methods for replacing damaged or lost brain cells in an array of neurological disorders.
Effects of age and dietary restriction on lifespan and oxidative stress of SAMP8 mice with learning and memory impairments.
Nutr Health Aging. 2000;4(3):182-6.
Choi JH, Kim D.
Faculty of Food Science and Biotechnology, Pukyong National University; 599-1 Daeyeon-Dong, -Gu, Pusan 608-737.
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 approximately 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 approximately 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.
Effects of Age and Dietary Restriction on Lifespan and Oxidative Stress of SAMP8 Mice with Learning and Memory impairments.
J Nutr Health Aging 2000;4(3):182-186
Choi J, Kim D. 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.
Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats.
J Mol Neurosci 2000 Oct;15(2):99-108
Lee J, Duan W, Long JM, Ingram DK, Mattson MP.
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.
Effects of dietary restriction on radial-arm maze performance and flavor memory in aged rats.
Neurobiol Aging 1989 Jan-Feb;10(1):27-30
Bond NW, Everitt AV, Walton J. 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.
Dietary restriction benefits learning and motor performance of aged mice.
J Gerontol 1987 Jan;42(1):78-81
Ingram DK, Weindruch R, Spangler EL, Freeman JR, Walford RL.
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. Arch Pediatr Adolesc Med. 1999 Sep;153(9):946-9 Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Freeman JM, Vining EP. 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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