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ABSTRACT: Alzheimer's disease (AD) involves progressive accumulation of amyloid β-peptide (Aβ) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Aβ deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model.
Neurobiology of aging 12/2012; · 5.94 Impact Factor
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ABSTRACT: The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
Nature Communications 12/2012; 3:1250. · 7.40 Impact Factor
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ABSTRACT: Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here, we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2-/- mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at midgestation compared with wild-type littermates. Cultured SOD2-/- NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex. STEM CELLS2012;30:2535-2547.
Stem Cells 09/2012; 30(11):2535-47. · 7.78 Impact Factor
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ABSTRACT: Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of α-synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of α-synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of α-synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of α-synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals.
Neurobiology of aging 08/2012; · 5.94 Impact Factor
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ABSTRACT: Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.
Annals of the New York Academy of Sciences 04/2012; 1264(1):49-63. · 3.15 Impact Factor
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ABSTRACT: Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms.
Neurobiology of aging 01/2012; 33(10):2398-410. · 5.94 Impact Factor
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ABSTRACT: Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD.
Neurobiology of aging 12/2011; 33(7):1481.e1-5. · 5.94 Impact Factor
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Guang Qiu, Ruiqian Wan,
Jingping Hu,
Mark P Mattson,
Edward Spangler,
Shan Liu,
Suk-Yu Yau,
Tatia M C Lee,
Marc Gleichmann,
Donald K Ingram,
Kwok-Fai So,
Sige Zou
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ABSTRACT: Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.
Age 06/2011; 33(2):155-65. · 6.28 Impact Factor
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ABSTRACT: glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. Because of its role as an incretin hormone, GLP-1 receptor analogs are used as a treatment for type 2 diabetes. Central or peripheral administration of GLP-1 increases blood pressure and heart rate, possibly by activating brainstem autonomic nuclei and increasing vagus nerve activity. However, the mechanism(s) by which GLP-1 receptor stimulation affects cardiovascular function are unknown. We used the long-lasting GLP-1 receptor agonist Exendin-4 (Ex-4) to test the hypothesis that GLP-1 signalling modulates central parasympathetic control of heart rate.
using a telemetry system, we assessed heart rate in mice during central Ex-4 administration. Heart rate was increased by both acute and chronic central Ex-4 administration. Spectral analysis indicated that the high frequency and low frequency powers of heart rate variability were diminished by Ex-4 treatment. Finally, Ex-4 decreased both excitatory glutamatergic and inhibitory glycinergic neurotransmission to preganglionic parasympathetic cardiac vagal neurons.
these data suggest that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate.
Cardiovascular research 01/2011; 89(1):72-8. · 5.80 Impact Factor
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ABSTRACT: Based on animal experiments and limited data from the few human trials, alternate-day fasting (ADF) resulted in weight loss, prolonged life, reduced metabolic risk factors for diabetes and cardiovascular diseases, and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats.
Four-month-old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine-volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The 6-month-long ADF diet resulted in a 9% reduction (P < .01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P < .01). Pressure-volume loop analyses revealed a "stiff" heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve.
Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted.
Journal of cardiac failure 10/2010; 16(10):843-53. · 3.25 Impact Factor
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Eitan Okun,
Kathleen Griffioen,
Boaz Barak,
Nicholas J Roberts,
Kamilah Castro,
Mario A Pita,
Aiwu Cheng,
Mohamed R Mughal, Ruiqian Wan,
Uri Ashery,
Mark P Mattson
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ABSTRACT: Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention.
Proceedings of the National Academy of Sciences 08/2010; 107(35):15625-30. · 9.68 Impact Factor
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Ilias Kazanis,
Justin D Lathia,
Tegy J Vadakkan,
Eric Raborn, Ruiqian Wan,
Mohamed R Mughal,
D Mark Eckley,
Takako Sasaki,
Bruce Patton,
Mark P Mattson,
Karen K Hirschi,
Mary E Dickinson,
Charles ffrench-Constant
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ABSTRACT: The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice--albeit with NSCs nearer ependymal cells--and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of alpha6beta1 integrin, syndecan-1, and lutheran, and in vivo blocking of beta1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.
Journal of Neuroscience 07/2010; 30(29):9771-81. · 7.11 Impact Factor
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ABSTRACT: Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms.
We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle-aged, and old mice that had been maintained on control or energy-restricted diets prior to middle cerebral artery occlusion and reperfusion.
Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice.
Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome.
Annals of Neurology 07/2009; 67(1):41-52. · 11.09 Impact Factor
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ABSTRACT: It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats. Echocardiographic analysis of heart structural and functional variables revealed that IF attenuates the growth-related increase in posterior ventricular wall thickness, end systolic and diastolic volumes, and reduces the ejection fraction. The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI. Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.
The Journal of nutritional biochemistry 06/2009; 21(5):413-7. · 4.29 Impact Factor
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ABSTRACT: During development, neurotrophic factors are known to play important roles in regulating the survival of neurons in the autonomic nervous system (ANS) and the formation of their synaptic connectivity with their peripheral targets in the cardiovascular, digestive, and other organ systems. Emerging findings suggest that neurotrophic factors may also affect the functionality of the ANS during adult life and may, in part, mediate the effects of environmental factors such as exercise and dietary energy intake on ANS neurons and target cells. In this article, we describe the evidence that ANS neurons express receptors for multiple neurotrophic factors, and data suggesting that activation of those receptors can modify plasticity in the ANS. Neurotrophic factors that may regulate ANS function include brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factors, and ciliary neurotrophic factor. The possibility that perturbed neurotrophic factor signaling is involved in the pathogenesis of ANS dysfunction in some neurological disorders is considered, together with implications for neurotrophic factor-based therapeutic interventions.
Neuromolecular medicine 02/2008; 10(3):157-68. · 5.00 Impact Factor
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Aiwu Cheng,
Kazuo Shin-ya, Ruiqian Wan,
Sung-chun Tang,
Takumi Miura,
Hongyang Tang,
Rina Khatri,
Marc Gleichman,
Xin Ouyang,
Dong Liu,
Hae-Rong Park,
Jeffrey Y Chiang,
Mark P Mattson
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ABSTRACT: Telomeres are DNA-protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons (NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain development in vivo and in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere- and DNA-damaging agents but did not affect the vulnerability of NGNs. These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2.
Journal of Neuroscience 05/2007; 27(14):3722-33. · 7.11 Impact Factor
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ABSTRACT: Dietary restriction (DR) has been shown to increase life span, delay or prevent age-associated diseases, and improve functional and metabolic cardiovascular risk factors in rodents and other species. To investigate the effects of DR on beat-to-beat heart rate and diastolic blood pressure variability (HRV and DPV) in male Sprague-Dawley rats, we implanted telemetric transmitters and animals were maintained on either intermittent fasting (every other day feeding) or calorie-restricted (40% caloric reduction) diets. Using power spectral analysis, we evaluated the temporal profiles of the low- and high-frequency oscillatory components in heart rate and diastolic blood pressure signals to assess cardiac autonomic activity. Body weight, heart rate, and systolic and diastolic blood pressure were all found to decrease in response to DR. Both methods of DR produced decreases in the low-frequency component of DPV spectra, a marker for sympathetic tone, and the high-frequency component of HRV spectra, a marker for parasympathetic activity, was increased. These parameters required at least 1 month to become maximal, but returned toward baseline values rapidly once rats resumed ad libitum diets. These results suggest an additional cardiovascular benefit of DR that merits further studies of this potential effect in humans.
The FASEB Journal 05/2006; 20(6):631-7. · 5.71 Impact Factor
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ABSTRACT: Intermittent fasting (IF), a dietary regimen in which food is available only every other day, increases the life span and reduces the incidence of age-associated diseases in rodents. We have reported neuroprotective effects of IF against ischemic injury of the brain. In this study, we examined the effects of IF on ischemic injury of the heart in rats.
After 3 months of IF or regular every-day feeding (control) diets started in 2-month-old rats, myocardial infarction (MI) was induced by coronary artery ligation. Twenty-four hours after MI, its size in the IF group was 2-fold smaller, the number of apoptotic myocytes in the area at risk was 4-fold less, and the inflammatory response was significantly reduced compared with the control diet group. Serial echocardiography revealed that during 10 weeks after MI (with continuation of the IF regimen), the left ventricular (LV) remodeling and MI expansion that were observed in the control diet group were absent in the IF group. In a subgroup of animals with similar MI size at 1 week after MI, further observation revealed less remodeling, better LV function, and no MI expansion in the IF group compared with the control group.
IF protects the heart from ischemic injury and attenuates post-MI cardiac remodeling, likely via antiapoptotic and antiinflammatory mechanisms.
Circulation 12/2005; 112(20):3115-21. · 14.74 Impact Factor
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ABSTRACT: 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.
The Journal of Nutritional Biochemistry 04/2005; 16(3):129-37. · 3.89 Impact Factor
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ABSTRACT: Dietary restriction and physical exercise can enhance stress resistance and reduce the risk of cardiovascular disease. We investigated the effects of dietary supplementation with 2-deoxy-d-glucose (2-DG), a glucose analog that limits glucose availability at the cellular level, on cardiovascular and neuroendocrine responses to stress in rats. Young adult male Sprague-Dawley rats were implanted with telemetry probes to monitor blood pressure (BP), heart rate, body temperature, and body movements. These variables were measured at designated times during a 6-mo period in rats fed control and 2-DG-supplemented (0.4% 2-DG, fed ad libitum on a schedule of 2 days on the diet and 1 day off the diet) diets during unperturbed conditions and during and after immobilization stress or cold-water swim stress. Rats fed the 2-DG diet exhibited significant reductions in resting BP, attenuated BP responses during stress, and accelerated recovery to baseline after stress. Plasma concentrations of ACTH and corticosterone were elevated under nonstress conditions in rats fed the 2-DG diet and exhibited differential responses to single (enhanced response) and multiple (reduced response) stress sessions compared with rats fed control rat chow ad libitum. The 2-DG diet improved glucose metabolism, as indicated by decreased concentrations of blood glucose and insulin under nonstress conditions, but glucose and insulin responses to stress were maintained. We conclude that improvements in some cardiovascular risk factors and stress adaptation in rats maintained on a 2-DG-supplemented diet are associated with reduced neuroendocrine responses to the stressors.
AJP Heart and Circulatory Physiology 10/2004; 287(3):H1186-93. · 3.71 Impact Factor
