Eating less to live longer with healthy brains

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Eating less to live longer with healthy brains is discussed in the below review pdf-availed paper.Eat Less, Live Longer? New Insights Into the Role of Caloric Restriction in the Brain.Levenson, W.; Rich, J.Nutrition Reviews, Sep2007, Vol. 65 Issue 9, p412-415, 4pKeywords:neurological diseases, neurotrophins, neurogenesis, dietary restriction, brain-derived neurotrophic factor, stem cells, N-methyl-D-aspartateAbstract:Caloric restriction has wide-ranging health benefits and may offer protection against age-related neuronal loss and neurodegenerative disorders such as Alzheimer's disease, possibly via enhanced adult neurogenesis. While a variety of interventions such as exercise increase neurogenesis, recent work suggests that exercise and caloric restriction may work to enhance neurogenesis by different neurobiological mechanisms, suggesting a role for both diet and exercise in disease

prevention.INTRODUCTIONThe possible chronic health benefits of reduced-caloriediets are receiving a great deal of attention. Notonly does long-term and consistent caloric restrictionresult in less weight gain over time, it has also beenshown to increase life span in every species tested to dateincluding yeast, roundworm, rodents, and monkeys.1 Asbody weight decreases, the risk of developing type IIdiabetes is significantly reduced. In fact, insulin sensitivity,blood glucose levels, and serum lipids have allbeen shown to be improved by caloric restriction.2 Itappears that the risk of hypertension is also reduced bycaloric restriction leading to a decrease in cardiovasculardisease, stroke, and kidney failure.3 In addition to thebenefits of caloric restriction for prevention of thesecommon chronic diseases, recent work has suggestedthat caloric restriction prevents age-related neuronal lossas well

as a variety of age-related neurodegenerativedisorders.CALORIC RESTRICTION PROTECTS THE CENTRAL NERVOUS SYSTEMOver 4 million Americans suffer from Alzheimer'sdisease, while 1.5 million suffer from Parkinson's disease,and at least 30,000 Americans suffer from Huntington'sdisease. Additionally, there is concern that thenumber of people who suffer from these age-relatedneurodegenerative disorders appears to be increasing.4Given the large numbers of people afflicted with thesedisorders and the debilitating nature of these age-relateddiseases of the central nervous system (CNS), the possibilitythat caloric restriction could play a role in preventionis very appealing. In fact, as recently reviewedby Prolla and Mattson5 there have been several promisingreports suggesting caloric restriction could play arole in preventing the symptoms associated with Alzheimer's,Huntington's, and Parkinson's

diseases.Caloric restriction may also have implications forrecovery after stroke. Rats fed every other day for 3months, resulting in an overall caloric reduction of 30-40%, had less brain damage (as measured by infarct size)following middle cerebral artery occlusion and reperfusion.6 This resulted in improved behavioral outcomes inthe rats fed the restricted diets compared to animals fedad lib and suggests that caloric restriction may havebenefits following ischemic attacks.CALORIC RESTRICTION INDUCES ADULT NEUROGENESISWhile the neurobiological mechanisms responsiblefor the role of caloric restriction in protection of the CNSare not fully understood, recent work suggests that caloricrestriction regulates adult neuronal stem cells, increasesadult neurogenesis in young adult rats,7 andreduces age-related declines in neurogenesis in olderanimals.8 While it has been known for many years thatthere

are stem cells in the rodent CNS that are capable ofdividing throughout the life span, it has only been relativelyrecently that this was definitively shown in theadult human brain. In a series of elegant studies performedby sson et al.9 in Fred Gage's lab at the SalkInstitute for Biological Studies, it was shown that notonly are adult stem cells present in the human brain, butin specific regions of the CNS, these cells can differentiateinto functional neurons.Adult stem cells located in the subventricular zone(SVZ) of the lateral ventricles8 proliferate and migratevia the rostral migratory stream (RMS) to the olfactorybulb and the prefrontal cortex10 where they undergodifferentiation. Adult stem cells in the human brain arealso found in the subgranular layer of the dentate gyrus.9These proliferative cells can not only differentiate intoneurons but also migrate into the granular cell layer ofthe dentate

and integrate themselves into the circuitry ofthe hippocampus, a region of the brain involved inlearning and memory. The hippocampus, like the olfactorybulb, is also part of the limbic system responsible forthe regulation of emotion.Caloric restriction is not the only intervention thatinduces neurogenesis (Figure 1). In rodents, both environmentalenrichment (toys, group housing, etc) andexercise enhance neurogenesis.11,12 For example, voluntary,but not forced, running increases neurogenesis inthe adult rat dentate gyrus leading to improved recoveryfrom stroke12 and enhanced learning and memory. It isalso now recognized that chronic administration of antidepressantdrugs, such as the commonly prescribed serotoninre-uptake inhibitors, as well as electroconvulsiveshock, a powerfully effective short-term treatment, increasethe number of stem cells in the subgranular layerand neurogenesis in the denate.13,14 In

fact, it nowappears that the efficacy of antidepressant drugs is dependenton the ability of these pharmacological agents toinduce stem cell proliferation and neurogenesis.15Figure 1. Chronic interventions that increase adult neurogenesis. Voluntary exercise increases stem cell proliferation via NMDA-dependent mechanisms, while caloric restriction acts to increase stem cell survival via NMDA-independent mechanisms that appear to include neurotrophic factors such as BDNF.HOW DOES CALORIC RESTRICTION INCREASE NEUROGENESIS?Before caloric restriction can be recommended forclinical use to induce neurogenesis for the treatment andprevention of neurodegenerative or neuropsychiatric disorders,it will be important to develop a better understandingof the mechanisms responsible for the effects ofcaloric restriction in the CNS. While current evidencesuggests the involvement of a host of mechanisms,

includingchaperone proteins such as Hsp 70, antioxidants,and a variety of postsynaptic receptors, it appears thatcaloric restriction acts primarily to increase the survivalof neuronal stem cells, rather than increasing proliferation.7,8 The mechanisms responsible for this protectiveeffect likely involve, at least in part, the regulation ofneurotrophic factors that promote survival of neuronalprecursor cells and mediate the differentiation of thesecells into neurons.7 Dietary restriction increased thelevels of brain derived neurotrophic factor (BDNF) andneurotrophin-3 (NT-3) in the hippocampus, but did notalter the abundance of the high affinity receptors forthese neurotrophins, trkB and trkC.7,16 However, therewas an increase in the ratio of full-length trkB to truncatedtrkB in mice that were fed the restricted diet for 3months. This would likely result in increased BDNFsignaling, improved stem cell

survival, and enhancedneurogenesis.7N-METHYL-D-ASPARTATE RECEPTORSIn addition to the reports showing a role for BDNF,NT-3, trkB, and other neurotrophins, recent work hasimplicated the N-methyl-D-aspartate (NMDA) family ofpost-synaptic receptors in neurogenesis. These transmembraneglutamate receptors contain four subunitsconsisting of two obligatory NR1 subunits and tworegionally localized NR2 subunits. They function as ionchannels that allow the passage of sodium, calcium, andpotassium ions across cell membranes to regulate excitatorysynaptic transmission17 and play fundamentalroles in the integration of new neurons, synaptic plasticity,and learning and memory.18The importance of NMDA receptors in neurogenesisis illustrated by a report showing that voluntary exercise,which has repeatedly been shown to increase neurogenesis,increases the NMDA receptor NR2B subunit expressionin the dentate

gyrus.19 Furthermore, exerciseinducedneurogenesis is impaired in mice that lack theNMDA receptor epsilon1 subunit (NR1). Interestingly,BDNF levels were increased in the NR1 animals, suggestingthat the ability of BDNF to induce stem cellproliferation is dependent on NMDA receptors.20NMDA RECEPTORS AND CALORIC RESTRICTIONThe finding that exercise-induced neurogenesis isdependent on NMDA receptors, led to a recent follow-upstudy designed to examine the role of NMDA receptorsin neurogenesis induced by caloric restriction. This reportby Kitamura et al.21 showed that alternate-day feedingreduced the body weight of both wild-type and NR1knockout mice.21 After 3 months of either ad libitumaccess to food or dietary restriction, mice were given asingle injection of bromodeoxyuridine (BrdU), a thymidineanalog that is incorporated into newly proliferatingcells. After an additional month of caloric

restriction, themice were killed and BrdU was measured by immunohistochemistryto evaluate the survival of BrdU-labeledcells.While it was expected from previous work thatcaloric restriction would increase the survival of newlyproliferated stem cells in the dentate gyrus of wild-typemice, the investigators showed that the NR1 knockoutanimals also responded to caloric restriction with thesame increase in BrdU labeling density in the dentate aswild-type animals. This suggests that the induction ofneurogenesis by caloric restriction in the adult mouse isnot dependent on NMDA receptors. Furthermore, thiswork shows that the mechanisms responsible for enhancedneurogenesis related to caloric restriction andexercise are different.20,21CONCLUSIONSIt now appears that at least some of the benefitsassociated with caloric restriction, particularly those relatedto the CNS, can be attributed to the ability

ofreduced caloric intake to increase neurogenesis in theadult CNS. Most studies showing significant improvementin neurogenesis in rodents have used an approximately30% reduction in calories over a period of 3months, either from a daily reduction in the number ofcalories consumed or in the form of alternate-day feeding.This may be difficult to apply to humans because itis unlikely that this level of caloric restriction will be metwith any significant compliance in the general population,regardless of the possible benefits. Thus, futureresearch is needed to determine the following: 1) if a lesssevere restriction is still beneficial for inducing neurogenesis,2) how long the restriction must be continued inorder to see benefits in humans, 3) if the effects arelong-lasting or only active during the restriction period,and 4) if a single high-calorie meal or short periods of adlib feeding eliminate the positive

effects of long-termrestriction.While it has been known for some time that caloricrestriction is not the only intervention that can enhanceneurogenesis (Figure 1), the information reviewed heremakes a particular contribution to our understanding ofthe mechanisms responsible for neurogenesis. Specifically,exercise increases neurogenesis via NMDA-dependentmechanisms that increase stem cell proliferation,while caloric restriction increases neurogenesis via non-NMDA-dependent mechanisms, such as the induction ofBDNF, that increase stem cell survival. Thus, while thenet effect of both caloric restriction and exercise is toincrease neurogenesis, the mechanisms are likely to bequite different (Figure 1). The finding that exercise andcaloric restriction act via different mechanisms may havea significant impact on the way we make clinical recommendations.Specifically, these data suggest there may beadvantages

to combining limited caloric restriction witha regular exercise program to increase neurogenesis anddecrease the risk of neurodegenerative disorders. Needlessto say, additional research is needed to determine ifthere are synergistic or additive effects of exercise andcaloric restriction, but the finding of different mecha-nisms suggests that investigation of this approach iswarranted.Despite the gaps in our current knowledge, theinformation we have clearly shows the importance ofcaloric intake on the development and prevention ofneurodegenerative disorders. This emerging literaturedeserves the attention of clinicians and basic researcherswho have an interest in the role of diet and brainfunction.-- Al Pater, alpater@...

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