CR May Provide Some Protection Against Alzheimers and Other Neurodegenerative Diseases

Following are excerpts and references from animal studies of the effects of CR on neurodegenerative diseases such as Alzheimers. In all cases the original paper should be read for a full understanding of what was being studied and what could be concluded.

Animal Studies - Primate

1. Title: "Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys"

   Ricki J. Colman, Rozalyn M. Anderson, Sterling C. Johnson, Erik K. Kastman, Kristopher J. Kosmatka, T. Mark Beasley, David B. Allison, Christina Cruzen, Heather A. Simmons, Joseph W. Kemnitz, and Richard Weindruch
   Science 10 July 2009: 201-204

   Excerpt:

   "Brain atrophy is a characteristic of human aging that is not accurately reproduced in smaller mammals (15). We therefore determined the regional effects of age, diet, and age by diet interactions on gray matter (GM) volume (16). There were several cortical regions (the bilateral frontal and temporal cortex) where decreases in volume with age were observed independent of diet (Fig. 4, A to C) (17). However, animals subjected to CR had statistically significant preservation of GM volume in subcortical regions (Fig. 4, D to F), including the caudate and putamen and the left insula. The examination of group differences in the slope of age-related GM atrophy (age by diet group interaction) reveals regions where CR significantly modified the aging effect (Fig. 4, G to I) in the midcingulate cortex, lateral temporal cortex bilaterally, and right dorsolateral frontal lobe, indicating relative preservation of volume with age in the CR group. Thus, CR reduced age-associated brain atrophy in key regions that subserve motor function and aspects of executive function."

2. Title: "Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.[see comment]"

   Proceedings of the National Academy of Sciences of the United States of America. 101(52):18171-6, 2004 Dec 28.; Maswood, Navin. Young, Jennifer. Tilmont, Edward. Zhang, Zhiming. Gash, Don M. Gerhardt, Greg A. Grondin, Richard. Roth, George S. Mattison, Julie. Lane, Mark A. Carson, Richard E. Cohen, Robert M. Mouton, Peter R. Quigley, Christopher. Mattson, Mark P. Ingram, Donald K.

   "We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition.."

   "Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet."

   PMID: 15604149

3. Title: "Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in squirrel monkeys (Saimiri sciureus)."

   J Alzheimers Dis. 2006 Dec;10(4):417-22.; Weiping Qin, Mark Chachich, Mark Lane, George Roth, Mark Bryant, Rafael de Cabo, Mary Ann Ottinger, Julie Mattison, Donald Ingram, Samuel Gandy, Giulio Maria Pasinetti

   PMID: 17183154 [PubMed - indexed for MEDLINE]

   "Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-ß (Aß) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys ( Saimiri sciureus )..."

   "Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not ß- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD."

Animal Studies - Non-Primate

1. Title: "Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise"

   Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14863-8. Epub 2010 Aug 2.
   Valdez G, Tapia JC, Kang H, Clemenson GD Jr, Gage FH, Lichtman JW, Sanes JR.
   Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.

   PMID: 20679195 [PubMed - indexed for MEDLINE]

   "Abstract

   The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes."

2. Title: "Caloric restriction and brain function."

   Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):686-92.; Gillette-Guyonnet S, Vellas B.

   PMID: 18827571 [PubMed - in process]

   "PURPOSE OF REVIEW: In addition to extending lifespan, animal research shows that specific diets benefit brain functioning. Indeed, it has been proven that caloric restriction prevents age-related neuronal damage. What are those mechanisms involved in the effects of caloric restriction on brain functioning? Could caloric restriction be proposed in the future to prevent or treat neurodegenerative disorders such as Alzheimer's disease? Is there a future for caloric restriction interventions in adults?"

   "SUMMARY: It is now well established that caloric restriction could be used to promote successful brain aging. Data from randomized controlled trials in humans are limited. No positive effect on cognitive impairment was found probably due to methodological limitations. The long-term effects of caloric restriction in adults must be clarified before engaging in such preventive strategy."

3. Title: "Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability."

   Exp Neurol. 2008 May;211(1):141-9. Epub 2008 Feb 8.Click here to read; Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK.

   Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. miadams@wfubmc.edu

   PMID: 18342310

   "...CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline. Thus, we determined the effects of age and CR on key synaptic proteins in the CA3 region of the hippocampus and whether these changes were correlated with differences in behavior on a hippocampal-dependent learning and memory task."

   "Thus, the decrease in key synaptic proteins in CA3 and cognitive decline occurring across lifespan are stabilized by CR. This age-related decrease and CR-induced stabilization are likely to affect CA3 synaptic plasticity and, as a result, hippocampal function..."

4. Title: "Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in squirrel monkeys (Saimiri sciureus)."

   J Alzheimers Dis. 2006 Dec;10(4):417-22.; Weiping Qin, Mark Chachich, Mark Lane, George Roth, Mark Bryant, Rafael de Cabo, Mary Ann Ottinger, Julie Mattison, Donald Ingram, Samuel Gandy, Giulio Maria Pasinetti

   PMID: 17183154 [PubMed - indexed for MEDLINE]

   "Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-ß (Aß) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys ( Saimiri sciureus )..."

   "Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not ß- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD."

5. Title: "Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction."

   J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2.; Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM

   PMID: 16751189

   "Nicotinamide adenine dinucleotide (NAD)+-dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD+-dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor protein.."

   "These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment."

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