Alzheimer's disease can be prevented and treated by means of periodic fasting and caloric restriction. Experimental and clinical evidence:
Ketone bodies as a therapeutic for Alzheimer's disease.
Neurotherapeutics. 2008 Jul;5(3):470-80.
Accera, Inc., Broomfield, Colorado 80021, USA.
An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, beta-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.
Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease.
Neurobiol Dis. 2007 Apr;26(1):212-20. Epub 2007 Jan 13.
Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP.
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function associated with the neuropathological hallmarks amyloid beta-peptide (Abeta) plaques and neurofibrillary tangles. Because aging is the major risk factor for AD, and dietary energy restriction can retard aging processes in the brain, we tested the hypothesis that two different energy restriction regimens, 40% calorie restriction (CR) and intermittent fasting (IF) can protect against cognitive decline in the triple-transgenic mouse model of AD (3xTgAD mice). Groups of 3xTgAD mice were maintained on an ad libitum control diet, or CR or IF diets, beginning at 3 months of age. Half of the mice in each diet group were subjected to behavioral testing (Morris swim task and open field apparatus) at 10 months of age and the other half at 17 months of age. At 10 months 3xTgAD mice on the control diet exhibited reduced exploratory activity compared to non-transgenic mice and to 3xTgAD mice on CR and IF diets. Overall, there were no major differences in performance in the water maze among genotypes or diets in 10-month-old mice. In 17-month-old 3xTgAD mice the CR and IF groups exhibited higher levels of exploratory behavior, and performed better in both the goal latency and probe trials of the swim task, compared to 3xTgAD mice on the control diet. 3xTgAD mice in the CR group showed lower levels of Abeta1-40, Abeta1-42 and phospho-tau in the hippocampus compared to the control diet group, whereas Abeta and phospho-tau levels were not decreased in 3xTgAD mice in the IF group. IF may therefore protect neurons against adverse effects of Abeta and tau pathologies on synaptic function. We conclude that CR and IF dietary regimens can ameliorate age-related deficits in cognitive function by mechanisms that may or may not be related to Abeta and tau pathologies.
Caloric restriction and intermittent fasting: two potential diets for successful brain aging.
Ageing Res Rev. 2006 Aug;5(3):332-53. Epub 2006 Aug 8.
Martin B, Mattson MP, Maudsley S.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span. CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease. A better understanding of the impact of CR and IF on the aging nervous system will likely lead to novel approaches for preventing and treating neurodegenerative disorders.
Caloric restriction attenuates amyloid deposition in middle-aged dtg APP/PS1 mice.
Neurosci Lett. 2009 Oct 30;464(3):184-7. Epub 2009 Aug 20.
Mouton PR, Chachich ME, Quigley C, Spangler E, Ingram DK.
Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, United States.
Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13-14-month-old) mice that co-express two mutations related to familial AD, amyloid precursor protein (APP) and presenilin 1 (PS1), were fed balanced diets with 40% fewer calories than ad libitum-fed controls. Following 18 weeks of treatment, mice were killed and brains were processed for quantification of total volume of amyloid-beta (Abeta) in the hippocampal formation and the overlying neocortex. Computerized stereology confirmed that CR reduced the total Abeta volume by about one-third compared to that in age-matched controls. Thus, CR appears to attenuate the accumulation of AD-type neuropathology in two cortical brain regions of middle-aged dtg APP/PS1 mice. These findings support the view that CR could be a potentially effective, non-pharmacology strategy for reducing relatively heavy Abeta deposition in older adult dtg APP/PS1 mice, and possibly afford similar protection against the onset and progression of AD in older adult humans.
Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer's disease-type amyloid neuropathology and spatial memory deterioration.
Ann N Y Acad Sci. 2008 Dec;1147:335-47.
Qin W, Zhao W, Ho L, Wang J, Walsh K, Gandy S, Pasinetti GM.
Department of Psychiatry, Mount Sinnai School of Medicine, New York, NY 10029, USA.
Forkhead transcription factor FoxO3a, also known as DAF-16 in Caenorhabditis elegans, is a key regulator of the insulin receptor (IR)/insulin-like growth factor-I signaling pathway mediated extension of life span in worms and yeast. In this study, we report that calorie restriction (CR)-mediated activation of the IR signaling pathway leads to hyperphosphorylation of FoxO3a transcription factor and, consequently, its exclusion from the nucleus. This inactivation of FoxO3a activity is correlated with attenuation of Alzheimer's disease (AD)-type amyloid neuropathology and with preservation of spatial reference memory in the Tg2576 mouse model of AD. Further, in vitro studies reveal that exogenous expression of viral, triple-mutant, constitutively active FoxO3a resulting in increased nuclear FoxO3a activity in primary neuron cultures derived from Tg2576 mouse embryos, causally promotes AD amyloid-beta peptide (Abeta) levels by inhibiting nonamyloidogenic alpha-secretase activity, indicating the existence of an inverse correlation between FoxO3a activity and cerebral Abeta amyloidosis. Moreover, we report for the first time that the exclusion of the FoxO3a transcription factor from the nucleus in combination with inhibition of nuclear FoxO3a activity by SIRT1-mediated deacetylation in response to CR is a mechanism resulting in the repression of Rho-associated protein kinase-1 gene expression, thereby activating nonamyloidogenic alpha-secretase processing of the amyloid precursor protein and lowering Abeta generation. This study provides a novel metabolic pathway for prevention and/or treatment of AD.
Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus).
J Alzheimers Dis. 2006 Dec;10(4):417-22.
Qin W, Chachich M, Lane M, Roth G, Bryant M, de Cabo R, Ottinger MA, Mattison J, Ingram D, Gandy S, Pasinetti GM.
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) 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). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- 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.
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