Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM et al.. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol Dis 26: 212-220

Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
Neurobiology of Disease (Impact Factor: 5.08). 05/2007; 26(1):212-20. DOI: 10.1016/j.nbd.2006.12.019
Source: PubMed


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.

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Available from: Roy G Cutler, Jul 07, 2015
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    • "Accordingly, we found that the activation of gene sets related to brain aging and to AD in SAMP8 astrocytes reverted to control values under CR treatment. In the fight against AD, CR may have additional effects by decreasing amyloid and tau pathologies (Halagappa et al., 2007). Some of these beneficial effects of CR are at least partially mediated through activation of the sirtuin family gene SIRT1 in neurons (Qin et al., 2006). "
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    ABSTRACT: Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related pathways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mitochondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 02/2015; 14(3). DOI:10.1111/acel.12259 · 6.34 Impact Factor
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    • "IF decreases levels of circulating leptin and increases levels of adiponectin, changes associated with improved energy metabolism and cardioprotection (Wan et al., 2010; Hui et al., 2012). IF can also increase neurotrophic factor signaling in brain cells, which may contribute to its abilities to enhance hippocampal neurogenesis (Lee et al., 2002) and protect neurons against oxidative and metabolic stress in animal models of Parkinson's disease (Duan and Mattson, 1999), Huntington's disease (Duan et al., 2003), Alzheimer's disease (Halagappa et al., 2007) and stroke (Yu and Mattson, 1999; Arumugam et al., 2010). There is considerable evidence from the historical record, self-reports , interviews and case studies that IF improves health and can counteract disease processes. "
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    ABSTRACT: Humans and their predecessors evolved in environments where they were challenged intermittently with: 1) food scarcity; 2) the need for aerobic fitness to catch/kill prey and avoid or repel attackers; and 3) exposure to biological toxins present in foodstuffs. Accordingly, cells and organ systems acquired and retained molecular signaling and metabolic pathways through which the environmental challenges enhanced the functionality and resilience of the cells and organisms. Within the past 60 years there has been a precipitous diminution of such challenges in modern societies because of the development of technologies that provide a continuous supply of energy-dense processed foods and that largely eliminate the need for physical exertion. As a consequence of the modern 'couch potato' lifestyle, signaling pathways that mediate beneficial effects of environmental challenges on health and disease resistance are disengaged, thereby rendering people vulnerable to obesity, diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Reversal of the epidemic of diseases caused by unchallenging lifestyles will require a society-wide effort to re-introduce intermittent fasting, exercise and consumption of plants containing hormetic phytochemicals into daily and weekly routines.
    Dose-Response 12/2014; 12(4):600-18. DOI:10.2203/dose-response.14-028.Mattson · 1.22 Impact Factor
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    • "The ability of calorie restriction (CR) to increase lifespan and reduce the incidence of age-related diseases has now been demonstrated across numerous species including primates (McCay et al., 1935; Weindruch and Walford, 1988; Colman et al., 2014). In addition, CR has been shown to inhibit immunosenescence (Koubova and Guarente, 2007), delay cell death in animal models of neurodegenerative diseases (Maswood et al., 2004; Halagappa et al., 2007; Piccio et al., 2008), and improve the fidelity of both learning and memory processes (Grayson et al., 2013). With respect to the principal mechanisms altered by CR, modification of peripheral immune function has drawn significant attention. "
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    ABSTRACT: Calorie restriction (CR) increases longevity and elicits many health promoting benefits including delaying immunosenescence and reducing the incidence of age-related diseases. Although the mechanisms underlying the health-enhancing effects of CR are not known, a likely contributing factor is alterations in immune system functioning. CR suppresses lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines, blocks LPS-induced fever, and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Furthermore, we have recently shown that CR attenuates LPS-stimulated microglial activation in the hypothalamic arcuate nucleus (ARC), a brain region containing neurons that synthesize neuropeptide Y (NPY), an orexigenic neuropeptide that is upregulated by a CR diet and has anti-inflammatory properties. To determine if increased NPY expression in the ARC following CR was associated with changes in microglial activation, a set of brain sections from mice that were exposed to 50% CR or ad libitum feeding for 28days before being injected with LPS were immunostained for NPY. The density of NPY-immunolabeling was assessed across the rostrocaudal extent of the ARC and hypothalamic paraventricular nucleus (PVN). An adjacent set of sections were immunostained for ionized calcium-binding adapter molecule-1 (Iba1) and immunostained microglia in the ARC were digitally reconstructed to investigate the effects of CR on microglial morphology. We demonstrated that exposure to CR increased NPY expression in the ARC, but not the PVN. Digital reconstruction of microglia revealed that LPS increased Iba1 intensity in ad libitum fed mice but had no effect on Iba1 intensity in CR mice. CR also decreased the size of ARC microglial cells following LPS. Correlational analyses revealed strong associations between NPY and body temperature, and body temperature and microglia area. Together these results suggest that CR-induced changes in NPY are not directly involved in the suppression of LPS-induced microglial activation, however, NPY may indirectly affect microglial morphology through changes in body temperature. Copyright © 2014. Published by Elsevier Ltd.
    Neuroscience 11/2014; 285. DOI:10.1016/j.neuroscience.2014.11.014 · 3.36 Impact Factor
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