Epidemiological studies showed that dietary fat intake is associated with Alzheimer's disease (AD) and dementia risk, however, the association remain inconsistent. This metaanalysis aimed to systematically examine the association of dietary fat intake with AD and dementia risk.We have systematically searched PubMed, Embase and the Cochrane Library up to May 1st 2017. Prospective cohort studies were included if they reported on the association of dietary fat intake with AD and dementia risk. Multivariate-adjusted relative risks (RRs) for the highest versus lowest category were pooled by using a random-effects model.A total of 8630 participants and 633 cases from four independent prospective cohort studies were included in the present meta-analysis. A higher dietary saturated fat intake was significantly associated with an increased risk of 39% and 105% for AD (RR: 1.39; 95% CI: 1.00, 1.94) and dementia (RR: 2.05; 95% CI: 1.06, 3.98), respectively. Dose-response analysis indicated a 4 g/day increment of saturated fat intake was related to 15% higher risk of AD (RR: 1.15; 95% CI: 1.01, 1.31). However, there was no significant association found between dietary intake of total, monounsaturated, polyunsaturated fat and AD or dementia risk.This meta-analysis provides significant evidence of positive association between higher saturated fat intake and AD and dementia risk.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Recent estimates suggesting that over half of Alzheimer's disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors.Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimer's disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimer's disease cases to 2050.Worldwide, the highest estimated PAR was for low educational attainment (19·1%, 95% CI 12·3-25·6). The highest estimated PAR was for physical inactivity in the USA (21·0%, 95% CI 5·8-36·6), Europe (20·3%, 5·6-35·6), and the UK (21·8%, 6·1-37·7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49·4% (95% CI 25·7-68·4), which equates to 16·8 million attributable cases (95% CI 8·7-23·2 million) of 33·9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28·2% (95% CI 14·2-41·5), which equates to 9·6 million attributable cases (95% CI 4·8-14·1 million) of 33·9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimer's disease in 2050 by 8·3% worldwide.After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression.National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough.Copyright © 2014 Elsevier Ltd. All rights reserved.

The concept of brain circuit disorders has been proposed for a variety of neuropsychiatric diseases, characterized by pathological disturbances of neuronal networks including changes in oscillatory signaling of re-entrant cortico-subcortical loops in the basal ganglia system. Parts of this circuitry play a pivotal role in energy homeostasis. We therefore investigated whether high-fat diet (HFD) induced obesity is associated with changes in oscillatory signaling in the limbic cortico-basal ganglia loop. We performed multi-site in-vivo electrophysiological recordings of local field potentials within this network under urethane anesthesia in adult rats after 4 weeks of HFD feeding compared to age-matched controls. Recordings were performed at baseline and during systemic glucose challenge. Our analysis demonstrates increased oscillatory beta power in the nucleus accumbens (NAC) associated with decreased beta coherence between cortex and NAC in animals fed a HFD. Spontaneous beta oscillatory power strongly correlated with endocrine markers of obesity. The glucose challenge increased beta oscillations in control animals but not in animals receiving the HFD. Furthermore direct intracerebroventricular insulin injection increased beta oscillations in the NAC. The present study provides evidence for aberrant oscillatory signaling in the limbic cortico-basal ganglia loop that might contribute to the dysfunctional information processing in obesity.

For decades, dietary advice was based on the premise that high intakes of fat cause obesity, diabetes, heart disease, and possibly cancer. Recently, evidence for the adverse metabolic effects of processed carbohydrate has led to a resurgence in interest in lower-carbohydrate and ketogenic diets with high fat content. However, some argue that the relative quantity of dietary fat and carbohydrate has little relevance to health and that focus should instead be placed on which particular fat or carbohydrate sources are consumed. This review, by nutrition scientists with widely varying perspectives, summarizes existing evidence to identify areas of broad consensus amid ongoing controversy regarding macronutrients and chronic disease.Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Findings from observational studies in China show that increased dietary fat consumption might be a contributor to the developing obesity epidemic. However, some cohort studies suggest that carbohydrate intake, especially from white rice, is a risk factor for obesity, type 2 diabetes and coronary heart disease in China. Our study aims to determine whether the traditional lower-fat, higher-carbohydrate Chinese or the Western higher-fat, lower-carbohydrate dietary pattern is more effective for weight control and the related cardiometabolic profiles increasingly found among contemporary Chinese.The Optimal Dietary Macronutrient Distribution in China (ODMDC) trial is a 6-month, multi-centre, three-arm controlled feeding study. Based on the macronutrient transition in the past 30 years in China, three isoenergetic diets with a spectrum of fat and carbohydrate intake, but same protein contents, have been formulated. Percentages of fat, carbohydrate, and protein energy are one of 20, 66 and 14%; 30, 56 and 14%; 40, 46 and 14%, respectively. Participants will be provided with all their food and most beverages for 6 months.The study population is planned to be 300 healthy non-obese adults aged 18 to 35 years. The primary outcome is body weight and the secondary variables are waist circumference and cardiometabolic risk factors.The ODMDC trial will have implications for nutrition policy in regard to weight control and related cardiometabolic disturbances among otherwise healthy non-obese Chinese.

Globally, 50 million people live with dementia, with Alzheimer disease (AD) being responsible for two-thirds of the total cases. As ageing is the main risk factor for dementia-related neurodegeneration, changes in the timing or nature of the cellular hallmarks of normal ageing might be key to understanding the events that convert normal ageing into neurodegeneration. Cellular senescence is a candidate mechanism that might be important for this conversion. Under persistent stress, as occurs in ageing, both postmitotic cells - including neurons - and proliferative cells - such as astrocytes and microglia, among others - can engender a state of chronic cellular senescence that is characterized by the secretion of pro-inflammatory molecules that promote the functional decline of tissues and organs. Ablation of senescent cells has been postulated as a promising therapeutic venue to target the ageing phenotype and, thus, prevent or mitigate ageing-related diseases. However, owing to a lack of evidence, it is not possible to label cellular senescence as a cause or a consequence of neurodegeneration. This Review examines cellular senescence in the context of ageing and AD, and discusses which of the processes - cellular senescence or AD - might come first.

Aging is a natural process that is associated with cognitive decline as well as functional and social impairments. One structure of particular interest when considering aging and cognitive decline is the hippocampus, a brain region known to play an important role in learning and memory consolidation as well as in affective behaviours and mood regulation, and where both functional and structural plasticity (e.g., neurogenesis) occur well into adulthood. Neurobiological alterations seen in the aging hippocampus including increased oxidative stress and neuroinflammation, altered intracellular signalling and gene expression, as well as reduced neurogenesis and synaptic plasticity, are thought to be associated with age-related cognitive decline. Non-invasive strategies such as caloric restriction, physical exercise, and environmental enrichment have been shown to counteract many of the age-induced alterations in hippocampal signalling, structure, and function. Thus, such approaches may have therapeutic value in counteracting the deleterious effects of aging and protecting the brain against age-associated neurodegenerative processes.Copyright © 2017 Elsevier Ltd. All rights reserved.

Dementia and type 2 diabetes mellitus (T2DM) are two of the epidemics of our time; in which insulin resistance (IR) is playing the central role. Epidemiological studies found that different types of dementia development may be promoted by the presence of T2DM.We aimed in this review to highlight the role of insulin and the IR in the brain as a pathophysiological factor of dementia development and also to expand our understanding of T2DM as a mediator of IR in the brain and to review the possible mechanisms of action that may explain the association.A critical review of the relevant published English articles up to 2018, using PubMed, Google Scholar, Science Direct, ADI, and WHO database was carried out. Keywords were included insulin resistance, T3DM, T2DM, dementia, brain insulin resistance were used.The rapidly increased prevalence of dementia concurrently with T2DM and obesity need urgent action to illustrate guidelines for prevention, modifying, and treatment based on mechanistic studies.Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.

Adequate dietary intake and nutritional status have important effects on brain functions and on brain health. Energy intake and specific nutrients excess or deficiency from diet differently affect cognitive processes, emotions, behaviour, neuroendocrine functions and synaptic plasticity with possible protective or detrimental effects on neuronal physiology. Lipids, in particular, play structural and functional roles in neurons. Here the importance of dietary fats and the need to understand the brain mechanisms activated by peripheral and central metabolic sensors. Thus, the manipulation of lifestyle factors such as dietary interventions may represent a successful therapeutic approach to maintain and preserve brain health along lifespan.This review aims at summarizing the impact of dietary fats on brain functions.Starting from fat consumption, nutrient sensing and food-related reward, the impact of gut-brain communications will be discussed in brain health and disease. A specific focus will be on the impact of fats on the molecular pathways within the hypothalamus involved in the control of reproduction via the expression and the release of Gonadotropin-Releasing Hormone. Lastly, the effects of specific lipid classes such as polyunsaturated fatty acids and of the "fattest" of all diets, commonly known as "ketogenic diets", on brain functions will also be discussed.Despite the knowledge of the molecular mechanisms is still a work in progress, the clinical relevance of the manipulation of dietary fats is well acknowledged and such manipulations are in fact currently in use for the treatment of brain diseases.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species, but the effects in humans and other primates remain controversial. Here we report the most advanced survival data and the associated follow-up to our knowledge of age-related alterations in a cohort of grey mouse lemurs (, lemurid primate) exposed to a chronic moderate (30%) caloric restriction. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases and preserved loss of brain white matter in several brain regions. However, caloric restriction accelerated loss of grey matter throughout much of the cerebrum. Cognitive and behavioural performances were, however, not modulated by caloric restriction. Thus chronic moderate caloric restriction can extend lifespan and enhance health of a primate, but it affects brain grey matter integrity without affecting cognitive performances.

To understand the underlying brain mechanisms involved in the aging process and mental deterioration could be key to the development of behavioral patterns that guarantee reaching advanced ages with the highest possible quality of life and reduce the cognitive loss associated with senescence.To describe and analyze different animal and human studies that demonstrate that a caloric restriction diet may rescue cerebral aging and the cognitive decline associated to aging.For more than 100 years it has been known that caloric restriction extends life span in many laboratory animal. This effect seems to derive from the reduction of age-related symptoms, such as obesity, the onset of cancerous tumors and some metabolic diseases. However, while the consequences of caloric restriction on health are well-established, their ability to reverse age-dependent memory deficits remains a controversial issue. The analyses of the effects of caloric restriction on different animals provides progress for the understanding of its beneficial effects on the neurobiology of cognitive processes during aging.Caloric restriction attenuates the normal or pathological aging of the brain and reduces age-related memory problems. Dietary intervention could become a very effective method to promote a better quality of life and prevent the age-related cognitive deficits.

The high-fat ketogenic diet (KD) has become an increasingly popular diet not only in overweight/obese populations, or those with clinical conditions, but also in healthy non-overweight populations.Because there are concerns about the association between high-fat diets and cognitive decline, this study aimed to determine the effects of a KD compared with an isocaloric high-carbohydrate, low-fat (HCLF) diet on cognitive function, sleep, and mood in healthy, normal-weight individuals.Eleven healthy, normal-weight participants (mean age: 30 ± 9 y) completed this randomized, controlled, crossover study. Participants followed 2 isocaloric diets-an HCLF diet (55% carbohydrate, 20% fat, and 25% protein) and a KD (15% carbohydrate, 60% fat, and 25% protein)-in a randomized order for a minimum of 3 wk, with a 1-wk washout period between diets. Measures of β-hydroxybutyrate confirmed that all participants were in a state of nutritional ketosis during post-KD assessments (baseline: 0.2 ± 0.2 mmol/L; KD: 1.0 ± 0.5 mmol/L; washout: 0.2 ± 0.1 mmol/L; and HCLF: 0.3 ± 0.2 mmol/L). Cognitive function was assessed using a validated, psychological computer-based test battery before and after each diet. Subjective measures of mood and sleep were also monitored throughout the study using validated scales.Three weeks of sustained nutritional ketosis, compared with the HCLF diet, had no effect on speed and accuracy responses in tasks designed to measure vigilance (speed: P = 0.39, Cohen's d = 0.26; accuracy: P = 0.99, Cohen's d = 0.04), visual learning and memory (speed: P = 0.99, Cohen's d = 0.04; accuracy: P = 0.99, Cohen's d = 0.03), working memory (speed: P = 0.62, Cohen's d = 0.26; accuracy: P = 0.98, Cohen's d = 0.07), and executive function (speed: P = 0.60, Cohen's d = 0.31; accuracy: P = 0.90, Cohen's d = 0.19). Likewise, mood, sleep quality, and morning vigilance did not differ (P > 0.05) between the dietary interventions.The results of our randomized, crossover, controlled study suggest that 3 wk of sustained nutritional ketosis had no effect on cognitive performance, mood, or subjective sleep quality in a sample of healthy individuals. This trial was registered in the Pan African Clinical Trial Registry as PACTR201707002406306.Copyright © American Society for Nutrition 2019.

Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.Copyright © 2017 Elsevier Inc. All rights reserved.

Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.Published by Elsevier Inc.

Carbohydrate restriction markedly improves glycemic control in patients with type 2 diabetes (T2D) but necessitates prompt medication changes. Therefore, we assessed the effectiveness and safety of a novel care model providing continuous remote care with medication management based on biometric feedback combined with the metabolic approach of nutritional ketosis for T2D management.We conducted an open-label, non-randomized, controlled, before-and-after 1-year study of this continuous care intervention (CCI) and usual care (UC). Primary outcomes were glycosylated hemoglobin (HbA), weight, and medication use. Secondary outcomes included fasting serum glucose and insulin, HOMA-IR, blood lipids and lipoproteins, liver and kidney function markers, and high-sensitivity C-reactive protein (hsCRP).349 adults with T2D enrolled: CCI: n = 262 [mean (SD); 54 (8) years, 116.5 (25.9) kg, 40.4 (8.8) kg m, 92% obese, 88% prescribed T2D medication]; UC: n = 87 (52 (10) years, 105.6 (22.15) kg, 36.72 (7.26) kg m, 82% obese, 87% prescribed T2D medication]. 218 participants (83%) remained enrolled in the CCI at 1 year. Intention-to-treat analysis of the CCI (mean ± SE) revealed HbA declined from 59.6 ± 1.0 to 45.2 ± 0.8 mmol mol (7.6 ± 0.09% to 6.3 ± 0.07%, P < 1.0 × 10), weight declined 13.8 ± 0.71 kg (P < 1.0 × 10), and T2D medication prescription other than metformin declined from 56.9 ± 3.1% to 29.7 ± 3.0% (P < 1.0 × 10). Insulin therapy was reduced or eliminated in 94% of users; sulfonylureas were entirely eliminated in the CCI. No adverse events were attributed to the CCI. Additional CCI 1-year effects were HOMA-IR - 55% (P = 3.2 × 10), hsCRP - 39% (P < 1.0 × 10), triglycerides - 24% (P < 1.0 × 10), HDL-cholesterol + 18% (P < 1.0 × 10), and LDL-cholesterol + 10% (P = 5.1 × 10); serum creatinine and liver enzymes (ALT, AST, and ALP) declined (P ≤ 0.0001), and apolipoprotein B was unchanged (P = 0.37). UC participants had no significant changes in biomarkers or T2D medication prescription at 1 year.These results demonstrate that a novel metabolic and continuous remote care model can support adults with T2D to safely improve HbA, weight, and other biomarkers while reducing diabetes medication use. CLINICALTRIALS.NCT02519309.Virta Health Corp.